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Li L, Chen M, Reis RL, Kundu SC, Xiao B, Shi X. Advancements of nanoscale drug formulations for combination treatment of colorectal cancer. Int J Pharm 2025; 674:125508. [PMID: 40132771 DOI: 10.1016/j.ijpharm.2025.125508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/10/2025] [Accepted: 03/21/2025] [Indexed: 03/27/2025]
Abstract
Combination chemotherapy is widely utilized in treating colorectal cancer (CRC), particularly for patients who are ineligible for surgery or those with metastatic CRC (mCRC). While this therapeutic method has demonstrated efficacy in managing CRC and mCRC, its broader clinical application is limited due to the unique physical properties, mechanisms of action, and pharmacokinetics of different chemotherapeutic drugs. Consequently, achieving satisfactory treatment outcomes proves to be challenging. Nanotechnology has given rise to innovative drug systems that are precise, controllable, and highly efficient in drug delivery. These nanoscale drug delivery systems can integrate the advantageous aspects of various therapeutic modalities, including chemotherapy, gene therapy, and immunotherapy. This review aims to explain the application of nano-drug delivery system in the treatment of colorectal cancer. Through its unique physical/chemical properties and biological functions, it can solve the limitations of traditional therapy and achieve more accurate, efficient and safe treatment. The advantages/disadvantages, physical and chemical characteristics of various drug delivery systems are described in detail, and suggestions on selecting reasonable NDDSs according to different drug combination methods are given to achieve the best therapeutic effect. This review paper presents an exhaustive summary of the diverse range of drugs utilized in chemotherapy, in addition to outlining strategies for effectively integrating chemotherapy with other treatment modalities. Furthermore, it delves into the principle of selecting carriers for various drug combinations.
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Affiliation(s)
- Liqi Li
- Department of General Surgery, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Maohua Chen
- Department of Pharmacy, Xinqiao Hospital, Army Medical University, Chongqing 400037, China
| | - Rui L Reis
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs - Research Institute on Biomaterials, Biodegradables and Biomimetic, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Barco, Guimarães 4805-017, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga, Guimarães 4800-058, Portugal
| | - Bo Xiao
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610054, China.
| | - Xiaoxiao Shi
- State Key Laboratory of Resource Insects, College of Sericulture, Textile, and Biomass Sciences, Southwest University, Beibei, Chongqing 400715, China.
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Alhalmi A, Amin S, Ralli T, Ali KS, Kohli K. Therapeutic role of naringin in cancer: molecular pathways, synergy with other agents, and nanocarrier innovations. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3595-3615. [PMID: 39614898 DOI: 10.1007/s00210-024-03672-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 11/24/2024] [Indexed: 04/10/2025]
Abstract
Naringin, a flavanone glycoside found abundantly in citrus fruits, is well-known for its various pharmacological properties, particularly its significant anticancer effects. Research, both in vitro and in vivo, has shown that naringin is effective against several types of cancer, including liver, breast, thyroid, prostate, colon, bladder, cervical, lung, ovarian, brain, melanoma, and leukemia. Its anticancer properties are mediated through multiple mechanisms, such as apoptosis induction, inhibition of cell proliferation, cell cycle arrest, and suppression of angiogenesis, metastasis, and invasion, all while exhibiting minimal toxicity and adverse effects. Naringin's molecular mechanisms involve the modulation of essential signaling pathways, including PI3K/Akt/mTOR, FAK/MMPs, FAK/bads, FAKp-Try397, IKKs/IB/NF-κB, JNK, ERK, β-catenin, p21CIPI/WAFI, and p38-MAPK. Additionally, it targets several signaling proteins, such as Bax, TNF-α, Zeb1, Bcl-2, caspases, VEGF, COX-2, VCAM-1, and interleukins, contributing to its wide-ranging antitumor effects. The remarkable therapeutic potential of naringin, along with its favorable safety profile, highlights its promise as a candidate for cancer treatment. This comprehensive review examines the molecular mechanisms behind naringin's chemopreventive and anticancer effects, including its pharmacokinetics and bioavailability. Furthermore, it discusses advancements in nanocarrier technologies designed to enhance these characteristics and explores the synergistic benefits of combining naringin with other anticancer agents, focusing on improved therapeutic efficacy and drug bioavailability.
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Affiliation(s)
- Abdulsalam Alhalmi
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- Department of Pharmaceutics, Faculty of Pharmacy, University of Aden, Aden, Yemen
| | - Saima Amin
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Tanya Ralli
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
- School of Pharmacy, COER University, Roorkee, 247667, India
| | - Khaled Saeed Ali
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Aden, Aden, Yemen
| | - Kanchan Kohli
- Faculty of Pharmacy, Lloyd Institute of Management and Technology, Greater Noida, 201308, India.
- Department of Pharmaceutical Sciences, Gurugram University, Haryana, 122003, India.
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Niu YR, Xiang MD, Yang WW, Fang YT, Qian HL, Sun YK. NAD+/SIRT1 pathway regulates glycolysis to promote oxaliplatin resistance in colorectal cancer. World J Gastroenterol 2025; 31:100785. [PMID: 40124268 PMCID: PMC11924001 DOI: 10.3748/wjg.v31.i11.100785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 12/13/2024] [Accepted: 02/13/2025] [Indexed: 03/13/2025] Open
Abstract
BACKGROUND Glycolysis provides growth advantages and leads to drug resistance in colorectal cancer (CRC) cells. SIRT1, an NAD+-dependent deacetylase, regulates various cellular processes, and its upregulation results in antitumor effects. This study investigated the role of SIRT1 in metabolic reprogramming and oxaliplatin resistance in CRC cells. AIM To investigate the role of SIRT1 in metabolic reprogramming and overcoming oxaliplatin resistance in CRC cells. METHODS We performed transcriptome sequencing of human CRC parental cells and oxaliplatin-resistant cells to identify differentially expressed genes. Key regulators were identified via the LINCS database. NAD+ levels were measured by flow cytometry, and the effects of SIRT1 on oxaliplatin sensitivity were assessed by MTS assays, colony formation assays, and xenograft models. Glycolytic function was measured using Western blot and Seahorse assays. RESULTS Salermide, a SIRT1 inhibitor, was identified as a candidate compound that enhances oxaliplatin resistance. In oxaliplatin-resistant cells, SIRT1 was downregulated, whereas γH2AX and PARP were upregulated. PARP activation led to NAD+ depletion and SIRT1 inhibition, which were reversed by PARP inhibitor treatment. The increase in SIRT1 expression overcame oxaliplatin resistance, and while SIRT1 inhibition increased glycolysis, the increase in SIRT1 inhibited glycolysis in resistant CRC cells, which was characterized by reduced expression of the glycolytic enzymes PKM2 and LDHA, as well as a decreased extracellular acidification rate. The PKM2 inhibitor shikonin inhibited glycolysis and reversed oxaliplatin resistance induced by SIRT1 inhibition. CONCLUSION SIRT1 expression is reduced in oxaliplatin-resistant CRC cells due to PARP activation, which in turn increases glycolysis. Restoring SIRT1 expression reverses oxaliplatin resistance in CRC cells, offering a promising therapeutic strategy to overcome drug resistance.
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Affiliation(s)
- Ya-Ru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mi-Dan Xiang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Wen-Wei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yu-Ting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hai-Li Qian
- National Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yong-Kun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Usman H, Witonsky D, Bielski MC, Lawrence KM, Laxman B, Kupfer SS. Genomic and cellular responses to aspirin in colonic organoids from African- and European-Americans. Physiol Genomics 2025; 57:103-114. [PMID: 39812338 DOI: 10.1152/physiolgenomics.00015.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 03/20/2024] [Accepted: 11/27/2024] [Indexed: 01/16/2025] Open
Abstract
Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer (CRC), though interindividual responses and cellular mechanisms are not well characterized. Human organoids are ideal to study treatment responses across individuals. Here, colonic organoids from African-Americans (AA) and European-Americans (EA) were used to profile genomic and cellular ASA responses. Colonic organoids from 67 participants, 33 AA and 34 EA, were treated with 3 mM ASA or vehicle control for 24 h. Gene expression was assessed by RNA-seq, and differentially responsive genes were analyzed by condition, population, and for gene set enrichment. Top differentially responsive genes were assessed by time and ASA doses in independent organoids. Expression quantitative trait loci (eQTL) mapping was performed to identify variants associated with condition-specific responses. Apoptosis and necrosis assays were performed, and apoptosis gene expression was measured in organoids. Overall, 8,343 genes were differentially responsive to ASA with differences between AA and EA. Significant enrichment for fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signaling was found. Significant treatment eQTLs were identified for relevant genes involved in FAO, apoptosis, and prostaglandin metabolism. ASA-induced apoptosis and secondary necrosis were confirmed with the identification of significant differential responses of apoptotic genes to ASA. Results demonstrate large transcriptional responses to ASA treatment with differences in responses between individuals. Genomic and cellular results suggest that ASA effects on the mitochondria are key mechanisms of action that could underlie clinical effects. These results could be used to assess clinical treatment responses for chemoprevention in the future.NEW & NOTEWORTHY Aspirin treatment in colonic organoids from diverse individuals revealed significant transcriptome-wide responses, especially for genes in lipid and apoptosis signaling pathways. In normal organoids, apoptosis was induced by aspirin, providing one possible mechanism of colorectal cancer chemoprevention. Our results are a first step toward implementation of personalized medicine for aspirin in colorectal cancer prevention.
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Affiliation(s)
- Hina Usman
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - David Witonsky
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Margaret C Bielski
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Kristi M Lawrence
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Bharathi Laxman
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
| | - Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois, United States
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5
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Lai C, Liu J, Zhou J, Zhou H. The first-line antihypertensive nitrendipine potentiated the therapeutic effect of oxaliplatin by downregulating CACNA1D in colorectal cancer. Open Med (Wars) 2025; 20:20241138. [PMID: 39958978 PMCID: PMC11826243 DOI: 10.1515/med-2024-1138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/10/2024] [Accepted: 12/24/2024] [Indexed: 02/18/2025] Open
Abstract
Background Oxaliplatin (OXA) is among the most common chemotherapy drugs and is the base component of the FOLFOX regimen (OXA + leucovorin + 5-fluorouracil) and CapeOX regimen (OXA + capecitabine). Resistance to and failure of these two OXA-based regimens often results in poor outcomes in patients with colorectal cancer (CRC). Nitrendipine (NTD) is a first-line antihypertensive drug commonly used in hypertension and coronary heart disease with confirmed low toxicity and side effects. However, the potential benefits of NTD for CRC progression and therapy remain unclear. Methods Cell counting kit-8 (CCK-8) detection, colony formation assay, wound-healing assay, Transwell assay, SynergyFinder webtool, and subcutaneous tumor models were used to assess the effect of NTD with OXA on CRC inhibition in vitro and in vivo. Bioinformatics tools including Human Protein Atlas (HPA), quantitative real-time polymerase chain reaction, western blotting analyses, lentivirus transfection, and rescue experiment were used to investigate the mechanism(s) of the related action. Results Utilizing murine and human CRC cell lines, the in vitro and in vivo experiment demonstrated that NTD inhibited cell proliferation, migration, and invasion, and the synergy scores calculated by SynergyFinder indicated that NTD exhibited synergistic activity with the chemotherapeutic drug OXA. The CCK-8 detection, animal model, and rescue experiment results demonstrated that NTD suppressed CRC progression and potentiated OXA therapeutic effect by downregulating calcium voltage-gated channel subunit alpha1 D (CACNA1D). Conclusions This study presents novel data on first-line antihypertensive NTD, exerting inhibitory effects on cell proliferation and migration in CRC and revealing synergistic activity with OXA by downregulating CACNA1D. NTD may be a candidate as a promising chemosensitizer as an OXA new combination to improve the efficacy and safety of CRC therapy.
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Affiliation(s)
- Chengzhe Lai
- Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University, Zengcheng, Guangzhou, China
| | - Jinghu Liu
- Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University, Zengcheng, Guangzhou, China
| | - Jingna Zhou
- Department of Medicine, Taizhou University, Zhejiang, China
| | - Haokun Zhou
- Department of Cardiology, The Fourth Affiliated Hospital of Guangzhou Medical University, Zengcheng, Guangzhou, China
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Chan WC, Liu L, Bouras E, Zuber V, Wen W, Long J, Gill D, Murphy N, Gunter MJ, Assimes TL, Bujanda L, Gruber SB, Küry S, Lynch BM, Qu C, Thomas M, White E, Woods MO, Peters U, Li CI, Chan AT, Brenner H, Tsilidis KK, Zheng W. Associations of blood lipids and LDL cholesterol lowering drug-targets with colorectal cancer risk: a Mendelian randomisation study. Br J Cancer 2025; 132:103-110. [PMID: 39580580 PMCID: PMC11723917 DOI: 10.1038/s41416-024-02900-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Revised: 10/28/2024] [Accepted: 10/29/2024] [Indexed: 11/25/2024] Open
Abstract
BACKGROUND Whether blood lipids are causally associated with colorectal cancer (CRC) risk remains unclear. METHODS Using two-sample Mendelian randomisation (MR), our study examined the associations of genetically-predicted blood concentrations of lipids and lipoproteins (primary: LDL-C, HDL-C, triglycerides, and total cholesterol), and genetically-proxied inhibition of HMGCR, NPC1L1, and PCSK9 (which mimic therapeutic effects of LDL-lowering drugs), with risks of CRC and its subsites. Genetic associations with lipids were obtained from the Global Lipids Genetics Consortium (n = 1,320,016), while genetic associations with CRC were obtained from the largest existing CRC consortium (n = 58,221 cases and 67,694 controls). Our main analysis was a multivariable MR (MVMR) with mutual adjustments for LDL-C, HDL-C, and triglycerides. Secondary analyses, including MVMR additionally-adjusting for BMI or diabetes, were also performed. RESULTS Genetically-predicted LDL-C was positively associated with CRC risk in the MVMR adjusted for HDL-C and triglycerides (OR = 1.09; 95%CI 1.02-1.16 per SD increase) and additionally-adjusted for BMI (OR = 1.12; 95%CI 1.05-1.21) or diabetes (OR = 1.09; 95%CI 1.02-1.17). Associations were generally consistent across anatomical subsites. No clear evidence of association was found for other lipids, lipoproteins, or LDL-lowering drug-targets. CONCLUSIONS We found evidence of a weak positive association between LDL-C and CRC that did not appear to be explained by potential pleiotropic pathways such as via HDL-C, triglycerides, BMI, or diabetes.
