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Tao ZH, Han JX, Xu J, Zhao E, Wang M, Wang Z, Lin XL, Xiao XY, Hong J, Chen H, Chen YX, Chen HM, Fang JY. Screening of patient-derived organoids identifies mitophagy as a cell-intrinsic vulnerability in colorectal cancer during statin treatment. Cell Rep Med 2025; 6:102039. [PMID: 40154491 PMCID: PMC12047522 DOI: 10.1016/j.xcrm.2025.102039] [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: 09/22/2024] [Revised: 01/26/2025] [Accepted: 03/03/2025] [Indexed: 04/01/2025]
Abstract
Statins, commonly used to lower cholesterol, are associated with improved prognosis in colorectal cancer (CRC), though their effectiveness varies. This study investigates the anti-cancer effects of atorvastatin in CRC using patient-derived organoids (PDOs) and PDO-derived xenograft (PDOX) models. Our findings reveal that atorvastatin induces mitochondrial dysfunction, leading to apoptosis in cancer cells. In response, cancer cells induce mitophagy to clear damaged mitochondria, enhancing survival and reducing statin efficacy. Analysis of a clinical cohort confirms mitophagy's role in diminishing statin effectiveness. Importantly, inhibiting mitophagy significantly enhances the anti-cancer effects of atorvastatin in CRC PDOs, xenograft models, and azoxymethane (AOM)-dextran sulfate sodium (DSS) mouse models. These findings identify mitophagy as a critical pro-survival mechanism in CRC during statin treatment, providing insights into the variable responses observed in epidemiological studies. Targeting this vulnerability through combination therapy can elicit potent therapeutic responses.
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Affiliation(s)
- Zhi-Hang Tao
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ji-Xuan Han
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory of Systems Medicine for Cancer, 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
| | - Zheng Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Lin Lin
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiu-Ying Xiao
- Department of Oncology, 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 of Systems Medicine for Cancer, 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 of Systems Medicine for Cancer, 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 of Systems Medicine for Cancer, 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 of Systems Medicine for Cancer, 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 of Systems Medicine for Cancer, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
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Azizi L, Hausman H, Meyer AK, Wong M, Pajonk F. The Mevalonate Pathway in the Radiation Response of Cancer. Int J Radiat Oncol Biol Phys 2025:S0360-3016(25)00278-0. [PMID: 40194746 DOI: 10.1016/j.ijrobp.2025.03.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 02/14/2025] [Accepted: 03/19/2025] [Indexed: 04/09/2025]
Abstract
The mevalonate (MVA) pathway plays a critical role in cholesterol biosynthesis, protein prenylation, and metabolic reprogramming, all of which contribute to cancer progression and therapy resistance. Targeting the MVA pathway with statins and other inhibitors has shown promise in preclinical studies; however, clinical outcomes remain controversial, raising concerns about translating these findings into effective treatments. Additionally, the interaction between the MVA pathway and radiation therapy (RT) is not yet fully understood, as RT upregulates the pathway, which can enhance tumor cell survival. This review summarizes the current literature on MVA pathway inhibition in cancer therapy, focusing on its potential to enhance the efficacy of RT. A better understanding of the pathway's role in radiation responses will be essential to translate combination therapies that target this pathway.
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Affiliation(s)
- Linda Azizi
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.
| | - Hannah Hausman
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Alexandra K Meyer
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Matthew Wong
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
| | - Frank Pajonk
- Department of Radiation Oncology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Department of Neurosurgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California; Jonsson Comprehensive Cancer Center at University of California, Los Angeles, Los Angeles, California
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Kim E, Erazo-Oliveras A, Muñoz-Vega M, Fuentes NR, Salinas ML, George MJ, Zoh RS, Hensel ME, Patil BS, Ivanov I, Turner ND, Chapkin RS. Diet therapy abates mutant APC and KRas effects by reshaping plasma membrane cholesterol nanodomains. Biophys J 2025; 124:508-527. [PMID: 39709523 PMCID: PMC11866957 DOI: 10.1016/j.bpj.2024.12.020] [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: 05/10/2024] [Revised: 12/01/2024] [Accepted: 12/18/2024] [Indexed: 12/23/2024] Open
Abstract
Cholesterol-enriched plasma membrane domains are known to serve as signaling platforms in a diverse array of cellular processes. However, the link between cholesterol homeostasis and mutant APC-KRas-associated colorectal tumorigenesis remains to be established. Thus, we investigated the impact of Apc-Kras on 1) colonocyte plasma membrane cholesterol homeostasis, order, and receptor nanoclustering, 2) colonocyte cell proliferation, and 3) whether these effects are modulated by select membrane active dietaries (MADs). We observed that oncogenic APC-KRas increased membrane order by perturbing cholesterol homeostasis when cell proliferation is upregulated, in part by altering the expression of genes associated with cholesterol influx, export and de novo synthesis in mouse colorectal cancer (CRC) models and CRC patients. In addition, oncogene-induced loss of cholesterol homeostasis altered Fzd7, LRP6, and KRas cluster structure/organization. Notably, we show that the combination of chemoprotective MADs, i.e., n-3 PUFAs and curcumin, reduced colonic membrane free cholesterol, order, receptor cluster size, cell proliferation, and the number of dysplastic foci in mutant APC-KRas models. This work highlights the dynamic shaping of plasma membrane organization during colon tumorigenesis and the utility of membrane-targeted cancer therapy.
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Affiliation(s)
- Eunjoo Kim
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas
| | - Alfredo Erazo-Oliveras
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Nutrition, Texas A&M University, College Station, Texas; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, Texas
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Nutrition, Texas A&M University, College Station, Texas; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, Texas
| | - Natividad R Fuentes
- Department of Cancer Biology, MD Anderson Cancer Center, University of Texas, Houston, Texas
| | - Michael L Salinas
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Nutrition, Texas A&M University, College Station, Texas; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, Texas
| | - Miranda J George
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas
| | - Roger S Zoh
- Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington, Indiana
| | - Martha E Hensel
- Keeling Center for Comparative Medicine and Research, MD Anderson Cancer Center, University of Texas, Bastrop, Texas
| | - Bhimanagouda S Patil
- Vegetable and Fruit Improvement Center, Department of Horticultural Science, Texas A&M University, College Station, Texas
| | - Ivan Ivanov
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, Texas
| | - Nancy D Turner
- Department of Nutrition, Texas A&M University, College Station, Texas
| | - Robert S Chapkin
- Program in Integrative Nutrition & Complex Diseases, Texas A&M University, College Station, Texas; Department of Nutrition, Texas A&M University, College Station, Texas; CPRIT Regional Center of Excellence in Cancer Research, Texas A&M University, College Station, Texas.
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Zhang R, Zhang L, Fan S, Wang L, Wang B, Wang L. Squalene monooxygenase (SQLE) protects ovarian cancer cells from ferroptosis. Sci Rep 2024; 14:22646. [PMID: 39349544 PMCID: PMC11442994 DOI: 10.1038/s41598-024-72506-9] [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: 12/27/2023] [Accepted: 09/09/2024] [Indexed: 10/02/2024] Open
Abstract
Altered cholesterol metabolism has been linked to a poor prognosis in various types of cancer. Cholesterol oxidation can lead to lipid peroxidation, membrane damage, and cell death. Ferroptosis is a regulated form of cell death characterized by the accumulation of lipid peroxides, which significantly inhibits the growth of ovarian cancer cells. SQLE is the primary enzyme responsible for catalyzing cholesterol lipid synthesis and is notably expressed in ovarian cancer tissues and cells. This study aims to investigate the role of squalene monooxygenase (SQLE) in ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was assessed using qRT-PCR, Western Blot, and immunohistochemistry. The association between SQLE and ferroptosis was demonstrated through analysis of TCGA and GTEx databases, TMT protein sequencing, as well as validation by qRT-PCR, Western Blot, immunofluorescence, ROS detection, and lipid peroxide detection. Animal experiments further confirmed the relationship between SQLE and ferroptosis in ovarian cancer. The protein and mRNA expression of SQLE was found to be upregulated in both ovarian cancer tissues and cell lines. Decreased SQLE expression led to ferroptosis in ovarian cancer cells, thereby increasing their sensitivity to ferroptosis inducers. Our research demonstrates that SQLE is significantly upregulated in both ovarian cancer tissues and cells. The overexpression of SQLE in ovarian cancer may facilitate tumorigenesis by conferring resistance to ferroptosis, thus shedding light on potential novel therapeutic strategies for ovarian cancer.