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Affiliation(s)
- Wing Ching Chan
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
| | - Lili Liu
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Emmanouil Bouras
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Verena Zuber
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- MRC Centre for Environment and Health, School of Public Health, Imperial College London, London, UK
- UK Dementia Research Institute at Imperial College, Imperial College London, London, UK
| | - Wanqing Wen
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jirong Long
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dipender Gill
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Neil Murphy
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Marc J Gunter
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Themistocles L Assimes
- VA Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Luis Bujanda
- Department of Gastroenterology, Biodonostia Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain
| | - Stephen B Gruber
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Sébastien Küry
- Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France
| | - Brigid M Lynch
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
| | - Conghui Qu
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Minta Thomas
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Emily White
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Michael O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, NL, Canada
| | - Ulrike Peters
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Christopher I Li
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Konstantinos K Tsilidis
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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Geng Y, Li Y, Liu G, Jiao J. Identification of biomarkers for the diagnosis in colorectal polyps and metabolic dysfunction-associated steatohepatitis (MASH) by bioinformatics analysis and machine learning. Sci Rep 2024; 14:29463. [PMID: 39604470 PMCID: PMC11603146 DOI: 10.1038/s41598-024-81120-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/25/2024] [Indexed: 11/29/2024] Open
Abstract
Colorectal polyps are precursors of colorectal cancer. Metabolic dysfunction associated steatohepatitis (MASH) is one of metabolic dysfunction associated fatty liver disease (MAFLD) phenotypic manifestations. Much evidence has suggested an association between MASH and polyps. This study investigated the biomarkers of MASH and colorectal polyps, and the prediction of targeted drugs using an integrated bioinformatics analysis method. Differentially expressed genes (DEGs) analysis and weighted gene co-expression network analysis (WGCNA) were performed on GSE89632 and GSE41258 datasets, 49 shared genes revealed after intersection. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses depicted they were mainly enriched in apoptosis, proliferation and infection pathways. Machine learning algorithms identified S100P, FOXO1, and LPAR1 were biomarkers for colorectal polyps and MASH, ROC curve and violin plot showed ideal AUC and stable expression patterns in both the discovery and validation sets. GSEA analysis showed significant enrichment of bile acid and fatty acid pathways when grouped by the expression levels of the three candidate biomarkers. Immune infiltration analysis showed a significant infiltration of M0 macrophages and Treg cells in the colorectal polyps group. A total of 9 small molecule compounds were considered as potential chemoprevention agents in MASH and colorectal polyps by using the CMap website. Using integrated bioinformatics analysis, the molecular mechanism between MASH and colorectal polyps has been further explored.
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Affiliation(s)
- Ying Geng
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Yifang Li
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Ge Liu
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Jian Jiao
- Department of Gastroenterology and Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China.
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Kumawat M, Une H. Effect of Lactobacillus acidophilus, Calcium, and Moringa oleifera leaves extract co-administration can prevent chemical-induced carcinogenesis. Arab J Gastroenterol 2024; 25:421-436. [PMID: 39462726 DOI: 10.1016/j.ajg.2024.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 07/05/2024] [Accepted: 07/26/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND Colon cancer is the fourth leading cause of cancer deaths worldwide. The present study evaluated the chemopreventive effect of the combined treatment of Lactobacillus acidophilus, calcium citrate, and Moringa oleifera leaves extract against DMH (1,1-dimethylhydrazine hydrochloride) induced colon cancer. MATERIAL AND METHODS Sprague Dawley rats were grouped into 10 different groups and treated with DMH 30 mg/kg s.c. for 8 weeks, Successful induction of colon cancer was confirmed with the help of symptoms, Individual and combined treatments of Lactobacillus acidophilus (109 cfu p.o.), calcium citrate (2 mg/kg p.o.) and Moringa oleifera (100 & 200 mg/kg p.o.) leaves extracts were used for 4 weeks. RESULT After 4 weeks of treatment, it was observed that a significant reduction in aberrant crypt foci (ACFs) count, whereas liver and kidney function, AST (aspartate transaminase), ALT (alanine transaminase), urea and creatinine biomarkers were retained in its normal range. Upon DMH treatment, liver tissue loses histoarchitecture with mononuclear cell infiltration, nuclear enlargement, and hyperchromasia, this reverts due to the combined treatment of Lactobacillus acidophilus (LA), calcium citrate (CC) and hydroalcoholic extract of Moringa oleifera leaves (ME). From the results, it was revealed that individual and combined treatment of Lactobacillus acidophilus, calcium citrate, and hydroalcoholic extract of Moringa oleifera leaves shows beneficial effects against the carcinogen. CONCLUSION Combined treatment of Lactobacillus acidophilus, calcium citrate, and hydroalcoholic extract of Moringa oleifera leaves showed positive effects against carcinogenesis and lowered aberrant crypt foci count and shows histoarchitectural improvements in liver histology with no nuclear enlargement and hyperchromasia in liver tissue.
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Affiliation(s)
- Mrudula Kumawat
- Department of Pharmacology, Y. B. Chavan College of Pharmacy, Ch.Sambhajinagar, Maharashtra, India.
| | - Hemant Une
- Department of Pharmacology, Y. B. Chavan College of Pharmacy, Ch.Sambhajinagar, Maharashtra, India.
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Liu A, Liu C. In vitro and in vivo antineoplastic activities of solamargine in colorectal cancer through the suppression of PI3K/AKT pathway. Histol Histopathol 2024; 39:1317-1328. [PMID: 38357981 DOI: 10.14670/hh-18-717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
PURPOSE Previous research has demonstrated the efficacy of SM in inhibiting tumor growth in various cancer types. The objective of this study was to examine the antineoplastic effects and molecular mechanisms of Solamargine (SM) in colorectal cancer. METHODS Colorectal cancer (CRC) cells were treated with different concentrations of SM to evaluate the anticancer concentration for further experimental measurements. Additionally, the antitumor efficacy of SM was assessed in a subcutaneously implanted tumor model of colorectal cancer. RNA-seq and bioinformatics analyses were employed to identify differentially expressed genes (DEGs) and elucidate the underlying molecular mechanisms in LoVo cells. Subsequently, the specific mechanism of SM-mediated anti-tumor activities was analyzed by protein expression methods. RESULTS The results of in vitro assays demonstrated that SM exhibits significant inhibitory effects on cell proliferation, clone formation, and invasion, while also promoting apoptosis in SW48 and LoVo cells. In a mouse xenograft tumor model, intragastric administration of SM at doses of 5 or 10 mg/kg effectively suppressed tumor volume and weight, and induced cell apoptosis in vivo. SM treatment also down-regulated PCNA and Cyclin E protein expression, contributing to the regulation of apoptosis. Further analysis using RNA-seq, bioinformatics, and experimental measurements revealed that SM treatment upregulates PTEN expression, while significantly reducing the phosphorylation levels of Akt and mTOR in LoVo cells. CONCLUSION Our study provides further evidence to support the notion that SM primarily induces apoptosis in colorectal cancer cells through the inhibition of the PI3K/Akt signaling pathway. Additionally, our investigation demonstrated the favorable safety profile of SM in a mouse model of colorectal cancer, thereby suggesting its potential as a promising therapeutic approach for the management of CRC.
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Affiliation(s)
- Aihua Liu
- Department of Pathology, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Chunying Liu
- Department of Pathology, Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China.
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Sikavi DR, Wang K, Ma W, Drew DA, Ogino S, Giovannucci EL, Cao Y, Song M, Nguyen LH, Chan AT. Aspirin Use and Incidence of Colorectal Cancer According to Lifestyle Risk. JAMA Oncol 2024; 10:1354-1361. [PMID: 39088221 PMCID: PMC11295063 DOI: 10.1001/jamaoncol.2024.2503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 03/19/2024] [Indexed: 08/02/2024]
Abstract
Importance Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority. Objective To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors. Design, Setting, and Participants A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023. Exposures A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week. Main Outcome and Measures Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores. Results The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking. Conclusions and Relevance In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.
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Affiliation(s)
- Daniel R. Sikavi
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Kai Wang
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Wenjie Ma
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - David A. Drew
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
| | - Shuji Ogino
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts
| | - Edward L. Giovannucci
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri
- Alvin J. Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, Missouri
| | - Long H. Nguyen
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Andrew T. Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Immunology & Infectious Disease, Harvard T. H. Chan School of Public Health, Harvard University, Boston, Massachusetts
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11
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Singhal S, Riggs ED, Ruth KJ, Chavez-Salas JP, Chertock Y, Daly MB, Hall MJ. Uptake of Aspirin Chemoprevention in Patients With Lynch Syndrome. JCO Precis Oncol 2024; 8:e2400562. [PMID: 39546469 PMCID: PMC11573245 DOI: 10.1200/po-24-00562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 08/09/2024] [Accepted: 08/09/2024] [Indexed: 11/17/2024] Open
Abstract
PURPOSE Individuals with Lynch syndrome (LS) are at a high lifetime risk of colorectal cancer (CRC) and other cancers. Aspirin (ASA), a nonsteroidal anti-inflammatory drug (NSAID), has proven chemopreventive benefits in LS, with the CAPP2 randomized double-blind placebo-controlled trial demonstrating a 60% relative risk reduction for CRC among participants who adhered to ASA for 2 years or more. This study sought to characterize uptake of ASA/NSAIDs among individuals with LS and to understand factors associated with use. METHODS Individuals with LS were invited (June 2020-August 2022) to complete a one-time electronic survey about LS screening behaviors, uptake of ASA/NSAIDs, and current/emerging cancer prevention options. Participants were recruited from the Fox Chase Cancer Center (FCCC) Risk Assessment Program Registry and through a research invitation posted to two patient-facing LS advocacy websites. RESULTS Two hundred and ninety-six participants completed the survey including 116 (39.2%) from FCCC and 180 (60.8%) recruited via the Internet, including 14.9% non-US based individuals. Uptake of regular ASA or NSAIDs was modest at 34.8% and was even lower (25.7%) when focusing on individuals taking ASA or NSAIDs solely for chemoprevention of LS. More than half (55%) were taking <100 mg ASA daily. In multivariable modeling, lower perceived threat of LS (odds ratio [OR], 0.84 [95% CI, 0.72 to 0.98]), lower concern for side effects (OR, 0.86 [95% CI, 0.76 to 0.99]), and higher likelihood of recommending ASA/NSAIDs to family or a friend were all associated with ASA/NSAIDs use (OR, 1.70 [95% CI, 1.37 to 2.10]). CONCLUSION Uptake of ASA/NSAIDs chemoprevention is modest among individuals with LS. Patient perceptions of the pros and cons of ASA, more so than demographic and disease-related factors, were associated with chemoprevention uptake.
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Affiliation(s)
- Sachi Singhal
- Department of Clinical Genetics, Cancer Prevention and Control Program, Philadelphia PA
| | - Emma D Riggs
- Department of Clinical Genetics, Cancer Prevention and Control Program, Philadelphia PA
| | - Karen J Ruth
- Bioinformatics and Biostatistics, Fox Chase Cancer Center, Philadelphia PA
| | | | - Yana Chertock
- Department of Clinical Genetics, Cancer Prevention and Control Program, Philadelphia PA
| | - Mary B Daly
- Department of Clinical Genetics, Cancer Prevention and Control Program, Philadelphia PA
| | - Michael J Hall
- Department of Clinical Genetics, Cancer Prevention and Control Program, Philadelphia PA
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12
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Mao X, Cheung KS, Tan JT, Mak LY, Lee CH, Chiang CL, Cheng HM, Hui RWH, Yuen MF, Leung WK, Seto WK. Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study. Gut 2024; 73:1313-1320. [PMID: 38569845 DOI: 10.1136/gutjnl-2023-331701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 03/22/2024] [Indexed: 04/05/2024]
Abstract
OBJECTIVE Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.
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Affiliation(s)
- Xianhua Mao
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ka Shing Cheung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jing-Tong Tan
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Chi-Ho Lee
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Chi-Leung Chiang
- Department of Clinical Oncology, The University of Hong Kong, Hong Kong, Hong Kong
| | - Ho Ming Cheng
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Rex Wan-Hin Hui
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Man Fung Yuen
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai Keung Leung
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
- Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Fialková V, Ďúranová H, Borotová P, Klongová L, Grabacka M, Speváková I. Natural Stilbenes: Their Role in Colorectal Cancer Prevention, DNA Methylation, and Therapy. Nutr Cancer 2024; 76:760-788. [PMID: 38950568 DOI: 10.1080/01635581.2024.2364391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 05/29/2024] [Accepted: 05/31/2024] [Indexed: 07/03/2024]
Abstract
The resistance of colorectal cancer (CRC) to conventional therapeutic modalities, such as radiation therapy and chemotherapy, along with the associated side effects, significantly limits effective anticancer strategies. Numerous epigenetic investigations have unveiled that naturally occurring stilbenes can modify or reverse abnormal epigenetic alterations, particularly aberrant DNA methylation status, offering potential avenues for preventing or treating CRC. By modulating the activity of the DNA methylation machinery components, phytochemicals may influence the various stages of CRC carcinogenesis through multiple molecular mechanisms. Several epigenetic studies, especially preclinical research, have highlighted the effective DNA methylation modulatory effects of stilbenes with minimal adverse effects on organisms, particularly in combination therapies for CRC. However, the available preclinical and clinical data regarding the effects of commonly encountered stilbenes against CRC are currently limited. Therefore, additional epigenetic research is warranted to explore the preventive potential of these phytochemicals in CRC development and to validate their therapeutic application in the prevention and treatment of CRC. This review aims to provide an overview of selected bioactive stilbenes as potential chemopreventive agents for CRC with a focus on their modulatory mechanisms of action, especially in targeting alterations in DNA methylation machinery in CRC.
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Affiliation(s)
- Veronika Fialková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Hana Ďúranová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Petra Borotová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Lucia Klongová
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
| | - Maja Grabacka
- Department of Biotechnology and General Technology of Foods, Faculty of Food Technology, University of Agriculture, Cracow, Poland
| | - Ivana Speváková
- AgroBioTech Research Centre, Slovak University of Agriculture, Nitra, Slovakia
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Nafisi S, Støer NC, Veierød MB, Randel KR, Hoff G, Löfling L, Bosetti C, Botteri E. Low-Dose Aspirin and Prevention of Colorectal Cancer: Evidence From a Nationwide Registry-Based Cohort in Norway. Am J Gastroenterol 2024; 119:1402-1411. [PMID: 38300127 PMCID: PMC11208058 DOI: 10.14309/ajg.0000000000002695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/24/2024] [Indexed: 02/02/2024]
Abstract
INTRODUCTION To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC). METHODS In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use. RESULTS We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period. DISCUSSION In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.
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Affiliation(s)
- Sara Nafisi
- Department of Research, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
- Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Nathalie C. Støer
- Department of Research, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
| | - Marit B. Veierød
- Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kristin R. Randel
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
| | - Geir Hoff
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
- Department of Research and Development, Telemark Hospital Trust, Skien, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Lukas Löfling
- Department of Research, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
| | - Cristina Bosetti
- Department of Medical Epidemiology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Edoardo Botteri
- Department of Research, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, National Institute of Public Health, Oslo, Norway
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15
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Fryer E, Martin RM, Haycock P, Yarmolinsky J. Investigating the causal effect of previously reported therapeutic agents for colorectal cancer prevention: protocol for a Mendelian randomization analysis. Wellcome Open Res 2024; 9:30. [PMID: 38911899 PMCID: PMC11190651 DOI: 10.12688/wellcomeopenres.20861.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 06/25/2024] Open
Abstract
Background Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.9 million new cases in 2020 and a predicted rise to 3.2 million in 2040. Screening programmes are already in place to aid early detection and secondary prevention of CRC, but the rising prevalence means additional approaches are required in both primary and secondary prevention settings. Preventive therapy, whereby natural or synthetic agents are used to prevent, reverse or delay disease development, could be an effective strategy to further reduce cancer risk and potential agents have already been identified in conventional observational studies. However, as such studies are vulnerable to confounding and reverse causation, we aim to evaluate these observed relationships using Mendelian randomization (MR), an alternative causal inference approach which should be less susceptible to these biases. Methods and analysis We will use two-sample MR, which uses two independent samples for the exposure and outcome data, to investigate previously reported observational associations of multiple potential preventive agents with CRC risk. We define preventive agents as any synthetic (e.g. approved medication) or natural (e.g. micronutrient, endogenous hormone) molecule used to reduce the risk of cancer. We will first extract potential preventive agents that have been previously linked to CRC risk in observational studies from reviews of the literature. We will then evaluate whether we can develop a genetic instrument for each preventive agent from previously published genome-wide association studies (GWASs) of direct measures of molecular traits (e.g. circulating levels of protein drug targets, blood-based biomarkers of dietary vitamins). The summary statistics from these GWASs, and a large GWAS of CRC, will be used in two-sample MR analyses to investigate the causal effect of putative preventive therapy agents on CRC risk. Sensitivity analyses will be conducted to evaluate the robustness of findings to potential violations of MR assumptions.
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Affiliation(s)
- Ella Fryer
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England, BS8 2BN, UK
- Population Health Sciences, University of Bristol, Bristol, England, BS8 2BN, UK
| | - Richard M. Martin
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England, BS8 2BN, UK
- Population Health Sciences, University of Bristol, Bristol, England, BS8 2BN, UK
- NIHR Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust, University of Bristol, Bristol, England, BS8 2BN, UK
| | - Philip Haycock
- MRC Integrative Epidemiology Unit, University of Bristol, Bristol, England, BS8 2BN, UK
- Population Health Sciences, University of Bristol, Bristol, England, BS8 2BN, UK
| | - James Yarmolinsky
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, England, W2 1PG, UK
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Lin JR, Han DD, Wei W, Zeng Q, Rong ZX, Bai X, Zhang YP, Wang J, Cai XT, Rao XG, Ma SC, Dong ZY. Regular Use of Aspirin and Statins Reduces the Risk of Cancer in Individuals with Systemic Inflammatory Diseases. Cancer Res 2024; 84:1889-1897. [PMID: 38536116 DOI: 10.1158/0008-5472.can-23-2941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 01/11/2024] [Accepted: 03/22/2024] [Indexed: 06/05/2024]
Abstract
UNLABELLED Aspirin has shown potential for cancer prevention, but a recent large randomized controlled trial found no evidence for a reduction in cancer risk. Given the anti-inflammatory effects of aspirin, systemic inflammatory diseases (SID), such as osteoporosis, cardiovascular diseases, and metabolic diseases, could potentially modify the aspirin-cancer link. To investigate the impact of aspirin in people with SIDs, we conducted an observational study on a prospective cohort of 478,615 UK Biobank participants. Individuals with at least one of the 41 SIDs displayed a higher cancer risk than those without SIDs. Regular aspirin use showed protective effects exclusively in patients with SID, contrasting an elevated risk among their non-SID counterparts. Nonetheless, aspirin use demonstrated preventative potential only for 9 of 21 SID-associated cancer subtypes. Cholesterol emerged as another key mediator linking SIDs to cancer risk. Notably, regular statin use displayed protective properties in patients with SID but not in their non-SID counterparts. Concurrent use of aspirin and statins exhibited a stronger protective association in patients with SID, covering 14 common cancer subtypes. In summary, patients with SIDs may represent a population particularly responsive to regular aspirin and statin use. Promoting either combined or individual use of these medications within the context of SIDs could offer a promising chemoprevention strategy. SIGNIFICANCE Individuals with systemic inflammatory diseases derive chemoprotective benefits from aspirin and statins, providing a precision cancer prevention approach to address the personal and public challenges posed by cancer.
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Affiliation(s)
- Jia-Run Lin
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Duan-Duan Han
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wei Wei
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Oncology, XiangYang Central Hospital, Hubei University of Arts and Science, XiangYang, China
| | - Qin Zeng
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zi-Xuan Rong
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xue Bai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan-Pei Zhang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jian Wang
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiao-Ting Cai
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xu-Guang Rao
- Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Si-Cong Ma
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhong-Yi Dong
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Li W, Guan S, Hu X, Zhao H, Cai J, Li X, Zhang X, Zhu W, Pan X, Li S, Tian J. Lysimachia capillipes Hemsl. saponins ameliorate colorectal cancer in mice via regulating gut microbiota and restoring metabolic profiles. Fitoterapia 2024; 175:105959. [PMID: 38615754 DOI: 10.1016/j.fitote.2024.105959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 04/16/2024]
Abstract
Lysimachia capillipes Hemsl., a traditional Chinese medicine (TCM), is commonly prescribed for its anti-inflammatory and anti-tumor properties. Pharmacological studies have demonstrated that Lysimachia capillipes Hemsl. saponins (LCS) are the primary bioactive component. However, its mechanism for treating colorectal cancer (CRC) is still unknown. Increasing evidence suggests a close relationship between CRC, intestinal flora, and host metabolism. Thus, this study aims to investigate the mechanism of LCS amelioration of CRC from the perspective of the gut microbiome and metabolome. As a result, seven gut microbiotas and fourteen plasma metabolites were significantly altered between the control and model groups. Among them, one gut microbiota genera (Monoglobus) and six metabolites (Ureidopropionic acid, Cytosine, L-Proline, 3-hydroxyanthranilic acid, Cyclic AMP and Suberic acid) showed the most pronounced callback trend after LCS administration. Subsequently, the correlation analysis revealed significant associations between 68 pairs of associated metabolites and gut microbes, with 13 pairs of strongly associated metabolites regulated by the LCS. Taken together, these findings indicate that the amelioration of CRC by LCS is connected to the regulation of intestinal flora and the recasting of metabolic abnormalities. These insights highlight the potential of LCS as a candidate drug for the treatment of CRC.
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Affiliation(s)
- Wei Li
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China; College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou 310027, China
| | - Shenghong Guan
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China; College of Pharmacy Science, Zhejiang University of Technology, Hangzhou 310027, China
| | - Xueli Hu
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China; College of Pharmacy Science, Zhejiang Chinese Medical University, Hangzhou 310027, China
| | - Huan Zhao
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China; Urology & Nephrology Center, Department of Nephrology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou 310002, China
| | - Jinhong Cai
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China; College of Pharmacy Science, Zhejiang University of Technology, Hangzhou 310027, China
| | - Xiaohan Li
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China
| | - Xiaoyong Zhang
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China
| | - Wei Zhu
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China
| | - Xin Pan
- School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China
| | - Shouxin Li
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China
| | - Jingkui Tian
- Key Laboratory for Molecular Medicine and Chinese Medicine Preparations, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310002, China.
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Huang Y, Chan S, Chen S, Liu X, Li M, Zheng L, Dong Z, Yang Z, Liu Z, Zhou D, Zhang X, Zhang B. Wnt/β-catenin signalling activates IMPDH2-mediated purine metabolism to facilitate oxaliplatin resistance by inhibiting caspase-dependent apoptosis in colorectal cancer. J Transl Med 2024; 22:133. [PMID: 38310229 PMCID: PMC10838440 DOI: 10.1186/s12967-024-04934-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 01/26/2024] [Indexed: 02/05/2024] Open
Abstract
BACKGROUND Oxaliplatin resistance usually leads to therapeutic failure and poor prognosis in colorectal cancer (CRC), while the underlying mechanisms are not yet fully understood. Metabolic reprogramming is strongly linked to drug resistance, however, the role and mechanism of metabolic reprogramming in oxaliplatin resistance remain unclear. Here, we aim to explore the functions and mechanisms of purine metabolism on the oxaliplatin-induced apoptosis of CRC. METHODS An oxaliplatin-resistant CRC cell line was generated, and untargeted metabolomics analysis was conducted. The inosine 5'-monophosphate dehydrogenase type II (IMPDH2) expression in CRC cell lines was determined by quantitative real-time polymerase chain reaction (qPCR) and western blotting analysis. The effects of IMPDH2 overexpression, knockdown and pharmacological inhibition on oxaliplatin resistance in CRC were assessed by flow cytometry analysis of cell apoptosis in vivo and in vitro. RESULTS Metabolic analysis revealed that the levels of purine metabolites, especially guanosine monophosphate (GMP), were markedly elevated in oxaliplatin-resistant CRC cells. The accumulation of purine metabolites mainly arose from the upregulation of IMPDH2 expression. Gene set enrichment analysis (GSEA) indicated high IMPDH2 expression in CRC correlates with PURINE_METABOLISM and MULTIPLE-DRUG-RESISTANCE pathways. CRC cells with higher IMPDH2 expression were more resistant to oxaliplatin-induced apoptosis. Overexpression of IMPDH2 in CRC cells resulted in reduced cell death upon treatment with oxaliplatin, whereas knockdown of IMPDH2 led to increased sensitivity to oxaliplatin through influencing the activation of the Caspase 7/8/9 and PARP1 proteins on cell apoptosis. Targeted inhibition of IMPDH2 by mycophenolic acid (MPA) or mycophenolate mofetil (MMF) enhanced cell apoptosis in vitro and decreased in vivo tumour burden when combined with oxaliplatin treatment. Mechanistically, the Wnt/β-catenin signalling was hyperactivated in oxaliplatin-resistant CRC cells, and a reciprocal positive regulatory mechanism existed between Wnt/β-catenin and IMPDH2. Blocking the Wnt/β-catenin pathway could resensitize resistant cells to oxaliplatin, which could be restored by the addition of GMP. CONCLUSIONS IMPDH2 is a predictive biomarker and therapeutic target for oxaliplatin resistance in CRC.