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Affiliation(s)
- Rong Zhang
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China
| | - Lingmei Zhang
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China
| | - Sizhe Fan
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China
| | - Liangliang Wang
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China
| | - Beibei Wang
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China
| | - Lihua Wang
- The First Affiliated Hospital of Bengbu Medical College, 287 Changhuai Road, Longzih, Bengbu, Anhui, China.
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Xu Y, Che H, Liu J, Ye P. Association of metformin and statin uses with the prognosis of colon cancer: a meta-analysis. Eur J Cancer Prev 2024; 33:414-424. [PMID: 38215022 DOI: 10.1097/cej.0000000000000872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2024]
Abstract
BACKGROUND Metformin and statins are commonly used globally for the treatment of type 2 diabetes mellitus and dyslipidemia, respectively. Recently, multiple novel pathways have been discovered, which may contribute to the treatment of various types of cancer. Several meta-analysis studies have reported that the use of metformin or statins is associated with a lower risk of colon cancer compared to nonusers. In this study, our aim was to perform a meta-analysis and investigate the prognostic roles of these two medications in colon cancer. METHODS To identify relevant articles, literature searches were performed in the PubMed and Web of Science databases using a combination of keywords related to metformin, statins and colon cancer prognosis until August 2023. The study utilized STATA 12.0 software (Stata Corporation, College Station, Texas, USA) to compute all the hazard ratios (HRs) and 95% confidence intervals (CIs) regarding the association between metformin or statin uses and prognostic-related outcomes. RESULTS Our analysis revealed that the use of metformin was associated with a significantly lower overall mortality of colon cancer (HR = 0.63; 95% CI = 0.51-0.77; I2 = 94.9%; P < 0.001), as well as lower cancer-specific mortality of colon cancer (HR = 0.68; 95% CI = 0.50-0.94; I2 = 91.9%; P < 0.001). Similarly, the use of statins was also associated with a lower overall mortality of colon cancer (HR = 0.68; 95% CI = 0.60-0.78; I2 = 93.8%; P < 0.001), as well as a lower cancer-specific mortality of colon cancer (HR = 0.74; 95% CI = 0.67-0.81; I2 = 82.2%; P < 0.001). CONCLUSION Our meta-analysis study suggests that statins and metformin may have potential as adjuvant agents with significant benefits in the prognosis of colon cancer.
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Affiliation(s)
- Yanyan Xu
- Department of Anus and Colorectal Surgery, Shaoxing People's Hospital, Shaoxing, China
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Wang R, Yan Q, Liu X, Wu J. Unraveling lipid metabolism reprogramming for overcoming drug resistance in melanoma. Biochem Pharmacol 2024; 223:116122. [PMID: 38467377 DOI: 10.1016/j.bcp.2024.116122] [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: 01/17/2024] [Revised: 02/27/2024] [Accepted: 03/07/2024] [Indexed: 03/13/2024]
Abstract
Cutaneous melanoma is the deadliest form of skin cancer, and its incidence is continuing to increase worldwide in the last decades. Traditional therapies for melanoma can easily cause drug resistance, thus the treatment of melanoma remains a challenge. Various studies have focused on reversing the drug resistance. As tumors grow and progress, cancer cells face a constantly changing microenvironment made up of different nutrients, metabolites, and cell types. Multiple studies have shown that metabolic reprogramming of cancer is not static, but a highly dynamic process. There is a growing interest in exploring the relationship between melanoma andmetabolic reprogramming, one of which may belipid metabolism. This review frames the recent research progresses on lipid metabolism in melanoma.In addition, we emphasize the dynamic ability of metabolism during tumorigenesis as a target for improving response to different therapies and for overcoming drug resistance in melanoma.
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Affiliation(s)
- Ruilong Wang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Qin Yan
- Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Xiao Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
| | - Jinfeng Wu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China.
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Erazo-Oliveras A, Muñoz-Vega M, Salinas ML, Wang X, Chapkin RS. Dysregulation of cellular membrane homeostasis as a crucial modulator of cancer risk. FEBS J 2024; 291:1299-1352. [PMID: 36282100 PMCID: PMC10126207 DOI: 10.1111/febs.16665] [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: 06/18/2022] [Revised: 09/09/2022] [Accepted: 10/24/2022] [Indexed: 11/07/2022]
Abstract
Cellular membranes serve as an epicentre combining extracellular and cytosolic components with membranous effectors, which together support numerous fundamental cellular signalling pathways that mediate biological responses. To execute their functions, membrane proteins, lipids and carbohydrates arrange, in a highly coordinated manner, into well-defined assemblies displaying diverse biological and biophysical characteristics that modulate several signalling events. The loss of membrane homeostasis can trigger oncogenic signalling. More recently, it has been documented that select membrane active dietaries (MADs) can reshape biological membranes and subsequently decrease cancer risk. In this review, we emphasize the significance of membrane domain structure, organization and their signalling functionalities as well as how loss of membrane homeostasis can steer aberrant signalling. Moreover, we describe in detail the complexities associated with the examination of these membrane domains and their association with cancer. Finally, we summarize the current literature on MADs and their effects on cellular membranes, including various mechanisms of dietary chemoprevention/interception and the functional links between nutritional bioactives, membrane homeostasis and cancer biology.
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Affiliation(s)
- Alfredo Erazo-Oliveras
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Mónica Muñoz-Vega
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Michael L. Salinas
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Xiaoli Wang
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
| | - Robert S. Chapkin
- Program in Integrative Nutrition and Complex Diseases; Texas A&M University; College Station, Texas, 77843; USA
- Department of Nutrition; Texas A&M University; College Station, Texas, 77843; USA
- Center for Environmental Health Research; Texas A&M University; College Station, Texas, 77843; USA
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Gupta A, Das D, Taneja R. Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors. Cancers (Basel) 2024; 16:1313. [PMID: 38610991 PMCID: PMC11010992 DOI: 10.3390/cancers16071313] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 03/19/2024] [Accepted: 03/24/2024] [Indexed: 04/14/2024] Open
Abstract
Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.
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Affiliation(s)
| | | | - Reshma Taneja
- Department of Physiology, Healthy Longevity and NUS Centre for Cancer Research Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore 117593, Singapore
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Yoo J, Jeon J, Baik M, Kim J. Risk of thromboembolism according to statin treatment in patients with cancer: A nationwide nested case-control study. Thromb Res 2024; 235:32-40. [PMID: 38295599 DOI: 10.1016/j.thromres.2024.01.016] [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: 10/02/2023] [Revised: 01/12/2024] [Accepted: 01/19/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Thromboembolic events exhibit increased prevalence in patients with cancer and can negatively affect prognoses. We investigated whether statin treatment would reduce thromboembolic risk in patients with cancer. METHODS We conducted a nested case-control study using a Korean nationwide health claims database. The study included patients newly diagnosed with cancer without a prior history of cardiovascular disease between 2014 and 2016. Cases who developed arterial thromboembolism (ATE) or venous thromboembolism (VTE) after cancer diagnosis and three individually matched controls were selected. Conditional logistic regression was used to assess the association between thromboembolic risk and statin therapy after cancer diagnosis. RESULTS Among 455,805 newly diagnosed patients with cancer followed for a mean of 4.3 ± 2.0 years, 22,249 patients developed thromboembolic events (ATE: 6341, VTE: 15,908), resulting in an incidence rate of 1133 per 100,000 person-years. The nested case-control study included 21,289 cases with thromboembolic events and 63,867 controls. Statin use was less frequent in the case group (18.0 % vs. 23.7 %). Statin treatment was associated with a lower risk of thromboembolic events (adjusted odds ratio [OR] 0.70; 95 % confidence interval [CI] 0.67-0.73). This association was observed for both ATE (adjusted OR 0.68; 95 % CI 0.63-0.74) and VTE (adjusted OR 0.71; 95 % CI 0.67-0.75). Longer statin use and better adherence were also associated with lower risk for thromboembolic events. Statin treatment was significantly associated with fewer thromboembolic events in most cancer types. CONCLUSIONS Statin use was associated with lower risk for thromboembolic events in patients newly diagnosed with cancer.
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Affiliation(s)
- Joonsang Yoo
- Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea
| | - Jimin Jeon
- Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea
| | - Minyoul Baik
- Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea
| | - Jinkwon Kim
- Department of Neurology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Republic of Korea; Institute for Innovation in Digital Healthcare, Yonsei University Health System, Seoul, Republic of Korea.
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Hong Y, Zhang L, Lin W, Yang Y, Cao Z, Feng X, Yu Z, Gao Y. Transcriptome Sequencing Unveils a Molecular-Stratification-Predicting Prognosis of Sarcoma Associated with Lipid Metabolism. Int J Mol Sci 2024; 25:1643. [PMID: 38338920 PMCID: PMC10855378 DOI: 10.3390/ijms25031643] [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: 10/14/2023] [Revised: 01/05/2024] [Accepted: 01/16/2024] [Indexed: 02/12/2024] Open
Abstract
Sarcomas are heterogeneous connective tissue malignancies that have been historically categorized into soft tissue and bone cancers. Although multimodal therapies are implemented, many sarcoma subtypes are still difficult to treat. Lipids play vital roles in cellular activities; however, ectopic levels of lipid metabolites have an impact on tumor recurrence, metastasis, and drug resistance. Thus, precision therapies targeting lipid metabolism in sarcoma need to be explored. In this study, we performed a comprehensive analysis of molecular stratification based on lipid metabolism-associated genes (LMAGs) using both public datasets and the data of patients in our cohort and constructed a novel prognostic model consisting of squalene epoxidase (SQLE) and tumor necrosis factor (TNF). We first integrated information on gene expression profile and survival outcomes to divide TCGA sarcoma patients into high- and low-risk subgroups and further revealed the prognosis value of the metabolic signature and immune infiltration of patients in both groups, thus proposing various therapeutic recommendations for sarcoma. We observed that the low-risk sarcoma patients in the TCGA-SARC cohort were characterized by high proportions of immune cells and increased expression of immune checkpoint genes. Subsequently, this lipid metabolic signature was validated in four external independent sarcoma datasets including the CHCAMS cohort. Notably, SQLE, a rate-limiting enzyme in cholesterol biosynthesis, was identified as a potential therapeutic target for sarcoma. Knockdown of SQLE substantially inhibited cell proliferation and colony formation while promoting the apoptosis of sarcoma cells. Terbinafine, an inhibitor of SQLE, displayed similar tumor suppression capacity in vitro. The prognostic predictive model and the potential drug target SQLE might serve as valuable hints for further in-depth biological, diagnostic, and therapeutic exploration of sarcoma.
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Affiliation(s)
- Yuheng Hong
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Weihao Lin
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yannan Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Cao
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiaoli Feng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
| | - Yibo Gao
- Central Laboratory & Shenzhen Key Laboratory of Epigenetics and Precision Medicine for Cancers, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518116, China
- Laboratory of Translational Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- State 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
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11
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Fu X, Wang Z. DHCR24 in Tumor Diagnosis and Treatment: A Comprehensive Review. Technol Cancer Res Treat 2024; 23:15330338241259780. [PMID: 38847653 PMCID: PMC11162140 DOI: 10.1177/15330338241259780] [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] [Indexed: 06/10/2024] Open
Abstract
As an important nutrient in the human body, cholesterol can not only provide structural components for the body's cells, but also can be transformed into a variety of active substances to regulate cell signaling pathways. As an important cholesterol synthase, DHCR24 participates in important regulatory processes in the body. The application of DHCR24 in tumor clinical diagnosis and treatment also attracts much attention. This article reviews the structure and regulatory characteristics of DHCR24, and the research of DHCR24 on tumor progression. We summarize the possible mechanisms of DHCR24 promoting tumor progression through reactive oxygen species (ROS), p53, Ras and PI3K-AKT pathways. Through our review, we hope to provide more research ideas and reference value for the application of DHCR24 in tumor prevention and treatment.
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Affiliation(s)
- Xin Fu
- Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhaosong Wang
- National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
- Laboratory Animal Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
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12
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Muta Y, Linares JF, Martinez-Ordoñez A, Duran A, Cid-Diaz T, Kinoshita H, Zhang X, Han Q, Nakanishi Y, Nakanishi N, Cordes T, Arora GK, Ruiz-Martinez M, Reina-Campos M, Kasashima H, Yashiro M, Maeda K, Albaladejo-Gonzalez A, Torres-Moreno D, García-Solano J, Conesa-Zamora P, Inghirami G, Metallo CM, Osborne TF, Diaz-Meco MT, Moscat J. Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis. Nat Commun 2023; 14:8075. [PMID: 38092754 PMCID: PMC10719313 DOI: 10.1038/s41467-023-43690-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/16/2023] [Indexed: 12/17/2023] Open
Abstract
The metabolic and signaling pathways regulating aggressive mesenchymal colorectal cancer (CRC) initiation and progression through the serrated route are largely unknown. Although relatively well characterized as BRAF mutant cancers, their poor response to current targeted therapy, difficult preneoplastic detection, and challenging endoscopic resection make the identification of their metabolic requirements a priority. Here, we demonstrate that the phosphorylation of SCAP by the atypical PKC (aPKC), PKCλ/ι promotes its degradation and inhibits the processing and activation of SREBP2, the master regulator of cholesterol biosynthesis. We show that the upregulation of SREBP2 and cholesterol by reduced aPKC levels is essential for controlling metaplasia and generating the most aggressive cell subpopulation in serrated tumors in mice and humans. Since these alterations are also detected prior to neoplastic transformation, together with the sensitivity of these tumors to cholesterol metabolism inhibitors, our data indicate that targeting cholesterol biosynthesis is a potential mechanism for serrated chemoprevention.
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Affiliation(s)
- Yu Muta
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Juan F Linares
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Anxo Martinez-Ordoñez
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Angeles Duran
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Tania Cid-Diaz
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Hiroto Kinoshita
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Xiao Zhang
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Qixiu Han
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Naoko Nakanishi
- Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Thekla Cordes
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Department of Bioinformatics and Biochemistry, Braunschweig Integrated Centre of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, 38106, Germany
| | - Gurpreet K Arora
- Cell and Molecular Biology of Cancer Program, Sanford Burnham Prebys, La Jolla, CA, 92037, USA
| | - Marc Ruiz-Martinez
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Miguel Reina-Campos
- School of Biological Sciences, Department of Molecular Biology, University of California San Diego, San Diego, CA, USA
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka city, 545-8585, Japan
| | - Ana Albaladejo-Gonzalez
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Daniel Torres-Moreno
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - José García-Solano
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Pathology, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Pablo Conesa-Zamora
- Department of Histology and Pathology, Faculty of Life Sciences, Universidad Católica de Murcia (UCAM), 30107, Murcia, Spain
- Department of Clinical Analysis, Santa Lucía General University Hospital (HGUSL), Calle Mezquita sn, 30202, Cartagena, Spain
| | - Giorgio Inghirami
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA
| | - Christian M Metallo
- Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Timothy F Osborne
- Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children's Hospital, St, Petersburg, FL, USA
| | - Maria T Diaz-Meco
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
| | - Jorge Moscat
- Department of Pathology and Laboratory Medicine and Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.
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13
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Zhang S, Shi YN, Gu J, He P, Ai QD, Zhou XD, Wang W, Qin L. Mechanisms of dihydromyricetin against hepatocellular carcinoma elucidated by network pharmacology combined with experimental validation. PHARMACEUTICAL BIOLOGY 2023; 61:1108-1119. [PMID: 37462387 DOI: 10.1080/13880209.2023.2234000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 06/03/2023] [Accepted: 07/03/2023] [Indexed: 07/21/2023]
Abstract
CONTEXT Dihydromyricetin (DMY) is extracted from vine tea, a traditional Chinese herbal medicine with anti-cancer, liver protection, and cholesterol-lowering effects. OBJECTIVE This study investigated the mechanism of DMY against hepatocellular carcinoma (HCC). MATERIALS AND METHODS Potential DMY, HCC, and cholesterol targets were collected from relevant databases. PPI networks were created by STRING. Then, the hub genes of co-targets, screened using CytoHubba. GO and KEGG pathway enrichment, were performed by Metascape. Based on the above results, a series of in vitro experiments were conducted by using 40-160 μM DMY for 24 h, including transwell migration/invasion assay, western blotting, and Bodipy stain assay. RESULTS Network pharmacology identified 98 common targets and 10 hub genes of DMY, HCC, and cholesterol, and revealed that the anti-HCC effect of DMY may be related to the positive regulation of lipid rafts. Further experiments confirmed that DMY inhibits the proliferation, migration, and invasion of HCC cells and reduces their cholesterol levels in vitro. The IC50 is 894.4, 814.4, 467.8, 1,878.8, 151.8, and 156.9 μM for 97H, Hep3B, Sk-Hep1, SMMC-7721, HepG2, and Huh7 cells, respectively. In addition, DMY downregulates the expression of lipid raft markers (CAV1, FLOT1), as well as EGFR, PI3K, Akt, STAT3, and Erk. DISCUSSION AND CONCLUSION The present study reveals that DMY suppresses EGFR and its downstream pathways by reducing cholesterol to disrupt lipid rafts, thereby inhibiting HCC, which provides a promising candidate drug with low toxicity for the treatment of HCC.