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Affiliation(s)
- Yuting Huang
- Department of Interventional Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Szehoi Chan
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Shuna Chen
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Xueqi Liu
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Miao Li
- Department of Dermatovenereology, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Liyuan Zheng
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Zhaoxia Dong
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Ziyi Yang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Zixuan Liu
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Disheng Zhou
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China
| | - Xingding Zhang
- Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, China.
| | - Bo Zhang
- Department of Interventional Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
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Wierzbicki J, Bednarz-Misa I, Lewandowski Ł, Lipiński A, Kłopot A, Neubauer K, Krzystek-Korpacka M. Macrophage Inflammatory Proteins (MIPs) Contribute to Malignant Potential of Colorectal Polyps and Modulate Likelihood of Cancerization Associated with Standard Risk Factors. Int J Mol Sci 2024; 25:1383. [PMID: 38338661 PMCID: PMC10855842 DOI: 10.3390/ijms25031383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 01/15/2024] [Accepted: 01/19/2024] [Indexed: 02/12/2024] Open
Abstract
Better understanding of molecular changes leading to neoplastic transformation is prerequisite to optimize risk assessment and chemopreventive and surveillance strategies. Data on macrophage inflammatory proteins (MIPs) in colorectal carcinogenesis are scanty and their clinical relevance remains unknown. Therefore, transcript and protein expression of CCL3, CCL4, CXCL2, and CCL19 were determined in 173 and 62 patients, respectively, using RT-qPCR and immunohistochemistry with reference to polyps' characteristics. The likelihood of malignancy was modeled using probit regression. With the increasing malignancy potential of hyperplastic-tubular-tubulo-villous-villous polyps, the expression of CCL3, CCL4, and CCL19 in lesions decreased. CCL19 expression decreased also in normal mucosa while that of CXCL2 increased. Likewise, lesion CCL3 and lesion and normal mucosa CCL19 decreased and normal CXCL2 increased along the hyperplasia-low-high dysplasia grade. The bigger the lesion, the lower CCL3 and higher CXCL2 in normal mucosa. Singular polyps had higher CCL3, CCL4, and CCL19 levels in normal mucosa. CCL3, CCL4 and CXCL2 modulated the likelihood of malignancy associated with traditional risk factors. There was no correlation between the protein and mRNA expression of CCL3 and CCL19. In summary, the polyp-adjacent mucosa contributes to gaining potential for malignancy by polyps. MIPs may help in specifying cancerization probability estimated based on standard risk factors.
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Affiliation(s)
- Jarosław Wierzbicki
- Department of Minimally Invasive Surgery and Proctology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Iwona Bednarz-Misa
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (A.K.)
| | - Łukasz Lewandowski
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (A.K.)
| | - Artur Lipiński
- Department of Clinical Pathology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Anna Kłopot
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (A.K.)
| | - Katarzyna Neubauer
- Department of Gastroenterology and Hepatology, Wroclaw Medical University, 50-556 Wroclaw, Poland;
| | - Małgorzata Krzystek-Korpacka
- Department of Biochemistry and Immunochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (Ł.L.); (A.K.)
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20
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Ozawa N, Yokobori T, Osone K, Bilguun EO, Okami H, Shimoda Y, Shiraishi T, Okada T, Sano A, Sakai M, Sohda M, Miyazaki T, Ide M, Ogawa H, Yao T, Oyama T, Shirabe K, Saeki H. MAdCAM-1 targeting strategy can prevent colitic cancer carcinogenesis and progression via suppression of immune cell infiltration and inflammatory signals. Int J Cancer 2024; 154:359-371. [PMID: 37676657 DOI: 10.1002/ijc.34722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Revised: 05/19/2023] [Accepted: 06/13/2023] [Indexed: 09/08/2023]
Abstract
Chronic inflammation caused by infiltrating immune cells can promote colitis-associated dysplasia/colitic cancer in ulcerative colitis (UC) by activating inflammatory cytokine signalling through the IL-6/p-STAT3 and TNFα/NF-κB pathways. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on high endothelial venules promotes the migration of immune cells from the bloodstream to the gut via interaction with α4β7 integrin expressed on the immune cells. MAdCAM-1, has therefore drawn interest as a novel therapeutic target for treating active UC. However, the role of MAdCAM-1-positive endothelial cells in immune cell infiltration in dysplasia/colitic cancers remains unclear. We evaluated the expression of MAdCAM-1, CD31 and immune cell markers (CD8, CD68, CD163 and FOXP3) in samples surgically resected from 11 UC patients with dysplasia/colitic cancer and 17 patients with sporadic colorectal cancer (SCRC), using immunohistochemical staining. We used an azoxymethane/dextran sodium sulphate mouse model (AOM/DSS mouse) to evaluate whether dysplasia/colitic cancer could be suppressed with an anti-MAdCAM-1 blocking antibody by preventing immune cell infiltration. The number of MAdCAM-1-positive vessels and infiltrating CD8+ , CD68+ and CD163+ immune cells was significantly higher in dysplasia/colitic cancer than in normal, SCRC and UC mucosa. In AOM/DSS mice, the anti-MAdCAM-1 antibody reduced the number, mean diameter, depth of tumours, Ki67 positivity, number of CD8+ , CD68+ and CD163+ immune cells and the IL-6/p-STAT3 and TNF-α/NF-κB signalling. Our results indicate that targeting MAdCAM-1 is a promising strategy for controlling not only UC severity but also carcinogenesis and tumour progression by regulating inflammation/immune cell infiltration in patients with UC.
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Affiliation(s)
- Naoya Ozawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takehiko Yokobori
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan
| | - Katsuya Osone
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Erkhem-Ochir Bilguun
- Division of Integrated Oncology Research, Gunma University, Initiative for Advanced Research (GIAR), Maebashi, Gunma, Japan
| | - Haruka Okami
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Yuki Shimoda
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine
| | - Takuya Shiraishi
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takuhisa Okada
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Akihiko Sano
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Makoto Sakai
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Makoto Sohda
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Tatsuya Miyazaki
- Department of Gastroenterological Surgery, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan
| | - Munenori Ide
- Department of Pathology Diagnosis, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan
| | - Hiroomi Ogawa
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Bunkyouku, Tokyo, Japan
| | - Tetsunari Oyama
- Department of Diagnostic Pathology, Gunma University Graduate School of Medicine
| | - Ken Shirabe
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
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21
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Munteanu C, Schwartz B. B Vitamins, Glucoronolactone and the Immune System: Bioavailability, Doses and Efficiency. Nutrients 2023; 16:24. [PMID: 38201854 PMCID: PMC10780850 DOI: 10.3390/nu16010024] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 12/13/2023] [Accepted: 12/19/2023] [Indexed: 01/12/2024] Open
Abstract
The present review deals with two main ingredients of energy/power drinks: B vitamins and glucuronolactone and their possible effect on the immune system. There is a strong relationship between the recommended daily dose of selected B vitamins and a functional immune system. Regarding specific B vitamins: (1) Riboflavin is necessary for the optimization of reactive oxygen species (ROS) in the fight against bacterial infections caused by Staphylococcus aureus and Listeria monocytogenes. (2) Niacin administered within normal doses to obese rats can change the phenotype of skeletal fibers, and thereby affect muscle metabolism. This metabolic phenotype induced by niacin treatment is also confirmed by stimulation of the expression of genes involved in the metabolism of free fatty acids (FFAs) and oxidative phosphorylation at this level. (3) Vitamin B5 effects depend primarily on the dose, thus large doses can cause diarrhea or functional disorders of the digestive tract whereas normal levels are effective in wound healing, liver detoxification, and joint health support. (4) High vitamin B6 concentrations (>2000 mg per day) have been shown to exert a significant negative impact on the dorsal root ganglia. Whereas, at doses of approximately 70 ng/mL, sensory symptoms were reported in 80% of cases. (5) Chronic increases in vitamin B12 have been associated with the increased incidence of solid cancers. Additionally, glucuronolactone, whose effects are not well known, represents a controversial compound. (6) Supplementing with D-glucarates, such as glucuronolactone, may help the body's natural defense system function better to inhibit different tumor promoters and carcinogens and their consequences. Cumulatively, the present review aims to evaluate the relationship between the selected B vitamins group, glucuronolactone, and the immune system and their associations to bioavailability, doses, and efficiency.
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Affiliation(s)
- Camelia Munteanu
- Department of Plant Culture, Faculty of Agriculture, University of Agricultural Sciences and Veterinary Medicine, 400372 Cluj-Napoca, Romania
| | - Betty Schwartz
- The Institute of Biochemistry, Food Science and Nutrition, The School of Nutritional Sciences, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel
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22
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Lloyd KE, Hall LH, Ziegler L, Foy R, Green SMC, MacKenzie M, Taylor DG, Smith SG. Acceptability of aspirin for cancer preventive therapy: a survey and qualitative study exploring the views of the UK general population. BMJ Open 2023; 13:e078703. [PMID: 38110374 DOI: 10.1136/bmjopen-2023-078703] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2023] Open
Abstract
OBJECTIVES Aspirin could be offered for colorectal cancer prevention for the UK general population. To ensure the views of the general population are considered in future guidance, we explored public perceptions of aspirin for preventive therapy. DESIGN We conducted an online survey to investigate aspirin use, and awareness of aspirin for cancer prevention among the UK general population. We conducted semistructured interviews with a subsample of survey respondents to explore participants' acceptability towards aspirin for cancer preventive therapy. We analysed the interview data using reflexive thematic analysis and mapped the themes onto the Theoretical Domains Framework, and the Necessity and Concerns Framework. SETTING Online survey and remote interviews. PARTICIPANTS We recruited 400 UK respondents aged 50-70 years through a market research company to the survey. We purposefully sampled, recruited and interviewed 20 survey respondents. RESULTS In the survey, 19.0% (76/400) of respondents were aware that aspirin can be used to prevent cancer. Among those who had previously taken aspirin, 1.9% (4/216) had taken it for cancer prevention. The interviews generated three themes: (1) perceived necessity of aspirin; (2) concerns about side effects; and (3) preferred information sources. Participants with a personal or family history of cancer were more likely to perceive aspirin as necessary for cancer prevention. Concerns about taking aspirin at higher doses and its side effects, such as gastrointestinal bleeding, were common. Many described wanting guidance and advice on aspirin to be communicated from sources perceived as trustworthy, such as healthcare professionals. CONCLUSIONS Among the general population, those with a personal or family history of cancer may be more receptive towards taking aspirin for preventive therapy. Future policies and campaigns recommending aspirin may be of particular interest to these groups. Multiple considerations about the benefits and risks of aspirin highlight the need to support informed decisions on the medication.
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Affiliation(s)
- Kelly E Lloyd
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
| | - Louise H Hall
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
| | - Lucy Ziegler
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
| | - Robbie Foy
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
| | - Sophie M C Green
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
| | | | - David G Taylor
- School of Pharmacy, University College London, London, UK
| | - Samuel G Smith
- Leeds Institute of Health Sciences, University of Leeds Faculty of Medicine and Health, Leeds, UK
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23
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Li X, Yan Y, Du X, Zhang H, Li H, Chen W. Yogurt Prevents Colitis-Associated Colorectal Cancer in Mice. Mol Nutr Food Res 2023; 67:e2300444. [PMID: 37897323 DOI: 10.1002/mnfr.202300444] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/15/2023] [Indexed: 10/30/2023]
Abstract
SCOPE Epidemiological studies indicate an inverse correlation between yogurt consumption and colorectal cancer (CRC), but whether there is a cause-and-effect relationship has not yet been validated. This study aims to investigate the effects and possible mechanisms of yogurt on colitis-associated colorectal cancer (CAC) in mice. METHODS AND RESULTS Experimental CAC is induced by azoxymethane (AOM, 10 mg kg-1 , ip) followed by three cycles of dextran sulfate sodium (DSS, 3%) treatment. Colitis is induced by adding DSS (3%) in drinking water for 5 days. Primary mouse macrophages are isolated for mechanistic studies. Data clearly show that yogurt (15 g kg-1 body weight) significantly reduces the multiplicity of colonic neoplasms by 38.83% in mice. Yogurt protects mice from colitis dependent on lactate receptor GPR81. The deficiency of Gpr81 exacerbates colitis and CAC in mice. Further investigation reveals that GPR81 may be dispensable for gut barrier function but essential for colonic mucosal repair. d-lactate in yogurt can activate GPR81 to suppress proinflammatory macrophage polarization, thereby facilitating inflammatory resolution after colonic injury and consequently suppressing CAC progression. CONCLUSION Yogurt effectively protects against colitis-associated colorectal tumorigenesis in mice, and this study provides a rationale for introducing yogurt supplementation to patients with chronic inflammatory bowel diseases.
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Affiliation(s)
- Xiaojing Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yongheng Yan
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Xinru Du
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Hao Zhang
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Haitao Li
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Wei Chen
- State Key Laboratory of Food Science and Resources, Jiangnan University, Wuxi, 214122, China
- School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
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24
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Yang J, Liao Y, Wang B, Cui L, Yu X, Wu F, Zhang Y, Liu R, Yao Y. EDARADD promotes colon cancer progression by suppressing E3 ligase Trim21-mediated ubiquitination and degradation of Snail. Cancer Lett 2023; 577:216427. [PMID: 37838280 DOI: 10.1016/j.canlet.2023.216427] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/28/2023] [Accepted: 09/29/2023] [Indexed: 10/16/2023]
Abstract
Tumor cell migration, specifically epithelial-mesenchymal transition (EMT), serves as a key contributor to treatment failure in colon cancer patients. However, the limited comprehension of its genetic and biological aspects presents challenges for its investigation. EDAR-associated death domain (EDARADD), an important TNFR superfamily member, is elevated in colon cancer. However, it remains unclear about the exact role of EDARADD in the progression of colon cancer metastasis. In this study, we initially demonstrated that both protein and mRNA levels of EDDARADD are elevated in colon cancer tissues and cells, associated with reduced overall survival. Furthermore, functional experiments demonstrated that EDARADD promotes colon cancer cell proliferation and participates in EMT both in vitro and vivo. Mechanistically, Co-IP verified EDARADD could stabilize Snail1 by interacting with E3 ubiquitin ligase Trim21 to inhibit ubiquitination of Snail1. Interestingly, RNA-seq and ubiquitination assay revealed EDARADD's dual downregulation of Trim21 expression at the translational level via Cul1-mediated ubiquitin degradation, and at the transcriptional level through PPARa regulation. Moreover, EDARADD activates NF-κB signaling and experiences feedback transcriptional regulation by p65. In conclusion, this study highlights the signal pathway of EDARADD-PPARa-Trim21-Snail1-EMT and a feedback regulation of NF-κB signaling on EDARADD, which indicated EDARADD as an emerging therapeutic target for colon cancer.