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Affiliation(s)
- Shuo Zhang
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Ya-Ning Shi
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- Science and Technology Innovation Center, Hunan University of Chinese Medicine, Changsha, China
| | - Jia Gu
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Peng He
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Qi-Di Ai
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Xu-Dong Zhou
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Material Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Wei Wang
- TCM and Ethnomedicine Innovation & Development International Laboratory, Innovative Material Medical Research Institute, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
| | - Li Qin
- Laboratory of Stem Cell Regulation with Chinese Medicine and Its Application, School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China
- Institutional Key Laboratory of Vascular Biology and Translational Medicine in Hunan Province, Hunan University of Chinese Medicine, Changsha, China
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14
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Zhang P, Shi Y, Xu Y, Liang Y, Huang C, Zhong D, Zhang Z, Yu Y, Zhang Z, Zhang J, Yu L, Zuo Y, Wang X, Niu H. A Nano-Autophagy Inhibitor Triggering Reciprocal Feedback Control of Cholesterol Depletion for Solid Tumor Therapy. Adv Healthc Mater 2023; 12:e2302020. [PMID: 37767984 DOI: 10.1002/adhm.202302020] [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] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 09/04/2023] [Indexed: 09/29/2023]
Abstract
Solid tumors are characterized by enhanced metabolism of lipid, particularly cholesterol, inspiring the exploration of metabolic therapy through cholesterol oxidase (COD)-mediated cholesterol deprivation. However, the therapeutic efficacy of COD is limited due to the hypoxic tumor microenvironment and the protective autophagy triggered by cholesterol deprivation. Herein, a combination therapy for metabolically treating solid tumors through COD in conjunction with molybdenum oxide nanodots (MONDs), which serve as both potent oxygen generators and autophagy inhibitors, is reported. MONDs convert H2 O2 (arising from COD-mediated cholesterol oxidation) into O2 , which is then recycled by COD to form reciprocal feedback for cholesterol depletion. Concurrently, MONDs can overcome autophagy-induced therapeutic resistance frequently occurring in conventional nutrient deprivation therapy by activating AKT/mTOR pathway phosphorylation. Combination therapy in the xenograft model results in an ≈5-fold increase in therapeutic efficiency as compared with COD treatment alone. This functionally cooperative metabolic coupling strategy holds great promise as a novel polytherapy approach that will benefit patients with solid tumors.
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Affiliation(s)
- Pengfei Zhang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yanfeng Shi
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Yuanhong Xu
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Ye Liang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Chao Huang
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Di Zhong
- Department of Genetics and Cell Biology, Basic Medical College, Qingdao University, Qingdao, Shandong, 266071, China
| | - Zhilei Zhang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yongbo Yu
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Zhao Zhang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Jianfeng Zhang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Lei Yu
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Yuhui Zuo
- Institute of Biomedical Engineering, College of Life Sciences, Qingdao University, Qingdao, 266071, China
| | - Xinsheng Wang
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Haitao Niu
- Department of Urology, the Affiliated Hospital of Qingdao University, Qingdao, 266003, China
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15
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He X, Lan H, Jin K, Liu F. Cholesterol in colorectal cancer: an essential but tumorigenic precursor? Front Oncol 2023; 13:1276654. [PMID: 38023258 PMCID: PMC10655112 DOI: 10.3389/fonc.2023.1276654] [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: 08/16/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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16
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Xiao M, Xu J, Wang W, Zhang B, Liu J, Li J, Xu H, Zhao Y, Yu X, Shi S. Functional significance of cholesterol metabolism in cancer: from threat to treatment. Exp Mol Med 2023; 55:1982-1995. [PMID: 37653037 PMCID: PMC10545798 DOI: 10.1038/s12276-023-01079-w] [Citation(s) in RCA: 64] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 05/18/2023] [Accepted: 06/20/2023] [Indexed: 09/02/2023] Open
Abstract
Cholesterol is an essential structural component of membranes that contributes to membrane integrity and fluidity. Cholesterol homeostasis plays a critical role in the maintenance of cellular activities. Recently, increasing evidence has indicated that cholesterol is a major determinant by modulating cell signaling events governing the hallmarks of cancer. Numerous studies have shown the functional significance of cholesterol metabolism in tumorigenesis, cancer progression and metastasis through its regulatory effects on the immune response, ferroptosis, autophagy, cell stemness, and the DNA damage response. Here, we summarize recent literature describing cholesterol metabolism in cancer cells, including the cholesterol metabolism pathways and the mutual regulatory mechanisms involved in cancer progression and cholesterol metabolism. We also discuss various drugs targeting cholesterol metabolism to suggest new strategies for cancer treatment.
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Affiliation(s)
- Mingming Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Wei Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Jialin Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Hang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China
| | - Yingjun Zhao
- Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China.
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China.
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
- Shanghai Pancreatic Center Institute, Shanghai, 200032, China.
- Pancreatic Center Institute, Fudan University, Shanghai, 200032, China.
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17
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Nardi-Agmon I, Cohen G, Itzhaki Ben Zadok O, Steinberg DM, Kornowski R, Gerber Y. Cancer Incidence and Survival Among Patients Following an Acute Coronary Syndrome. Am J Cardiol 2023; 202:50-57. [PMID: 37423174 DOI: 10.1016/j.amjcard.2023.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 05/17/2023] [Accepted: 06/06/2023] [Indexed: 07/11/2023]
Abstract
To examine the role of acute coronary syndrome (ACS) in subsequent cancer incidence and survival, 2 cohorts of patients hospitalized with ACS were matched 1:1 by gender and age (±3 years) to cardiovascular disease (CVD)-free patients from 2 cycles of the Israeli National Health and Nutrition Surveys. Data on all-cause mortality were retrieved from national registries. Cancer incidence with death treated as a competing event, overall survival, and mortality risk associated with incident cancer as a time-dependent variable were compared between the groups. Our cohort included 2,040 cancer-free matched pairs (mean age of 60±14 years, 42.5% women). Despite higher rates of smokers and patients with hypertension and diabetes mellitus, 10-year cumulative cancer incidence was significantly lower in the ACS group compared with CVD-free group (8.0% vs 11.4%, p = 0.02). This decreased risk was more pronounced in women than men (pinteraction = 0.05). Although being free of CVD meant a significant (p <0.001) survival advantage in the general cohort, this advantage faded once a cancer diagnosis was made (p = 0.80). After adjustment for sociodemographic and clinical covariates, the hazard ratios for mortality associated with a cancer diagnosis were 2.96 (95% confidence interval: 2.36 to 3.71) in the ACS group versus 6.41 (95% confidence interval: 4.96 to 8.28) in the CVD-free group (Pinteraction<0.001). In conclusion, in this matched cohort, ACS was associated with a lower risk of cancer and mitigated the excess risk of mortality associated with cancer incidence.