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Affiliation(s)
- Jiani Yang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Yuanyu Liao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Bojun Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China; Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, 150080, China
| | - Luying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Xuefan Yu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China
| | - Feng Wu
- Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150080, China; Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150000, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China; Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, 150080, China; Key Laboratory of Tumor Immunology in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, 150080, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150080, China.
| | - Ruiqi Liu
- Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, China.
| | - Yuanfei Yao
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China; Key Laboratory of Tumor Immunology in Heilongjiang, Harbin Medical University Cancer Hospital, Harbin, 150080, China; Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, 150080, China.
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25
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Cheng Y, Di YM, Zhang AL, Hu P, Mo J, Zhang H, Xue CC, Zhang B. Does Chinese herbal medicine (CHM) reduce colorectal adenoma (CRA) recurrence: protocol of a registry-based, cohort study and a qualitative interview. BMJ Open 2023; 13:e073969. [PMID: 37984951 PMCID: PMC10660202 DOI: 10.1136/bmjopen-2023-073969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Accepted: 10/30/2023] [Indexed: 11/22/2023] Open
Abstract
INTRODUCTION Colorectal adenoma (CRA) is a precancerous lesion for colorectal cancer. Endoscopic resection is the first-line treatment for CRA. However, CRA recurrence rate is high. This proposed study aims to determine if Chinese herbal medicine (CHM) reduces CRA recurrence. METHODS AND ANALYSIS This project encompasses an observational, registry-based, cohort study and a nested qualitative study. The cohort study aims to include 364 postpolypectomy CRA participants at Guangdong Provincial Hospital of Chinese Medicine (GPHCM), China, with a follow-up phase of up to 1 year. In addition to routine care, these participants will receive a CHM treatment prescribed by experienced Chinese medicine (CM) clinicians. The CHM treatment encompasses CHM products and CHM formulae according to CM syndromes. The primary outcome is CRA recurrence rate at 1 year after enrolment. Secondary outcomes include characteristics of recurrent CRA, incidence of colorectal polyp (except for CRA), incidence of advanced CRA, incidence of colorectal cancer, improvement of gastrointestinal symptoms commonly seen in CRA patients, faecal occult blood test result, lipid level, fasting plasma glucose level, uric acid level, carcinoembryonic antigen, carbohydrate antigen 19-9, quality of life and safety evaluations. Logistic regression analysis will be used to explore the correlation between exposure and outcome. Qualitative interviews will be conducted among approximate 30 CRA patients from the cohort study and 10 CM practitioners in Department of Gastroenterology at GPHCM. Thematic analysis will be used to analyse qualitative data. ETHICS AND DISSEMINATION Ethical approval has been obtained from the Human Research Ethics Committee (HREC) of GPHCM (YF2022-320-02) and registered at Royal Melbourne Institute of Technology (RMIT) HREC. The results will be disseminated in peer-reviewed journals and international academic conferences. TRIAL REGISTRATION NUMBER ChiCTR2200065713.
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Affiliation(s)
- Yi Cheng
- The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Yuan Ming Di
- The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
| | - Anthony Lin Zhang
- The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
| | - Peixin Hu
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Jiahao Mo
- The Second Clinical College of Guangzhou University of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haiyan Zhang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Charlie Changli Xue
- The China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
| | - Beiping Zhang
- Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, China
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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Cheng Y, Di YM, Zhang AL, Zhang B, Xue CC. Oral Chinese herbal medicine in reducing the recurrence of colorectal adenoma after polypectomy: A protocol for the systematic review and meta-analysis. PLoS One 2023; 18:e0293244. [PMID: 37862339 PMCID: PMC10588860 DOI: 10.1371/journal.pone.0293244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/09/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Colorectal adenoma (CRA) is a significant precancerous lesion of sporadic colorectal cancer (CRC). CRA is likely to recur after polypectomy, increasing the risk of CRC. Chinese herbal medicine (CHM) has been used to reduce CRA recurrence. This review aims to evaluate the effectiveness and safety of oral CHM in reducing CRA recurrence compared to other treatments (placebo, routine care, no treatment, and conventional medicine). METHODS We will search for randomised controlled trials (RCTs) from nine major biomedical databases in English and Chinese from their inception to July 2023. The RCTs that investigate the effects of oral CHM in reducing CRA recurrence compared to other treatments will be involved. We will exclude trials using CHM extract or external application of CHM, cohort study and cross-section study. The Cochrane Risk of Bias Tool version 2 will be used to assess the quality of included studies. Data will be analysed using Review Manager software 5.4 and STATA. The random effect model will be used. The heterogeneity of intervention effects will be tested by Chi2 (Cochrane Q) and I2 statistics. Funnel plots will assess publication bias if more than ten studies are included. Subgroup and sensitivity analysis will be conducted when possible. DISCUSSION This review will discuss the effectiveness and safety of oral CHM in reducing CRA recurrence. It will show the critical information for clinicians in the decision-making process and countries to develop clinical guidelines on CRA management. Systematic review registration PROSPERO CRD42023324197.
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Affiliation(s)
- Yi Cheng
- China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
- Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong Province, China
| | - Yuan Ming Di
- China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
| | - Anthony Lin Zhang
- China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
| | - Beiping Zhang
- Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong Province, China
| | - Charlie Changli Xue
- China-Australia International Research Centre for Chinese Medicine, School of Health and Biomedical Sciences, STEM College, RMIT University, Melbourne, Victoria, Australia
- Department of Gastroenterology, Guangdong Provincial Hospital of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong Province, China
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Foda ZH, Dharwadkar P, Katona BW. Preventive strategies in familial and hereditary colorectal cancer. Best Pract Res Clin Gastroenterol 2023; 66:101840. [PMID: 37852714 DOI: 10.1016/j.bpg.2023.101840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/05/2023] [Accepted: 05/17/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer is a leading cause of cancer-related deaths worldwide. While most cases are sporadic, a significant proportion of cases are associated with familial and hereditary syndromes. Individuals with a family history of colorectal cancer have an increased risk of developing the disease, and those with hereditary syndromes such as Lynch syndrome or familial adenomatous polyposis have a significantly higher risk. In these populations, preventive strategies are critical for reducing the incidence and mortality of colorectal cancer. This review provides an overview of current preventive strategies for individuals at increased risk of colorectal cancer due to familial or hereditary factors. The manuscript includes a discussion of risk assessment and genetic testing, highlighting the importance of identifying at-risk individuals and families. This review describes various preventive measures, including surveillance colonoscopy, chemoprevention, and prophylactic surgery, and their respective benefits and limitations. Together, this work highlights the importance of preventive strategies in familial and hereditary colorectal cancer.
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Affiliation(s)
- Zachariah H Foda
- The Sidney Kimmel Comprehensive Cancer Center and Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Pooja Dharwadkar
- Division of Gastroenterology, Department of Medicine, University of California, San Francisco, CA, USA
| | - Bryson W Katona
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Cao Y, Chan AT. Vitamin D and Early-Onset Colorectal Cancer-Rays of Hope? Gastroenterology 2023; 165:831-833. [PMID: 37544414 PMCID: PMC10726952 DOI: 10.1053/j.gastro.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/08/2023]
Affiliation(s)
- Yin Cao
- Division of Public Health Sciences, Department of Surgery, Alvin J. Siteman Cancer Center, Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Department of Medicine, Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Stone JK, Mehta NA, Singh H, El-Matary W, Bernstein CN. Endoscopic and chemopreventive management of familial adenomatous polyposis syndrome. Fam Cancer 2023; 22:413-422. [PMID: 37119510 DOI: 10.1007/s10689-023-00334-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 04/18/2023] [Indexed: 05/01/2023]
Abstract
Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome predisposing affected individuals to gastrointestinal (GI) cancers through a high burden of polyposis. Colorectal cancer rates reach 100% by the age of 45, making early colectomy a mainstay of treatment. While most patients undergo colectomy at an early age, ongoing screening and surveillance of the upper gastrointestinal tract and rectal pouch must continue throughout adulthood. Endoscopic therapy of gastric, duodenal, ampullary and rectal pouch polyps is critical to reduce morbidity and cancer related mortality. Management of these lesions is not uniform, and is dependent on their location, size, histology, and risk of malignant potential. Medical therapies targeting pathways that reduce the malignant progression of pre-cancerous lesions have been studied for many years. While studies on the use of aspirin and non-steroidal anti-inflammatories (NSAIDs) in chemoprevention have shown encouraging results in Lynch syndrome and primary colorectal cancer, the potential benefits of these medications have not been duplicated in FAP cohorts. While data remains limited on chemoprevention in FAP, a number of randomized trials are currently underway examining targeted therapies with the potential to slow the progression of the disease. This review aims to provide an in-depth review of the literature on current endoscopic options and chemopreventive therapies targeting FAP. While the endoscopic management has robust data for its use, chemoprevention in FAP is still in its infancy. The complementary use of chemopreventive agents and endoscopic therapy for FAP patients is quickly becoming a growing and exciting area of research.
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Affiliation(s)
- J K Stone
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
| | - N A Mehta
- Center for Interventional and Therapeutic Endoscopy, Digestive Diseases and Nutrition, Rush University Medical Center, Chicago, IL, USA
| | - H Singh
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada
| | - W El-Matary
- Section of Pediatric Gastroenterology, Department of Pediatrics, Max Rady College of Medicine, Winnipeg, MB, Canada
| | - C N Bernstein
- Section of Gastroenterology, Department of Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
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Luo Z, Wang B, Luo F, Guo Y, Jiang N, Wei J, Wang X, Tseng Y, Chen J, Zhao B, Liu J. Establishment of a large-scale patient-derived high-risk colorectal adenoma organoid biobank for high-throughput and high-content drug screening. BMC Med 2023; 21:336. [PMID: 37667332 PMCID: PMC10478412 DOI: 10.1186/s12916-023-03034-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 08/15/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Colorectal adenoma (CA), especially high-risk CA (HRCA), is a precancerous lesion with high prevalence and recurrence rate and accounts for about 90% incidence of sporadic colorectal cancer cases worldwide. Currently, recurrent CA can only be treated with repeated invasive polypectomies, while safe and promising pharmaceutical invention strategies are still missing due to the lack of reliable in vitro model for CA-related drug screening. METHODS We have established a large-scale patient-derived high-risk colorectal adenoma organoid (HRCA-PDO) biobank containing 37 PDO lines derived from 33 patients and then conducted a series of high-throughput and high-content HRCA drug screening. RESULTS We established the primary culture system with the non-WNT3a medium which highly improved the purity while maintained the viability of HRCA-PDOs. We also proved that the HRCA-PDOs replicated the histological features, cellular diversity, genetic mutations, and molecular characteristics of the primary adenomas. Especially, we identified the dysregulated stem genes including LGR5, c-Myc, and OLFM4 as the markers of adenoma, which are well preserved in HRCA-PDOs. Based on the HRCA-PDO biobank, a customized 139 compound library was applied for drug screening. Four drugs including metformin, BMS754807, panobinostat and AT9283 were screened out as potential hits with generally consistent inhibitory efficacy on HRCA-PDOs. As a representative, metformin was discovered to hinder HRCA-PDO growth in vitro and in vivo by restricting the stemness maintenance. CONCLUSIONS This study established a promising HRCA-PDO biobank and conducted the first high-throughput and high-content HRCA drug screening in order to shed light on the prevention of colorectal cancer.
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Affiliation(s)
- Zhongguang Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bangting Wang
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Feifei Luo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yumeng Guo
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Ning Jiang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Jinsong Wei
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Xin Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China
| | - Yujen Tseng
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Jian Chen
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Bing Zhao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200438, China.
- Institute of Organoid Technology, Kunming Medical University, Kunming, 650500, China.
| | - Jie Liu
- Department of Digestive Diseases, Huashan Hospital, Fudan University, Shanghai, 200040, China.
- Institute of Biomedical Sciences and Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
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Gweon TG. [Gut Microbiome and Colorectal Cancer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 82:56-62. [PMID: 37621240 DOI: 10.4166/kjg.2023.089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/04/2023] [Accepted: 08/06/2023] [Indexed: 08/26/2023]
Abstract
Colorectal cancer (CRC) is one of the most common cancers in Korea. A majority of CRCs are caused by progressive genomic alterations referred to as the adenoma-carcinoma sequence. The factors that may increase the risk of CRC include obesity and consumption of a high-fat diet, red meat, processed meat, and alcohol. Recently, the role of gut microbiota in the formation, progression and treatment of CRCs has been investigated in depth. An altered gut microbiota can drive carcinogenesis and cause the development of CRC. Studies have also shown the role of gut microbiota in the prevention of CRC and the impact of therapies involving gut microbiota on CRC. Herein, we summarize the current understanding of the role of the gut microbiota in the development of CRC and its therapeutic potential, including the prevention of CRC and in enhancing efficacy of chemotherapy and immunotherapy.