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Affiliation(s)
- Inbar Nardi-Agmon
- Department of Cardiology, Rabin Medical Center, Tel Aviv, Israel; Department of Cardiovascular Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Gali Cohen
- Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Stanley Steyer Institute for Cancer Epidemiology and Research, Tel Aviv University, Tel Aviv, Israel
| | - Osnat Itzhaki Ben Zadok
- Department of Cardiology, Rabin Medical Center, Tel Aviv, Israel; Department of Cardiovascular Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - David M Steinberg
- Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel
| | - Ran Kornowski
- Department of Cardiology, Rabin Medical Center, Tel Aviv, Israel; Department of Cardiovascular Medicine, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yariv Gerber
- Department of Epidemiology and Preventive Medicine, School of Public Health, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Stanley Steyer Institute for Cancer Epidemiology and Research, Tel Aviv University, Tel Aviv, Israel; Lilian and Marcel Pollak Chair in Biological Anthropology, Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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18
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Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, Bungau AF, Radu AF. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomed Pharmacother 2023; 164:115015. [PMID: 37321055 DOI: 10.1016/j.biopha.2023.115015] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023] Open
Abstract
Among the most extensively researched processes in the development and treatment of cancer is inflammatory condition. Although acute inflammation is essential for the wound healing and reconstruction of tissues that have been damaged, chronic inflammation may contribute to the onset and growth of a number of diseases, including cancer. By disrupting the signaling processes of cells, which result in cancer induction, invasion, and development, a variety of inflammatory molecules are linked to the development of cancer. The microenvironment surrounding the tumor is greatly influenced by inflammatory cells and their subsequent secretions, which also contribute significantly to the tumor's growth, survivability, and potential migration. These inflammatory variables have been mentioned in several publications as prospective diagnostic tools for anticipating the onset of cancer. Targeting inflammation with various therapies can reduce the inflammatory response and potentially limit or block the proliferation of cancer cells. The scientific medical literature from the past three decades has been studied to determine how inflammatory chemicals and cell signaling pathways related to cancer invasion and metastasis are related. The current narrative review updates the relevant literature while highlighting the specifics of inflammatory signaling pathways in cancer and their possible therapeutic possibilities.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, 9300 Bloemfontein, South Africa.
| | - Vishal Kumar Deb
- Dietetics and Nutrition Technology Division, CSIR Institute of Himalayan Bioresource Technology, 176061 Palampur, Himanchal Pradesh, India
| | - Deen Bandhu Dimri
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology BHU, Varanasi 221005, Uttar Pradesh, India
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Alexa Florina Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei-Flavius Radu
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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19
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Altered serum lipid levels are associated with prognosis of diffuse large B cell lymphoma and influenced by utility of rituximab. Ann Hematol 2023; 102:393-402. [PMID: 36670246 DOI: 10.1007/s00277-023-05092-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/31/2022] [Indexed: 01/22/2023]
Abstract
Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma, and the prognosis of the disease varied. This research aims to investigate the impact of serum lipid level on the outcome of DLBCL patients and their interaction with rituximab (RTX). Data of newly diagnosed DLBCL in the third affiliated hospital of Soochow University were retrospectively collected. Baseline serum lipid levels, clinical data, and survival information were simultaneously recorded. Data of healthy controls were collected with age matching. Serum lipid levels significantly differed for the patients. All were transformed into categorical variables for the analysis of survival. During a median follow-up of 58 months, 32.8% patients died. Univariate analysis revealed all serum lipid indicators were associated with overall survival (OS); all except for total cholesterol (TC) and apolipoprotein B (apoB) showed significant impact on progression-free survival (PFS). Multivariable analysis confirmed the adverse effect of triglyceride (TG) on PFS (P = 0.013) and favorable impact of high-density lipoprotein (HDL) on OS (P = 0.003). For cases treated without RTX, apolipoprotein A (apoA) had independent favorable effect on both PFS (P = 0.004) and OS (P = 0.001). Comparably, for patients who received RTX, HDL showed remarkably predictive value of PFS (P = 0.011) and OS (P = 0.019). In conclusion, the abnormal serum lipids occurred throughout the course of DLBCL, and the associations of serum lipids and the prognosis of the disease were interfered by RTX. Trial registration: 2022()CL033; June 26, 2022, retrospectively registered.
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Raskov H, Gaggar S, Tajik A, Orhan A, Gögenur I. Metabolic switch in cancer - Survival of the fittest. Eur J Cancer 2023; 180:30-51. [PMID: 36527974 DOI: 10.1016/j.ejca.2022.11.025] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
Cell metabolism is characterised by the highly coordinated conversion of nutrients into energy and biomass. In solid cancers, hypoxia, nutrient deficiencies, and tumour vasculature are incompatible with accelerated anabolic growth and require a rewiring of cancer cell metabolism. Driver gene mutations direct malignant cells away from oxidation to maximise energy production and biosynthesis while tumour-secreted factors degrade peripheral tissues to fuel disease progression and initiate metastasis. As it is vital to understand cancer cell metabolism and survival mechanisms, this review discusses the metabolic switch and current drug targets and clinical trials. In the future, metabolic markers may be included when phenotyping individual tumours to improve the therapeutic opportunities for personalised therapy.
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Affiliation(s)
- Hans Raskov
- Center for Surgical Science, Zealand University Hospital, Køge, 4600, Denmark.
| | - Shruti Gaggar
- Center for Surgical Science, Zealand University Hospital, Køge, 4600, Denmark
| | - Asma Tajik
- Center for Surgical Science, Zealand University Hospital, Køge, 4600, Denmark
| | - Adile Orhan
- Center for Surgical Science, Zealand University Hospital, Køge, 4600, Denmark; Department of Clinical Oncology, Zealand University Hospital, Roskilde, 4000, Denmark
| | - Ismail Gögenur
- Center for Surgical Science, Zealand University Hospital, Køge, 4600, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark
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21
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Zhou Y, Shao Y, Hu W, Zhang J, Shi Y, Kong X, Jiang J. A novel long noncoding RNA SP100-AS1 induces radioresistance of colorectal cancer via sponging miR-622 and stabilizing ATG3. Cell Death Differ 2023; 30:111-124. [PMID: 35978049 PMCID: PMC9883267 DOI: 10.1038/s41418-022-01049-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 07/27/2022] [Accepted: 07/28/2022] [Indexed: 02/01/2023] Open
Abstract
Although radiotherapy is an essential modality in the treatment of colorectal cancer (CRC), the incidence of radioresistance remains high clinically. Long noncoding RNAs (lncRNAs) reportedly play critical roles in CRC radioresistance by regulating genes or proteins at the transcriptional or post-translational levels. This study aimed to identify novel lncRNAs involved in radioresistance. We found that SP100-AS1 (lncRNA targeting antisense sequence of SP100 gene) was upregulated in radioresistant CRC patient tissues using RNA-seq analysis. Importantly, knockdown of SP100-AS1 significantly reduced radioresistance, cell proliferation, and tumor formation in vitro and in vivo. Mechanistically, mass spectrometry and bioinformatics analyses were used to identify the interacting proteins and microRNAs of SP100-AS1, respectively. Moreover, SP100-AS1 was found to interact with and stabilize ATG3 protein through the ubiquitination-dependent proteasome pathway. In addition, it could serve as a sponge for miR-622, which targeted ATG3 mRNA and affected autophagic activity. Thus, lncRNA SP100-AS1 could act as a radioresistance factor in CRC patients via RNA sponging and protein stabilizing mechanisms. In conclusion, the present study indicates that SP100-AS1/miR-622/ATG3 axis contributes to radioresistance and autophagic activity in CRC patients, suggesting it has huge prospects as a therapeutic target for improving CRC response to radiation therapy.
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Affiliation(s)
- You Zhou
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, China
- Institute of Cell Therapy, Soochow University, Changzhou, 213003, China
| | - Yingjie Shao
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Wenwei Hu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Jinping Zhang
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China
| | - Yufang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University Medical College, Suzhou, 215123, China
| | - Xiangyin Kong
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jingting Jiang
- Tumor Biological Diagnosis and Treatment Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China.
- Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, 213003, China.
- Institute of Cell Therapy, Soochow University, Changzhou, 213003, China.
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22
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Ejam SS, Saleh RO, Catalan Opulencia MJ, Najm MA, Makhmudova A, Jalil AT, Abdelbasset WK, Al-Gazally ME, Hammid AT, Mustafa YF, Sergeevna SE, Karampoor S, Mirzaei R. Pathogenic role of 25-hydroxycholesterol in cancer development and progression. Future Oncol 2022; 18:4415-4442. [PMID: 36651359 DOI: 10.2217/fon-2022-0819] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 12/06/2022] [Indexed: 01/19/2023] Open
Abstract
Cholesterol is an essential lipid that serves several important functions, including maintaining the homeostasis of cells, acting as a precursor to bile acid and steroid hormones and preserving the stability of membrane lipid rafts. 25-hydroxycholesterol (25-HC) is a cholesterol derivative that may be formed from cholesterol. 25-HC is a crucial component in various biological activities, including cholesterol metabolism. In recent years, growing evidence has shown that 25-HC performs a critical function in the etiology of cancer, infectious diseases and autoimmune disorders. This review will summarize the latest findings regarding 25-HC, including its biogenesis, immunomodulatory properties and role in innate/adaptive immunity, inflammation and the development of various types of cancer.
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Affiliation(s)
| | - Raed Obaid Saleh
- Department of Pharmacy, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Mazin Aa Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Aziza Makhmudova
- Department of Social Sciences & Humanities, Samarkand State Medical Institute, Samarkand, Uzbekistan
- Department of Scientific Affairs, Tashkent State Dental Institute, Makhtumkuli Street 103, Tashkent, 100047, Uzbekistan
| | - Abduladheem Turki Jalil
- Medical Laboratories Techniques Department, Al-Mustaqbal University College, Babylon, Hilla, 51001, Iraq
| | - Walid Kamal Abdelbasset
- Department of Health & Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia
- Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | | | - Ali Thaeer Hammid
- Computer Engineering Techniques Department, Faculty of Information Technology, Imam Ja'afar Al-Sadiq University, Baghdad, Iraq
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Sergushina Elena Sergeevna
- National Research Ogarev Mordovia State University, 68 Bolshevitskaya Street, Republic of Mordovia, Saransk, 430005, Russia
| | - Sajad Karampoor
- Gastrointestinal & Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Rasoul Mirzaei
- Venom & Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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Identification of ABCA5 among ATP-Binding Cassette Transporter Family as a New Biomarker for Colorectal Cancer. JOURNAL OF ONCOLOGY 2022; 2022:3399311. [PMID: 35783152 PMCID: PMC9242773 DOI: 10.1155/2022/3399311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/25/2022] [Indexed: 12/24/2022]
Abstract
Background The increasing incidence and mortality of colorectal cancer (CRC) urgently requires updated biomarkers. The ABC transporter family is a widespread family of membrane-bound proteins involved in the transportation of substrates associated with ATP hydrolysis, including metabolites, amino acids, peptides and proteins, sterols and lipids, organic and inorganic ions, sugars, metals, and drugs. They play an important role in the maintenance of homeostasis in the body. Purpose This study aims to search for new markers in the ABC transporter gene family for diagnostic and prognostic purposes through data mining of The Cancer Genome Atlas (TCGA) and GEO (Gene Expression Omnibus) datasets. Methods A total of 980 samples, including 684 CRC patients and 296 controls from five different datasets, were included for analysis. The construction of the PPI (protein-protein interaction) network and pathway analysis were performed in STRING database and DAVID (database for annotation, visualization, and integrated discovery), respectively. In addition, GSEA (gene set enrichment analysis) and WGCNA (weighted gene co-expression network analysis) were also used for functional analysis. Results After several rounds of screening and validation, only the ABCB5 gene was retained among the 49 genes. Conclusions The results demonstrated that ABCA5 expression is reduced in CRC and patients with high ABCA5 expression have better OS, which can provide guidance for better management and treatment of CRC in the future.
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Use of Hypolipidemic Drugs and the Risk of Second Primary Malignancy in Colorectal Cancer Patients. Cancers (Basel) 2022; 14:cancers14071699. [PMID: 35406471 PMCID: PMC8997159 DOI: 10.3390/cancers14071699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 11/25/2022] Open
Abstract
Simple Summary Hypolipidemic drugs are among the most frequently prescribed medications in the Western world. Since many studies have indicated their role in carcinogenesis, this work aimed to investigate their association with the occurrence of a second primary malignancy in colorectal cancer survivors. The overall incidence of a second neoplasm was not linked to hypolipidemic medication; however, a subgroup analysis revealed a lower incidence of secondary neoplasia in statin users. When stratified by cancer types, a significant increase in gastric and bladder cancer was detected among colorectal cancer patients using hypolipidemic drugs. Survival outcomes in patients with early-stage colorectal carcinoma who suffered second cancer were significantly worse if treated with hypolipidemic drugs. Although our results do not provide evidence for a causative relationship between hypolipidemic medication and carcinogenesis, these correlations might steer the direction of tertiary prevention care towards specific risk factors shared between cardiovascular diseases and cancer. Abstract An increasing number of studies has brought evidence of the protective role of statin use against different types of cancer. However, data on their association with second primary malignancies (SPMs) are lacking. The purpose of this study was to determine the role of hypolipidemic treatment in the prevention of second primary cancer in colorectal cancer (CRC) survivors. We conducted a retrospective single-institution study of 1401 patients with newly diagnosed colorectal cancer from January 2003 to December 2016, with follow-up until December 2020. An SPM was detected in 301 patients (21%), and the incidence was significantly lower in patients with statin medication. However, stratification by cancer types revealed an increased incidence of bladder and gastric cancer in hypolipidemic users. A Kaplan−Meier analysis of early-stage CRC survivors with an SPM showed a significant survival benefit in patients without a history of hypolipidemic treatment. Despite the protective role of statins on overall second cancer incidence, these data indicate that CRC survivors treated with hypolipidemic drugs should be screened more cautiously for SPMs, especially for gastric and bladder cancer.
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25
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Response Predictive Markers and Synergistic Agents for Drug Repositioning of Statins in Ovarian Cancer. Pharmaceuticals (Basel) 2022; 15:ph15020124. [PMID: 35215239 PMCID: PMC8880614 DOI: 10.3390/ph15020124] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/11/2022] [Accepted: 01/17/2022] [Indexed: 02/07/2023] Open
Abstract
In the field of drug repurposing, the use of statins for treating dyslipidemia is considered promising in ovarian cancer treatment based on epidemiological studies and basic research findings. Biomarkers should be established to identify patients who will respond to statin treatment to achieve clinical application. In the present study, we demonstrated that statins have a multifaceted mode of action in ovarian cancer and involve pathways other than protein prenylation. To identify biomarkers that predict the response to statins, we subjected ovarian cancer cells to microarray analysis and calculated Pearson’s correlation coefficients between gene expression and cell survival after statin treatment. The results showed that VDAC1 and LDLRAP1 were positively and negatively correlated with the response to statins, respectively. Histoculture drug response assays revealed that statins were effective in clinical samples. We also confirmed the synergistic effects of statins with paclitaxel and panobinostat and determined that statins are hematologically safe to administer to statin-treated mice. Future clinical trials based on the expression of the biomarkers identified in this study for repurposing statins for ovarian cancer treatment are warranted.
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26
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Colmenero J, Tabrizian P, Bhangui P, Pinato DJ, Rodríguez-Perálvarez ML, Sapisochin G, Bhoori S, Pascual S, Senzolo M, Al-Adra D, Herrero JI, Petrowsky H, Dawson LA, Hosni A, Kutzke JL, Gastaca M, Watt KD. De Novo Malignancy After Liver Transplantation: Risk Assessment, Prevention, and Management-Guidelines From the ILTS-SETH Consensus Conference. Transplantation 2022; 106:e30-e45. [PMID: 34905760 DOI: 10.1097/tp.0000000000003998] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
De novo malignancies (DNMs) following liver transplantation (LT) have been reported as 1 of the major causes of late mortality, being the most common cause of death in the second decade after LT. The overall incidence of DNMs is reported to be in the range of 3.1% to 14.4%, and the incidence is 2- to 3-fold higher in transplant recipients than in age- and sex-matched healthy controls. Long-term immunosuppressive therapy, which is the key in maintaining host tolerance and achieving good long-term outcomes, is known to contribute to a higher risk of DNMs. However, the incidence and type of DNM also depends on different risk factors, including patient demographics, cause of the underlying chronic liver disease, behavior (smoking and alcohol abuse), and pre-existing premalignant conditions. The estimated standardized incidence ratio for different DNMs is also variable. The International Liver Transplantation Society-Spanish Society of Liver Transplantation Consensus Conference working group on DNM has summarized and discussed the current available literature on epidemiology, risk factors, management, and survival after DNMs. Recommendations for screening and surveillance for specific tumors, as well as immunosuppression and cancer-specific management in patients with DNM, are summarized.