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Affiliation(s)
- Tae-Geun Gweon
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Nafisi S, Randel KR, Støer NC, Veierød MB, Hoff G, Holme Ø, Schult AL, Botteri E. Association between use of low-dose aspirin and detection of colorectal polyps and cancer in a screening setting. Dig Liver Dis 2023; 55:1126-1132. [PMID: 36754644 DOI: 10.1016/j.dld.2023.01.156] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/16/2023] [Accepted: 01/23/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND The possible protective effect of aspirin on risk of colorectal cancer (CRC) is still highly debated. METHODS We used data from Bowel Cancer Screening in Norway, a trial randomizing individuals from general population, aged 50-74 years, to flexible sigmoidoscopy or faecal immunochemical test (FIT), to study the association between aspirin use and detection of CRC and two CRC precursors: adenomas and advanced serrated lesions (ASL). Prescriptions of low-dose aspirin were obtained from Norwegian prescription database. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Among 64,889 screening participants (24,159 sigmoidoscopy, 40,730 FIT), 314 (0.5%) had CRC, 6,208 (9.6%) adenoma and 659 (1.0%) ASL. Overall and short-term use (<3 years) of low-dose aspirin, versus no use, were not associated with any colorectal lesion. Long-term use (≥3 years) was associated with lower detection of CRC (overall OR 0.66, 95%CI 0.46-0.93; sigmoidoscopy: 0.56, 0.33-0.97; FIT: 0.72, 0.45-1.15), adenomas in sigmoidoscopy arm (overall OR 0.95, 95%CI 0.87-1.03; sigmoidoscopy: 0.89, 0.80-0.99; FIT: 1.03, 0.89-1.18), but not ASLs. We did not observe significant differences in the effect of aspirin according to the location of colorectal lesions. CONCLUSION Our results suggest that long-term use of aspirin might have a protective effect against adenomas and colorectal cancer, but not ASLs.
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Affiliation(s)
- Sara Nafisi
- Department of Research, Cancer Registry of Norway, Oslo, Norway; Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Kristin R Randel
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway
| | - Nathalie C Støer
- Department of Research, Cancer Registry of Norway, Oslo, Norway; Norwegian Research Centre for Women's Health, Women's Clinic, Oslo University Hospital, Oslo, Norway
| | - Marit B Veierød
- Oslo Centre for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
| | - Geir Hoff
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway; Department of Research and Development, Telemark Hospital Trust, Skien, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Øyvind Holme
- Department of Medicine, Sørlandet Hospital, Kristiansand, Norway; Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Anna L Schult
- Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway; Department of Medicine, Vestre Viken Hospital Trust Bærum, Gjettum, Norway
| | - Edoardo Botteri
- Department of Research, Cancer Registry of Norway, Oslo, Norway; Section for Colorectal Cancer Screening, Cancer Registry of Norway, Oslo, Norway.
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Nascimento RDPD, Machado APDF. The preventive and therapeutic effects of anthocyanins on colorectal cancer: A comprehensive review based on up-to-date experimental studies. Food Res Int 2023; 170:113028. [PMID: 37316089 DOI: 10.1016/j.foodres.2023.113028] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 05/01/2023] [Accepted: 05/21/2023] [Indexed: 06/16/2023]
Abstract
Colorectal cancer (CRC) is the second most lethal and the third most diagnosed type of cancer worldwide. More than 75% of CRC cases are sporadic and lifestyle-related. Risk factors include diet, physical inactivity, genetics, smoking, alcohol, changes in the intestinal microbiota, and inflammation-related diseases such as obesity, diabetes, and inflammatory bowel diseases. The limits of conventional treatments (surgery, chemotherapy, radiotherapy), as demonstrated by the side effects and resistance of many CRC patients, are making professionals search for new chemopreventive alternatives. In this context, diets rich in fruits and vegetables or plant-based products, which contain high levels of phytochemicals, have been postulated as complementary therapeutic options. Anthocyanins, phenolic pigments responsible for the vivid colors of most red, purple, and blue fruits and vegetables, have been shown protective effects on CRC. Berries, grapes, Brazilian fruits, and vegetables such as black rice and purple sweet potato are examples of products rich in anthocyanins, which have been able to reduce cancer development by modulating signaling pathways associated with CRC. Therefore, this review has as main objective to present and discuss the potential preventive and therapeutic effects of anthocyanins present in fruits and vegetables, in plant extracts, or in their pure form on CRC, taking into account up-to-date experimental studies (2017-2023). Additionally, a highlight is given towards the mechanisms of action of anthocyanins on CRC.
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Affiliation(s)
- Roberto de Paula do Nascimento
- Laboratory of Nutrition and Metabolism (LANUM), Department of Food Science and Nutrition (DECAN), School of Food Engineering (FEA), University of Campinas (UNICAMP), Monteiro Lobato Street 80, 13083-862, Campinas, São Paulo, Brazil; European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Rd, CF24 4HQ, Cardiff, Wales, United Kingdom.
| | - Ana Paula da Fonseca Machado
- Study and Research Group on Agroindustrial Products from the Cerrado (GEPPAC), Faculty of Engineering (FAEN), Federal University of Grande Dourados (UFGD), Dourados-Itahum Highway Km 12, 79804-970, Dourados, Mato Grosso do Sul, Brazil.
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Begolli R, Chatziangelou M, Samiotaki M, Goutas A, Barda S, Goutzourelas N, Kevrekidis DP, Malea P, Trachana V, Liu M, Lin X, Kollatos N, Stagos D, Giakountis A. Transcriptome and proteome analysis reveals the anti-cancer properties of Hypnea musciformis marine macroalga extract in liver and intestinal cancer cells. Hum Genomics 2023; 17:71. [PMID: 37525271 PMCID: PMC10388463 DOI: 10.1186/s40246-023-00517-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 07/18/2023] [Indexed: 08/02/2023] Open
Abstract
BACKGROUND Marine seaweeds are considered as a rich source of health-promoting compounds by the food and pharmaceutical industry. Hypnea musciformis is a marine red macroalga (seaweed) that is widely distributed throughout the world, including the Mediterranean Sea. It is known to contain various bioactive compounds, including sulfated polysaccharides, flavonoids, and phlorotannins. Recent studies have investigated the potential anticancer effects of extracts from H. musciformis demonstrating their cytotoxic effects on various cancer cell lines. The anticancer effects of these extracts are thought to be due to the presence of bioactive compounds, particularly sulfated polysaccharides, which have been shown to have anticancer and immunomodulatory effects. However, further studies are needed to fully understand the molecular mechanisms that underlie their anticancer effects and to determine their potential as therapeutic agents for cancer treatment. METHODS H. musciformis was collected from the Aegean Sea (Greece) and used for extract preparation. Transcriptome and proteome analysis was performed in liver and colon cancer human cell lines following treatment with H. musciformis seaweed extracts to characterize its anticancer effect in detail at the molecular level and to link transcriptome and proteome responses to the observed phenotypes in cancer cells. RESULTS We have identified that treatment with the seaweed extract triggers a p53-mediated response at the transcriptional and protein level in liver cancer cells, in contrast to colon cancer cells in which the effects are more associated with metabolic changes. Furthermore, we show that in treated HepG2 liver cancer cells, p53 interacts with the chromatin of several target genes and facilitates their upregulation possibly through the recruitment of the p300 co-activator. CONCLUSIONS Overall, the available evidence suggests that extracts from H. musciformis have the potential to serve as a source of anticancer agents in liver cancer cells mainly through activation of a p53-mediated anti-tumor response that is linked to inhibition of cellular proliferation and induction of cell death.
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Affiliation(s)
- Rodiola Begolli
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Myrto Chatziangelou
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | | | - Andreas Goutas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Sofia Barda
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Nikolaos Goutzourelas
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Dimitrios Phaedon Kevrekidis
- Laboratory of Forensic Medicine and Toxicology, Department of Medicine, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Paraskevi Malea
- Department of Botany, School of Biology, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Varvara Trachana
- Department of Biology, Faculty of Medicine, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Ming Liu
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China
- Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266237, China
| | - Xiukun Lin
- College of Marine Sciences, Beibu Gulf University, 12 Binhai Rd, Qinzhou, 535011, Guangxi, China
| | - Nikolaos Kollatos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece
| | - Dimitrios Stagos
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece.
| | - Antonis Giakountis
- Department of Biochemistry and Biotechnology, School of Health Sciences, University of Thessaly, 41500, Biopolis, Larissa, Greece.
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Li X, Zhang W, Yuan S, Mao Q, Zhang C, Cai R, Lin H, Wang X. Publication trends and hotspots of colorectal adenoma during 2002-2022: a bibliometric and visualized analysis. Front Oncol 2023; 13:1142703. [PMID: 37492472 PMCID: PMC10364844 DOI: 10.3389/fonc.2023.1142703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 06/19/2023] [Indexed: 07/27/2023] Open
Abstract
Background Prevention and treatment of colorectal adenoma (CRA) are great significant to reduce morbidity and mortality of colorectal cancer. Although there have been numerous studies on CRA recently, few publications utilized the bibliometrics to evaluate this field. The objective of current study was to provide a comprehensive analysis of the current state and frontier progress of CRA over the past 20 years. Methods The Web of Science Core Collection was utilized to extracted all studies of CRA during 2002-2022. Bibliometric tools including CiteSpace, VOSviewer, and the Online Analysis Platform of Literature Metrology were used for statistical analysis. CiteSpace and the Online Analysis Platform were used to evaluate the contributions of various countries/regions, institutions, authors, and journals in this field. Research hotspots and trends were identified through keywords and references analysis by VOSviewer and CiteSpace. Results 2,268 publications from 2002 to 2022 in total were identified. The number of global publications in this field has increased annually. The USA was the most productive country, contributing nearly 30% of global publications. But in recent years, China's publications grew rapidly and had the highest citation strength. The most productive institutions was the National Cancer Institute. Baron JA from the USA was the most productive and the one of most co-cited authors. Cancer Epidemiology Biomarkers & Prevention had the highest number of publications and Gastroenterology was the most co-cited journals. Analysis of keywords clusters showed that "mechanism/pathophysiology", "risk factors and prevention", "colonoscopy screening and treatment", "metabolism", and "microbiota" were the major frontier topics and the main research directions. Conclusions CRA publications have shown a gradual upward trend in recent years, most of which have been published by developed countries. Developing countries should further focus on CRA research and transnational cooperation with developed countries in the future, in order to better improve the situation of the increasing morbidity and mortality of CRC. Baron JA was the most outstanding researcher in this field. More attention should be devoted to "pathogenesis of CRA", "less invasive diagnostic methods", "chemoprevention", and "screening and risk prediction of CRA including gut microbiome and metabolism", which will be frontiers in the future.
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Affiliation(s)
- Xue Li
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wenzheng Zhang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Surui Yuan
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
| | - Qiyuan Mao
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chuchu Zhang
- Institution of Information on Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
| | - Ruijuan Cai
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hongsheng Lin
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xueqian Wang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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He J, Yang X, Zhang C, Li A, Wang W, Xing J, E J, Xu X, Wang H, Yu E, Shi D, Wang H. CNN2 silencing inhibits colorectal cancer development through promoting ubiquitination of EGR1. Life Sci Alliance 2023; 6:e202201639. [PMID: 37188478 PMCID: PMC10185810 DOI: 10.26508/lsa.202201639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/17/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most commonly diagnosed malignant tumors of the digestive tract. H2-calponin (CNN2), an actin cytoskeleton-binding protein, is an isoform of the calponin protein family whose role in CRC is still unknown. Research based on clinical samples showed the up-regulation of CNN2 in CRC and its association with tumor development, metastasis, and poor prognosis of patients. Both in vitro loss-of-function and gain-of-function experiments showed that CNN2 participates in CRC development through influencing malignant cell phenotypes. In vivo, xenografts formed by CNN2 knockdown cells also showed a slower growth rate and smaller final tumors. Furthermore, EGR1 was identified as a downstream of CNN2, forming a complex with CNN2 and YAP1 and playing an essential role in the CNN2-induced regulation of CRC development. Mechanistically, CNN2 knockdown down-regulated EGR1 expression through enhancing its ubiquitination, thus decreasing its protein stability in a YAP1-dependent manner. In summary, CNN2 plays an EGR1-dependent promotion role in the development and progression of CRC, which may be a promising therapeutic target for CRC treatment.
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Affiliation(s)
- Jinghu He
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Xiaohong Yang
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Chuansen Zhang
- Department of Anatomy, Naval Medical University, Shanghai, China
| | - Ang Li
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Wei Wang
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Junjie Xing
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Jifu E
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Xiaodong Xu
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Hao Wang
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Enda Yu
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
| | - Debing Shi
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hantao Wang
- Department of General Surgery, Changhai HospitalAffiliated to Navy Medical University, Shanghai, China
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Słoka J, Madej M, Strzalka-Mrozik B. Molecular Mechanisms of the Antitumor Effects of Mesalazine and Its Preventive Potential in Colorectal Cancer. Molecules 2023; 28:5081. [PMID: 37446747 DOI: 10.3390/molecules28135081] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/18/2023] [Accepted: 06/27/2023] [Indexed: 07/15/2023] Open
Abstract
Chemoprevention is one of the ways to fight colorectal cancer, which is a huge challenge in oncology. Numerous pieces of evidence indicate that chronic inflammation in the course of Crohn's disease or ulcerative colitis (UC) is a significant cancer risk factor. Epidemiologic studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs), including mesalazine, has beneficial effects on colitis-associated colorectal cancer. Mesalazine is a first-line therapy for UC and is also widely used for maintaining remission in UC. Data showed that mesalazine has antiproliferative properties associated with cyclooxygenase (COX) inhibition but can also act through COX-independent pathways. This review summarizes knowledge about mesalazine's molecular mechanisms of action and chemopreventive effect by which it could interfere with colorectal cancer cell proliferation and survival.