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Affiliation(s)
- Jordi Colmenero
- Liver Transplantation, Liver Unit Hospital Clínic Barcelona, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain
| | | | - Prashant Bhangui
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Delhi NCR, India
| | - David James Pinato
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Manuel L Rodríguez-Perálvarez
- Department of Hepatology and Liver Transplantation, Hospital Universitario Reina Sofía, University of Córdoba, IMIBIC, CIBERehd, Córdoba, Spain
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, ON, Canada
| | - Sherrie Bhoori
- HPB Surgery, Hepatology and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori di Milano, Milan, Italy
| | - Sonia Pascual
- Liver Unit, CIBERehd, ISABIAL, HGU Alicante, Alicante, Spain
| | - Marco Senzolo
- Multivisceral Transplant Unit, University Hospital of Padua, Padua, Italy
| | - David Al-Adra
- University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - J Ignacio Herrero
- Liver Unit, Clinica Universidad de Navarra, IdiSNA, CIBERehd, Pamplona, Spain
| | - Henrik Petrowsky
- Swiss HPB and Transplantation Center, Department of Surgery and Transplantation, University Hospital Zurich, Zurich, Switzerland
| | - Laura A Dawson
- Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, ON, Canada
| | - Ali Hosni
- Princess Margaret Cancer Centre/University Health Network, University of Toronto, Toronto, ON, Canada
| | | | - Mikel Gastaca
- Cruces University Hospital, Biocruces Bizkaia Health Research Institute, University of the Basque Country, Bilbao, Spain
| | - Kymberly D Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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27
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de Mey S, Dufait I, De Ridder M. Radioresistance of Human Cancers: Clinical Implications of Genetic Expression Signatures. Front Oncol 2021; 11:761901. [PMID: 34778082 PMCID: PMC8579106 DOI: 10.3389/fonc.2021.761901] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Although radiotherapy is given to more than 50% of cancer patients, little progress has been made in identifying optimal radiotherapy - drug combinations to improve treatment efficacy. Using molecular data from The Cancer Genome Atlas (TCGA), we extracted a total of 1016 cancer patients that received radiotherapy. The patients were diagnosed with head-and-neck (HNSC - 294 patients), cervical (CESC - 166 patients) and breast (BRCA - 549 patients) cancer. We analyzed mRNA expression patterns of 50 hallmark gene sets of the MSigDB collection, which we divided in eight categories based on a shared biological or functional process. Tumor samples were split into upregulated, neutral or downregulated mRNA expression for all gene sets using a gene set analysis (GSEA) pre-ranked analysis and assessed for their clinical relevance. We found a prognostic association between three of the eight gene set categories (Radiobiological, Metabolism and Proliferation) and overall survival in all three cancer types. Furthermore, multiple single associations were revealed in the other categories considered. To the best of our knowledge, our study is the first report suggesting clinical relevance of molecular characterization based on hallmark gene sets to refine radiation strategies.
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Affiliation(s)
- Sven de Mey
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Inès Dufait
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Mark De Ridder
- Department of Radiotherapy, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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Zhang S, Ding J, Wang J, Yin T, Zhang Y, Yang J. CXCL5 Downregulation in Villous Tissue Is Correlated With Recurrent Spontaneous Abortion. Front Immunol 2021; 12:717483. [PMID: 34603292 PMCID: PMC8486294 DOI: 10.3389/fimmu.2021.717483] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 08/30/2021] [Indexed: 11/18/2022] Open
Abstract
Recurrent spontaneous abortion (RSA) affects 5% of childbearing-age women worldwide. Inadequate trophoblast invasion is one of the main reasons for the development of RSA; however, the underlying molecular mechanisms for RSA have not been fully understood, and further explanation is urgently needed. C-X-C motif chemokine ligand 5 (CXCL5) is reported to contribute to the invasion of cancer cells, and its aberrant expression is associated with the cellular process of tumor pathology. Considering the high behavioral similarity between trophoblast cells and cancer cells, we hypothesized that CXCL5 may influence trophoblast invasion, and its expression levels in villous tissue may be correlated with RSA. In this study, we firstly investigated the CXCL5 expression in placental villous tissues of 15 RSA patients and 13 control patients, and the results showed that CXCL5 levels were significantly lower in villous tissue from RSA patients than those of the controls. Further in vitro experiments presented that recombinant human CXCL5 can enhance trophoblast migration, invasion, and epithelial-to-mesenchymal transition (EMT) process. We also demonstrated that CXCL5 exerted these effects on trophoblast cells through PI3K/AKT/ERK1/2 signaling pathway. In conclusion, these data indicate that CXCL5 downregulation in human villous tissue is correlated with RSA. Additionally, we found that estrogen, progesterone, human chorionic gonadotropin, and decidual stromal cells can regulate CXCL5 and chemokine receptor 2 (CXCR2) expression of trophoblast in a cell manner.
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Affiliation(s)
- Sainan Zhang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Jinli Ding
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Jiayu Wang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Tailang Yin
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
| | - Yan Zhang
- Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jing Yang
- Reproductive Medical Center, Renmin Hospital of Wuhan University & Hubei Clinic Research Center for Assisted Reproductive Technology and Embryonic Development, Wuhan, China
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Asif K, Memeo L, Palazzolo S, Frión-Herrera Y, Parisi S, Caligiuri I, Canzonieri V, Granchi C, Tuccinardi T, Rizzolio F. STARD3: A Prospective Target for Cancer Therapy. Cancers (Basel) 2021; 13:4693. [PMID: 34572920 PMCID: PMC8472075 DOI: 10.3390/cancers13184693] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 09/10/2021] [Indexed: 12/24/2022] Open
Abstract
Cancer is one of the major causes of death in developed countries and current therapies are based on surgery, chemotherapeutic agents, and radiation. To overcome side effects induced by chemo- and radiotherapy, in recent decades, targeted therapies have been proposed in second and even first lines. Targeted drugs act on the essential pathways involved in tumor induction, progression, and metastasis, basically all the hallmark of cancers. Among emerging pathways, the cholesterol metabolic pathway is a strong candidate for this purpose. Cancer cells have an accelerated metabolic rate and require a continuous supply of cholesterol for cell division and membrane renewal. Steroidogenic acute regulatory related lipid transfer (START) proteins are a family of proteins involved in the transfer of lipids and some of them are important in non-vesicular cholesterol transportation within the cell. The alteration of their expression levels is implicated in several diseases, including cancers. In this review, we report the latest discoveries on StAR-related lipid transfer protein domain 3 (STARD3), a member of the START family, which has a potential role in cancer, focusing on the structural and biochemical characteristics and mechanisms that regulate its activity. The role of the STARD3 protein as a molecular target for the development of cancer therapies is also discussed. As STARD3 is a key protein in the cholesterol movement in cancer cells, it is of interest to identify inhibitors able to block its activity.
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Affiliation(s)
- Kanwal Asif
- Department of Molecular Sciences and Nanosystems, PhD School in Science and Technology of Bio and Nanomaterials, Ca’ Foscari University of Venice, 30172 Venice, Italy;
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Lorenzo Memeo
- Department of Experimental Oncology, Mediterranean Institute of Oncology, 95029 Catania, Italy;
| | - Stefano Palazzolo
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Yahima Frión-Herrera
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Venice, Italy; or
| | - Salvatore Parisi
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Isabella Caligiuri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
| | - Vincenzo Canzonieri
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Carlotta Granchi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (T.T.)
| | - Tiziano Tuccinardi
- Department of Pharmacy, University of Pisa, 56126 Pisa, Italy; (C.G.); (T.T.)
| | - Flavio Rizzolio
- Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; (S.P.); (S.P.); (V.C.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Venice, Italy; or
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30
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Statin therapy and its association with long-term survival after colon cancer surgery. Surgery 2021; 171:890-896. [PMID: 34507829 DOI: 10.1016/j.surg.2021.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/23/2021] [Accepted: 08/01/2021] [Indexed: 01/20/2023]
Abstract
BACKGROUND The current study aims to address the clinical equipoise regarding the association of ongoing statin therapy at time of surgery with long-term postoperative mortality rates after elective, curative, surgical resections of colon cancer by analyzing data from a large validated national register. METHODS All adults with stage I to III colon cancer who underwent elective surgery with curative intent between January 2007 and October 2016 were retrieved from the Swedish Colorectal Cancer Register, a prospectively collected national register. Patients were identified as having ongoing statin therapy if they filled a prescription within 12 months pre- and postoperatively. Study outcomes included 5-year all-cause and cancer-specific postoperative mortality. To reduce the impact of confounding from covariates owing to nonrandomization, the inverse probability of treatment weighting method was used. Subsequently, Cox proportional hazards models were fitted to the weighted cohorts. RESULTS In total, 19,118 patients underwent elective surgery for colon cancer in the specified period, of whom 31% (5,896) had ongoing statin therapy. Despite being older, having a higher preoperative risk, and having more comorbidities, patients with statin therapy had a higher postoperative survival. After inverse probability of treatment weighting, patients with statin therapy displayed a significantly lower mortality risk up to 5 years after surgery for both all-cause (hazard ratio 0.68, 95% confidence interval 0.63-0.74, P < .001) and cancer-specific mortality (hazard ratio 0.76, 95% confidence interval 0.66-0.89, P < .001). CONCLUSION The results of this study indicate that statin therapy is associated with a sustained reduction in all-cause and cancer-specific mortality up to 5 years after elective colon cancer surgery. The findings warrant validation in future prospective clinical trials.