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Affiliation(s)
- Joanna Słoka
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Marcel Madej
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
| | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland
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Surien O, Masre SF, Basri DF, Ghazali AR. Potential Chemopreventive Role of Pterostilbene in Its Modulation of the Apoptosis Pathway. Int J Mol Sci 2023; 24:ijms24119707. [PMID: 37298657 DOI: 10.3390/ijms24119707] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2023] [Revised: 04/08/2023] [Accepted: 04/21/2023] [Indexed: 06/12/2023] Open
Abstract
Cancer incidence keeps increasing every year around the world and is one of the leading causes of death worldwide. Cancer has imposed a major burden on the human population, including the deterioration of physical and mental health as well as economic or financial loss among cancer patients. Conventional cancer treatments including chemotherapy, surgery, and radiotherapy have improved the mortality rate. However, conventional treatments have many challenges; for example, drug resistance, side effects, and cancer recurrence. Chemoprevention is one of the promising interventions to reduce the burden of cancer together with cancer treatments and early detection. Pterostilbene is a natural chemopreventive compound with various pharmacological properties such as anti-oxidant, anti-proliferative, and anti-inflammatory properties. Moreover, pterostilbene, due to its potential chemopreventive effect on inducing apoptosis in eliminating the mutated cells or preventing the progression of premalignant cells to cancerous cells, should be explored as a chemopreventive agent. Hence, in the review, we discuss the role of pterostilbene as a chemopreventive agent against various types of cancer via its modulation of the apoptosis pathway at the molecular levels.
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Affiliation(s)
- Omchit Surien
- Center for Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Siti Fathiah Masre
- Center for Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Dayang Fredalina Basri
- Center for Diagnostic, Therapeutic & Investigative Studies (CODTIS), Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
| | - Ahmad Rohi Ghazali
- Center for Toxicology and Health Risk Studies (CORE), Faculty of Health Sciences, Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 50300, Malaysia
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Mraz KA, Hodan R, Rodgers-Fouche L, Arora S, Balaguer F, Guillem JG, Jeter JM, Kanth P, Li D, Liska D, Melson J, Perez K, Ricker C, Shirts BH, Vilar E, Katona BW, Dominguez-Valentin M. Current chemoprevention approaches in Lynch syndrome and Familial adenomatous polyposis: a global clinical practice survey. Front Oncol 2023; 13:1141810. [PMID: 37293588 PMCID: PMC10247284 DOI: 10.3389/fonc.2023.1141810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 05/02/2023] [Indexed: 06/10/2023] Open
Abstract
Background International chemoprevention preferences and approaches in Lynch syndrome (LS) and APC-associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored. Aim To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey. Results Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use. Conclusion Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.
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Affiliation(s)
- Kathryn A. Mraz
- Department of Genetics, Grey Genetics, Brooklyn, NY, United States
- Research Department, Center for Genomic Interpretation, Sandy, UT, United States
| | - Rachel Hodan
- Cancer Genetics, Stanford Health Care, Palo Alto, CA, United States
| | - Linda Rodgers-Fouche
- Center for Cancer Risk Assessment, Massachusetts General Hospital, Boston, MA, United States
| | - Sanjeevani Arora
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Jose G. Guillem
- Division of Gastrointestinal Surgery, University of North Carolina-Chapel Hill, Chapel Hill, NC, United States
| | - Joanne M. Jeter
- Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States
| | - Priyanka Kanth
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC, United States
| | - Dan Li
- Department of Gastroenterology, Kaiser Permanente Medical Center, Santa Clara, CA, United States
| | - David Liska
- Department of Colorectal Surgery and Sanford R. Weiss MD Center for Hereditary Colorectal Neoplasia, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, United States
| | - Joshua Melson
- Division of Gastroenterology, University of Arizona Cancer Center, Tucson, AZ, United States
| | - Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA, United States
| | - Charite Ricker
- Division of Medical Oncology, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Brian H. Shirts
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Bryson W. Katona
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo, Norway
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Rong K, He Q, Chen S, Yu Y, Mei L, Mi Y, Mu L, Zhu M, Nan M, Zhang X, Wan Z, Huang H, Zheng P. The mechanism of vitamin D3 in preventing colorectal cancer through network pharmacology. Front Pharmacol 2023; 14:1192210. [PMID: 37266156 PMCID: PMC10230033 DOI: 10.3389/fphar.2023.1192210] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 05/05/2023] [Indexed: 06/03/2023] Open
Abstract
Objective: Colorectal cancer (CRC) is a common cancer that cannot be detected at an early stage and is a major challenge in oncology research. Studies have shown that vitamin D3 has some anti-cancer and preventive effects on colorectal cancer, but the exact anti-cancer mechanism is not clear. We applied the relevant research methods of network pharmacology to speculate and validate the possible potential pharmacological mechanisms of vitamin D3 for the prevention of colorectal cancer, and to provide more theoretical support for the clinical anticancer effects of vitamin D3. Methods: The relevant targets for vitamin D3 and CRC were obtained from the database of drug and disease targets, respectively. The target of vitamin D3 and the target of colorectal cancer were taken to intersect to obtain common targets. Then, the PPI network was constructed. In addition, the pathways of drug-disease interactions were predicted by GO and KEGG enrichment analysis. Finally, the obtained results were verified to ensure the reliability of the experiments. Results: 51 targets of vitamin D3 for the prevention of colorectal cancer were obtained. The 10 core targets were obtained from the PPI network. The 10 core targets include: ALB, SRC, MMP9, PPARG, HSP90AA1, IGF1, EGFR, MAPK1, MAP2K1 and IGF1R. The core targets were further validated by molecular docking and animal experiments. The results suggest that vitamin D3 plays a key role in the prevention of CRC through core targets, PI3K-Akt pathway, HIF-1 pathway, and FoxO pathway. Conclusion: This study will provide more theoretical support for vitamin D3 to reduce the incidence of CRC and is important to explore more pharmacological effects of vitamin D3.
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Affiliation(s)
- Kang Rong
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Qingmin He
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shu Chen
- The First Clinical Medical School of Henan University of Chinese Medicine, Zhengzhou, China
| | - Yong Yu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lu Mei
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Mi
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liufan Mu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mingyang Zhu
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengjiao Nan
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoyang Zhang
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhaoyang Wan
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Huang Huang
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengyuan Zheng
- Henan Key Laboratory of Helicobacter Pylori and Microbiota and Gastrointestinal Cancer, Marshall B. J. Medical Research Center of Zhengzhou University, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Wong CC, Yu J. Gut microbiota in colorectal cancer development and therapy. Nat Rev Clin Oncol 2023:10.1038/s41571-023-00766-x. [PMID: 37169888 DOI: 10.1038/s41571-023-00766-x] [Citation(s) in RCA: 252] [Impact Index Per Article: 126.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/13/2023] [Indexed: 05/13/2023]
Abstract
Colorectal cancer (CRC) is one of the commonest cancers globally. A unique aspect of CRC is its intimate association with the gut microbiota, which forms an essential part of the tumour microenvironment. Research over the past decade has established that dysbiosis of gut bacteria, fungi, viruses and Archaea accompanies colorectal tumorigenesis, and these changes might be causative. Data from mechanistic studies demonstrate the ability of the gut microbiota to interact with the colonic epithelia and immune cells of the host via the release of a diverse range of metabolites, proteins and macromolecules that regulate CRC development. Preclinical and some clinical evidence also underscores the role of the gut microbiota in modifying the therapeutic responses of patients with CRC to chemotherapy and immunotherapy. Herein, we summarize our current understanding of the role of gut microbiota in CRC and outline the potential translational and clinical implications for CRC diagnosis, prevention and treatment. Emphasis is placed on how the gut microbiota could now be better harnessed by developing targeted microbial therapeutics as chemopreventive agents against colorectal tumorigenesis, as adjuvants for chemotherapy and immunotherapy to boost drug efficacy and safety, and as non-invasive biomarkers for CRC screening and patient stratification. Finally, we highlight the hurdles and potential solutions to translating our knowledge of the gut microbiota into clinical practice.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
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Li J, Li X, Zhou X, Yang L, Sun H, Kong L, Yan G, Han Y, Wang X. In Vivo Metabolite Profiling of DMU-212 in Apc Min/+ Mice Using UHPLC-Q/Orbitrap/LTQ MS. Molecules 2023; 28:3828. [PMID: 37175240 PMCID: PMC10180202 DOI: 10.3390/molecules28093828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2023] [Revised: 04/22/2023] [Accepted: 04/27/2023] [Indexed: 05/15/2023] Open
Abstract
3,4,5,4'-Trans-tetramethoxystilbene (Synonyms: DMU-212) is a resveratrol analogue with stronger antiproliferative activity and more bioavailability. However, the metabolite characterization of this component remains insufficient. An efficient strategy was proposed for the comprehensive in vivo metabolite profiling of DMU-212 after oral administration in ApcMin/+ mice based on the effectiveness of the medicine. Ultra-high performance liquid chromatography-quadrupole/orbitrap/linear ion trap mass spectrometry (UHPLC-Q/Orbitrap/LTQ MS) in the AcquireXTM intelligent data acquisition mode, combining the exact mass and structural information, was established for the profiling and identification of the metabolites of DMU-212 in vivo, and the possible metabolic pathways were subsequently proposed after the oral dose of 240mg/kg for 3 weeks in the colorectal adenoma (CRA) spontaneous model ApcMin/+ mice. A total of 63 metabolites of DMU-212 were tentatively identified, including 48, 48, 34 and 28 metabolites in the ApcMin/+ mice's intestinal contents, liver, serum, and colorectal tissues, respectively. The metabolic pathways, including demethylation, oxidation, desaturation, methylation, acetylation, glucuronide and cysteine conjugation were involved in the metabolism. Additionally, further verification of the representative active metabolites was employed using molecular docking analysis. This study provides important information for the further investigation of the active constituents of DMU-212 and its action mechanisms for CRA prevention.
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Affiliation(s)
- Jing Li
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Xinghua Li
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Xiaohang Zhou
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China
| | - Le Yang
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China
| | - Hui Sun
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Ling Kong
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Guangli Yan
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Ying Han
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
| | - Xijun Wang
- National Chinmedomics Research Center, National TCM Key Laboratory of Serum Pharmacochemistry, Metabolomics Laboratory, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Heping Road 24, Harbin 150040, China
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau 999078, China
- State Key Laboratory of Dampness Syndrome, The Second Affiliated Hospital Guangzhou University of Chinese Medicine, Dade Road 111, Guangzhou 510006, China
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Lepore Signorile M, Grossi V, Fasano C, Simone C. Colorectal Cancer Chemoprevention: A Dream Coming True? Int J Mol Sci 2023; 24:7597. [PMID: 37108756 PMCID: PMC10140862 DOI: 10.3390/ijms24087597] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 04/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the deadliest forms of cancer worldwide. CRC development occurs mainly through the adenoma-carcinoma sequence, which can last decades, giving the opportunity for primary prevention and early detection. CRC prevention involves different approaches, ranging from fecal occult blood testing and colonoscopy screening to chemoprevention. In this review, we discuss the main findings gathered in the field of CRC chemoprevention, focusing on different target populations and on various precancerous lesions that can be used as efficacy evaluation endpoints for chemoprevention. The ideal chemopreventive agent should be well tolerated and easy to administer, with low side effects. Moreover, it should be readily available at a low cost. These properties are crucial because these compounds are meant to be used for a long time in populations with different CRC risk profiles. Several agents have been investigated so far, some of which are currently used in clinical practice. However, further investigation is needed to devise a comprehensive and effective chemoprevention strategy for CRC.
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Affiliation(s)
- Martina Lepore Signorile
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Valentina Grossi
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Candida Fasano
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
| | - Cristiano Simone
- Medical Genetics, National Institute of Gastroenterology—IRCCS “Saverio de Bellis” Research Hospital, Castellana Grotte, 70013 Bari, Italy; (M.L.S.); (C.F.)
- Medical Genetics, Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
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Han JX, Tao ZH, Wang JL, Zhang L, Yu CY, Kang ZR, Xie Y, Li J, Lu S, Cui Y, Xu J, Zhao E, Wang M, Chen J, Wang Z, Liu Q, Chen HM, Su W, Zou TH, Zhou CB, Hong J, Chen H, Xiong H, Chen YX, Fang JY. Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer. Nat Microbiol 2023; 8:919-933. [PMID: 37069401 DOI: 10.1038/s41564-023-01363-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 47.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 03/16/2023] [Indexed: 04/19/2023]
Abstract
Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.
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Affiliation(s)
- Ji-Xuan Han
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Hang Tao
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ji-Lin Wang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lu Zhang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Chen-Yang Yu
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Ran Kang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuanhong Xie
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jialu Li
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shiyuan Lu
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun Cui
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jia Xu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Enhao Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jinxian Chen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui-Min Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenyu Su
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tian-Hui Zou
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Cheng-Bei Zhou
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jie Hong
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Haoyan Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hua Xiong
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology; Shanghai Institute of Digestive Disease; NHC Key Laboratory of Digestive Diseases; State Key Laboratory for Oncogenes and Related Genes; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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45
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Ma Y, Huangfu Y, Deng L, Wang P, Shen L, Zhou Y. High serum riboflavin is associated with the risk of sporadic colorectal cancer. Cancer Epidemiol 2023; 83:102342. [PMID: 36863217 DOI: 10.1016/j.canep.2023.102342] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/19/2023] [Accepted: 02/17/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Experimental results indicate that riboflavin is involved in tumorigenesis. Data regarding the relationship between riboflavin and colorectal cancer (CRC) are limited, and findings vary between observational studies. DESIGN This was a case-control retrospective study. OBJECTIVE This study aimed to evaluate the associations between serum riboflavin level and sporadic CRC risk. METHODS In total, 389 participants were enrolled in this study - including 83 CRC patients without family history and 306 healthy controls - between January 2020 and March 2021 at the Department of Colorectal Surgery and Endoscope Center at Xinhua Hospital, Shanghai Jiao Tong University School of Medicine. Age, sex, body mass index, history of polyps, disease conditions (e.g., diabetes), medications, and eight other vitamins were used as confounding factors. Adjusted smoothing spline plots, subgroup analysis, and multivariate logistic regression analysis were conducted to estimate the relative risk between serum riboflavin levels and sporadic CRC risk. After fully adjusting for the confounding factors, an increased risk of colorectal cancer was suggested for individuals with higher levels of serum riboflavin (OR = 1.08 (1.01, 1.15), p = 0.03) in a dose-response relationship. CONCLUSIONS Our results support the hypothesis that higher levels of riboflavin may play a role in facilitating colorectal carcinogenesis. The finding of high levels of circulating riboflavin in patients with CRC warrants further investigation.
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Affiliation(s)
- Yanhui Ma
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai 200092, China
| | - Yuchan Huangfu
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lin Deng
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Ping Wang
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lisong Shen
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Faculty of Medical Laboratory Science, College of Health Science and Technology, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China; Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai 200092, China.
| | - Yunlan Zhou
- Department of Laboratory Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
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46
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Jackson K, Samaddar S, Markiewicz MA, Bansal A. Vaccination-Based Immunoprevention of Colorectal Tumors: A Primer for the Clinician. J Clin Gastroenterol 2023; 57:246-252. [PMID: 36730670 PMCID: PMC9911105 DOI: 10.1097/mcg.0000000000001808] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Colorectal cancer (CRC) continues to be a significant public health problem worldwide. CRC screening programs have reduced the incidence rates of CRCs but still suffer from the problems of missed lesions and interval cancers. Chemopreventive strategies against CRC would benefit high-risk populations but trials testing synthetic and naturally occurring compounds have not yielded a front runner. Immune mechanisms promoting cancer have been modulated to develop immunotherapy for cancer treatment that has revolutionized cancer management, but could also be applied to cancer interception, that is, cancer immunoprevention. Cancer immunoprevention refers to approaches that can enhance the immune system, either directly or by removing natural breaks such as immune checkpoints, to survey and destroy tumor cells. In this primer, we aim to explain the concepts behind vaccine-based cancer immunoprevention. Multiple cancer vaccines have been tried in advanced cancer populations, but most have failed primarily because of an immunosuppressive environment that accompanies advanced cancers. Preventive vaccines in immunocompetent hosts may have a better clinical response compared with therapeutic vaccines in immunosuppressed hosts. The first randomized controlled trial testing the mucin1 vaccine against CRC in the prevention setting has been successfully completed. For the benefit of the clinician, we briefly discuss important concepts related to the workings of preventive vaccines. Prevention with vaccines is a highly attractive approach because of the potential for highly targeted therapy with minimal side effects that could theoretically provide lifelong protection.
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Affiliation(s)
- Katy Jackson
- Department of Medicine, The University of Kansas Health System
| | | | - Mary A. Markiewicz
- Department of Microbiology, Molecular Genetics and Immunology, The University of Kansas Medical Center
| | - Ajay Bansal
- Division of Gastroenterology and Hepatology
- The University of Kansas Cancer Center, Kansas City, KS
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47
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Witonsky D, Bielski MC, Li J, Lawrence KM, Mendoza IN, Usman H, Kupfer SS. Genomic and epigenomic responses to aspirin in human colonic organoids. Physiol Genomics 2023; 55:101-112. [PMID: 36645669 PMCID: PMC10069959 DOI: 10.1152/physiolgenomics.00070.2022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 01/17/2023] Open
Abstract
Aspirin (ASA) is a proven chemoprotective agent for colorectal cancer, though mechanisms underlying these effects are incompletely understood. Human organoids are an ideal system to study genomic and epigenomic host-environment interactions. We use human colonic organoids to profile ASA responses on genome-wide gene expression and chromatin accessibility. Human colonic organoids from one individual were cultured and treated in triplicate with 3 mM ASA or vehicle control (DMSO) for 24 h. Gene expression and chromatin accessibility were measured using RNA- and ATAC-sequencing, respectively. Differentially expressed genes were analyzed using DESeq2. Top genes were validated by qPCR. Gene set enrichment was performed by SetRank. Differentially accessible peaks were analyzed using DiffBind and edgeR. Peak annotation and differential transcription factor motifs were determined by HOMER and diffTF. The results showed robust transcriptional responses to ASA with significant enrichment for fatty acid oxidation and peroxisome proliferator-activated receptor (PPAR) signaling that were validated in independent organoid lines. A large number of differentially accessible chromatin regions were found in response to ASA with significant enrichment for Fos, Jun, and Hnf transcription factor motifs. Integrated analysis of epigenomic and genomic treatment responses highlighted gene regions that could mediate ASA's specific effects in the colon including those involved in chemoprotection and/or toxicity. Assessment of chromatin accessibility and transcriptional responses to ASA yielded new observations about genome-wide effects in the colon facilitated by application of human colonic organoids. This framework can be applied to study colonic ASA responses between individuals and populations in future studies.
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Affiliation(s)
- David Witonsky
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Margaret C Bielski
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Jinchao Li
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Kristi M Lawrence
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Ishmael N Mendoza
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Hina Usman
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Sonia S Kupfer
- Section of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Chicago, Chicago, Illinois
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48
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Jiang J, Li A, Lai X, Zhang H, Wang C, Wang H, Li L, Liu Y, Xie L, Yang C, Zhang C, Lu S, Li Y. Correlation between Metabolite of Prostaglandin E2 and the incidence of colorectal adenomas. Front Oncol 2023; 13:1068469. [PMID: 36923425 PMCID: PMC10009184 DOI: 10.3389/fonc.2023.1068469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 02/13/2023] [Indexed: 03/02/2023] Open
Abstract
Colorectal cancer is a common malignancy, and the incidence and mortality rates continue to rise. An important factor in the emergence of inflammation-induced colorectal carcinogenesis is elevated cyclooxygenase-2. Prostaglandin E2 (PGE2) over-production is frequently equated with cyclooxygenase-2 gene over-expression. PGE2 can be assessed by measuring the level of prostaglandin's main metabolite, PGE-M, in urine. Colorectal adenoma is a precancerous lesion that can lead to colorectal cancer. We conducted research to evaluate the association between urinary levels of the PGE-M and the risk of colorectal adenomas. In a western Chinese population, we identified 152 cases of adenoma and 152 controls patients without polyps. Adenoma cases were categorized into control, low-risk and high-risk groups. There was no significant change in PGE-M levels, between the control group and the low-risk adenoma group. In the high-risk group, the PGE-M levels were 23% higher than the control group. When compared to people with the lowest urine PGE-M levels (first quartile), people with greater urinary PGE-M levels had a higher chance of developing high-risk colorectal adenomas, with an adjusted odds ratio (95% CI) of 1.65 (0.76-3.57) in the fourth quartile group, (p= 0.013). We conclude urinary PGE-M is associated with the risk of developing high-risk adenomas. Urinary PGE-M level may be used as a non-invasive indicator for estimating cancer risk.
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Affiliation(s)
- Jia Jiang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Anjie Li
- Department of Medicine-Cardiovascular, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Xiaolian Lai
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Hanqun Zhang
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Chonghong Wang
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Huimin Wang
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Libo Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Yuncong Liu
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
| | - Lu Xie
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Can Yang
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Cui Zhang
- Zunyi Medical University, Zunyi, China
| | - Shuoyan Lu
- Department of Digestive, People's Hospital of Songtao Miao Autonomous County, Tongren, China
| | - Yong Li
- Department of Oncology, Guizhou Provincial People’s Hospital, Guiyang, China
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Zhou G, Lv X, Zhong X, Ying W, Li W, Feng Y, Xia Q, Li J, Jian S, Leng Z. Suspension culture strategies to enrich colon cancer stem cells. Oncol Lett 2023; 25:116. [PMID: 36844615 PMCID: PMC9950343 DOI: 10.3892/ol.2023.13702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 11/16/2021] [Indexed: 02/09/2023] Open
Abstract
How to efficiently obtain high-purity cancer stem cells (CSCs) has been the basis of CSC research, but the optimal conditions for serum-free suspension culture of CSCs are still unclear. The present study aimed to define the optimal culture medium composition and culture time for the enrichment of colon CSCs via suspension culture. Suspension cell cultures of colon cancer DLD-1 cells were prepared using serum-free medium (SFM) containing variable concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to produce spheroids. Culture times were set at 10, 20 and 30 days. A total of nine different concentrations of EGF and bFGF were added to SFM to generate nine experimental groups. The proportions of CD44+, CD133+, and CD44+CD133+ double-positive spheroid cells were detected via flow cytometry. mRNA expression of stemness-, epithelial-mesenchymal transition- and Wnt/β-catenin pathway-associated genes was determined via reverse transcription-quantitative PCR. Self-renewal ability was evaluated by a sphere-forming assay. Tumorigenesis was studied in vitro using a colony formation assay and in vivo via subcutaneous cell injection in nude mice. It was found that the highest expression proportions of CD133+ and CD44+ spheroid cells were observed in group (G)9 (20 ng/ml EGF + 20 ng/ml bFGF) at 30 days (F=123.554 and 99.528, respectively, P<0.001), CD133+CD44+ cells were also observed in G9 at 30 days (and at 10 days in G3 and 20 days in G6; F=57.897, P<0.001). G9 at 30 days also displayed the highest expression of Krüppel-like factor 4, leucine-rich repeat-containing G protein-coupled receptor 5, CD44, CD133, Vimentin and Wnt-3a (F=22.682, 25.401, 3.272, 7.852, 13.331 and 17.445, respectively, P<0.001) and the lowest expression of E-cadherin (F=10.851, P<0.001). G9 at 30 days produced the highest yield of cell spheroids, as determined by a sphere forming assay (F=19.147, P<0.001); colony formation assays also exhibited the greatest number of colonies derived from G9 spheroids at 30 days (F=60.767, P<0.01), which also generated the largest mean tumor volume in the subcutaneous tumorigenesis xenograft model (F=12.539, P<0.01). In conclusion, 20 ng/ml EGF + 20 ng/ml bFGF effectively enriched colon CSCs when added to suspension culture for 30 days, and conferred the highest efficiency compared with other combinations.
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Affiliation(s)
- Guojun Zhou
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaojiang Lv
- Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Xiaorong Zhong
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Wei Ying
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Wenbo Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Yanchao Feng
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Qinghua Xia
- Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China
| | - Jianshui Li
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Shunhai Jian
- Department of Pathology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Professor Shunhai Jian, Department of Pathology, Affiliated Hospital of North Sichuan Medical College, 63 Wenhua Road, Nanchong, Sichuan 637000, P.R. China, E-mail:
| | - Zhengwei Leng
- Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Cancer Stem Cells Research Center, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China,Correspondence to: Professor Zhengwei Leng, Department of Hepatobiliary Surgery, Affiliated Hospital of North Sichuan Medical College, 234, Fujiang Road, Nanchong, Sichuan 637000, P.R. China, E-mail:
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50
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De S, Paul S, Manna A, Majumder C, Pal K, Casarcia N, Mondal A, Banerjee S, Nelson VK, Ghosh S, Hazra J, Bhattacharjee A, Mandal SC, Pal M, Bishayee A. Phenolic Phytochemicals for Prevention and Treatment of Colorectal Cancer: A Critical Evaluation of In Vivo Studies. Cancers (Basel) 2023; 15:993. [PMID: 36765950 PMCID: PMC9913554 DOI: 10.3390/cancers15030993] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/30/2023] [Accepted: 01/30/2023] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed and second leading cause of cancer-related death worldwide. Limitations with existing treatment regimens have demanded the search for better treatment options. Different phytochemicals with promising anti-CRC activities have been reported, with the molecular mechanism of actions still emerging. This review aims to summarize recent progress on the study of natural phenolic compounds in ameliorating CRC using in vivo models. This review followed the guidelines of the Preferred Reporting Items for Systematic Reporting and Meta-Analysis. Information on the relevant topic was gathered by searching the PubMed, Scopus, ScienceDirect, and Web of Science databases using keywords, such as "colorectal cancer" AND "phenolic compounds", "colorectal cancer" AND "polyphenol", "colorectal cancer" AND "phenolic acids", "colorectal cancer" AND "flavonoids", "colorectal cancer" AND "stilbene", and "colorectal cancer" AND "lignan" from the reputed peer-reviewed journals published over the last 20 years. Publications that incorporated in vivo experimental designs and produced statistically significant results were considered for this review. Many of these polyphenols demonstrate anti-CRC activities by inhibiting key cellular factors. This inhibition has been demonstrated by antiapoptotic effects, antiproliferative effects, or by upregulating factors responsible for cell cycle arrest or cell death in various in vivo CRC models. Numerous studies from independent laboratories have highlighted different plant phenolic compounds for their anti-CRC activities. While promising anti-CRC activity in many of these agents has created interest in this area, in-depth mechanistic and well-designed clinical studies are needed to support the therapeutic use of these compounds for the prevention and treatment of CRC.
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Affiliation(s)
- Samhita De
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Sourav Paul
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | - Anirban Manna
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | | | - Koustav Pal
- Jawaharlal Institute Post Graduate Medical Education and Research, Puducherry 605 006, India
| | - Nicolette Casarcia
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
| | - Arijit Mondal
- Department of Pharmaceutical Chemistry, M.R. College of Pharmaceutical Sciences and Research, Balisha 743 234, India
| | - Sabyasachi Banerjee
- Department of Pharmaceutical Chemistry, Gupta College of Technological Sciences, Asansol 713 301, India
| | - Vinod Kumar Nelson
- Department of Pharmacology, Raghavendra Institute of Pharmaceutical Education and Research, Anantapur 515 721, India
| | - Suvranil Ghosh
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Joyita Hazra
- Department of Biotechnology, Indian Institute of Technology, Chennai 600 036, India
| | - Ashish Bhattacharjee
- Department of Biotechnology, National Institute of Technology, Durgapur 713 209, India
| | | | - Mahadeb Pal
- Division of Molecular Medicine, Bose Institute, Kolkata 700 054, India
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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