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31
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Li L, Cui N, Hao T, Zou J, Jiao W, Yi K, Yu W. Statins use and the prognosis of colorectal cancer: a meta-analysis. Clin Res Hepatol Gastroenterol 2021; 45:101588. [PMID: 33662632 DOI: 10.1016/j.clinre.2020.101588] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 11/09/2020] [Accepted: 11/24/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Previous observational studies regarding the prognostic value of statin on colorectal cancer (CRC) patients showed various results. METHODS Articles regarding the prognostic value of statin on CRC and published in English and before October 2020 were searched in the following databases: PubMed, Web of Science, EMBASE, Medline and Google Scholar. The multivariate hazard ratios (HRs) and their 95% confidence intervals (CI) were computed to explore associations between statins use and overall mortality or cancer-specific mortality of CRC. RESULTS The study included 5 retrospective case-control studies (including 475 statins users and 1925 no-statin users) and 11 prospective cohort studies (including 40659 statins users and 344459 no-statin users). The present study showed that statins use might be significantly associated with lower overall mortality in CRC with a random effects model (HR = 0.81, 95% CI 0.76 to 0.86, I2 = 61.9%, p value for Q test <0.001). In addition, statins use might be significantly associated with lower cancer-specific mortality in CRC with a random effects model (HR = 0.78, 95% CI 0.72 to 0.85, I2 = 57.3%, p value for Q test = 0.007). CONCLUSIONS In conclusion, the present study indicated that that statin use was a protective factor for CRC prognosis. However, the relationship between statins use and CRC prognosis requires repeated and large prospective studies to be verified.
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Affiliation(s)
- Liusheng Li
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Ning Cui
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Tengteng Hao
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Jianhua Zou
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wu Jiao
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Kangjun Yi
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China
| | - Wu Yu
- Department of Oncology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100091, China.
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Mahboobnia K, Pirro M, Marini E, Grignani F, Bezsonov EE, Jamialahmadi T, Sahebkar A. PCSK9 and cancer: Rethinking the link. Biomed Pharmacother 2021; 140:111758. [PMID: 34058443 DOI: 10.1016/j.biopha.2021.111758] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/17/2021] [Accepted: 05/20/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Cancer is emerging as a major problem globally, as it accounts for the second cause of death despite medical advances. According to epidemiological and basic studies, cholesterol is involved in cancer progression and there are abnormalities in cholesterol metabolism of cancer cells including prostate, breast, and colorectal carcinomas. However, the importance of cholesterol in carcinogenesis and thereby the role of cholesterol homeostasis as a therapeutic target is still a debated area in cancer therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, modulates cholesterol metabolism by attachment to the LDL receptor (LDLR) and reducing its recycling by targeting the receptor for lysosomal destruction. Published research has shown that PCSK9 is also involved in degradation of other LDLR family members namely very-low-density-lipoprotein receptor (VLDLR), lipoprotein receptor-related protein 1 (LRP-1), and apolipoprotein E receptor 2 (ApoER2). As a result, this protein represents an interesting therapeutic target for the treatment of hypercholesterolemia. Interestingly, clinical trials on PCSK9-specific monoclonal antibodies have reported promising results with high efficacy in lowering LDL-C and in turn reducing cardiovascular complications. It is important to note that PCSK9 mediates several other pathways apart from its role in lipid homeostasis, including antiviral activity, hepatic regeneration, neuronal apoptosis, and modulation of various signaling pathways. Furthermore, recent literature has illustrated that PCSK9 is closely associated with incidence and progression of several cancers. In a number of studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of the several studied tumor cells. Hence, a novel application of PCSK9 inhibitors/silencers in cancer/metastasis could be considered. However, due to poor data on effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition in these pathological conditions is still unknown. SEARCH METHODS A vast literature search was conducted to find intended studies from 1956 up to 2020, and inclusion criteria were original peer-reviewed publications. PURPOSE OF REVIEW To date, PCSK9 has been scantly investigated in cancer. The question that needs to be discussed is "How does PCSK9 act in cancer pathophysiology and what are the risks or benefits associated to its inhibition?". We reviewed the available publications highlighting the contribution of this proprotein convertase in pathways related to cancer, with focus on the potential implications of its long-term pharmacological inhibition in cancer therapy.
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Affiliation(s)
- Khadijeh Mahboobnia
- Department of Biochemistry, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Ettore Marini
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Francesco Grignani
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Evgeny E Bezsonov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, Moscow 117418, Russia; Laboratory of Angiopathology, Institute of General Pathology and Pathophysiology, 8 Baltiiskaya Street, Moscow 125315, Russia
| | - Tannaz Jamialahmadi
- Department of Food Science and Technology, Quchan Branch, Islamic Azad University, Quchan, Iran; Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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Garcia-Ruiz C, Conde de la Rosa L, Ribas V, Fernandez-Checa JC. MITOCHONDRIAL CHOLESTEROL AND CANCER. Semin Cancer Biol 2021; 73:76-85. [PMID: 32805396 PMCID: PMC7882000 DOI: 10.1016/j.semcancer.2020.07.014] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/29/2020] [Indexed: 12/11/2022]
Abstract
Cholesterol is a crucial component of membrane bilayers that determines their physical and functional properties. Cells largely satisfy their need for cholesterol through the novo synthesis from acetyl-CoA and this demand is particularly critical for cancer cells to sustain dysregulated cell proliferation. However, the association between serum or tissue cholesterol levels and cancer development is not well established as epidemiologic data do not consistently support this link. While most preclinical studies focused on the role of total celular cholesterol, the specific contribution of the mitochondrial cholesterol pool to alterations in cancer cell biology has been less explored. Although low compared to other bilayers, the mitochondrial cholesterol content plays an important physiological function in the synthesis of steroid hormones in steroidogenic tissues or bile acids in the liver and controls mitochondrial function. In addition, mitochondrial cholesterol metabolism generates oxysterols, which in turn, regulate multiple pathways, including cholesterol and lipid metabolism as well as cell proliferation. In the present review, we summarize the regulation of mitochondrial cholesterol, including its role in mitochondrial routine performance, cell death and chemotherapy resistance, highlighting its potential contribution to cancer. Of particular relevance is hepatocellular carcinoma, whose incidence in Western countries had tripled in the past decades due to the obesity and type II diabetes epidemic. A better understanding of the role of mitochondrial cholesterol in cancer development may open up novel opportunities for cancer therapy.
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Affiliation(s)
- Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Vicent Ribas
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
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Brånvall E, Ekberg S, Eloranta S, Wästerlid T, Birmann BM, Smedby KE. Statin use and survival in 16 098 patients with non-Hodgkin lymphoma or chronic lymphocytic leukaemia treated in the rituximab era. Br J Haematol 2021; 195:552-560. [PMID: 34331461 DOI: 10.1111/bjh.17733] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2021] [Revised: 07/06/2021] [Accepted: 07/13/2021] [Indexed: 01/09/2023]
Abstract
Statin use has been associated with reduced mortality from several cancers but also suggested, in vitro, to diminish the effectiveness of lymphoma treatments including rituximab. The present study aimed to assess the association of statin use with mortality in patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukaemia (CLL). We identified all incident NHLs and CLLs in Sweden from 2007 to 2013 with subtype information in the Swedish Lymphoma and Cancer Registers. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of pre- or post-diagnosis statin use (yes/no, intensity) with lymphoma-specific, cardiovascular, or all-cause mortality; and for follicular lymphoma (FL) by initial treatment strategy (active/watch-and-wait). Among 16 098 incident NHL/CLL patients, 20% used statins at diagnosis. Pre- and post-diagnosis statin use, and statin intensity were not consistently associated with any mortality outcome in patients with NHL, overall or for any subtype. For actively treated patients with FL, statin use did not appear to increase lymphoma-specific mortality (vs. non-users, HR [95% CI]after diagnosis 0·87 [0·45-1·67]). For CLL, statin use was associated with all-cause and cardiovascular but not consistently with lymphoma-specific mortality. In conclusion, statin use was not associated with improved lymphoma survival but appears safe to use during lymphoma treatment.
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Affiliation(s)
- Elsa Brånvall
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Department of Medicine, Division of Hematology, Capio S:t Görans Hospital, Stockholm, Sweden
| | - Sara Ekberg
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Sandra Eloranta
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Tove Wästerlid
- Division of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
| | - Brenda M Birmann
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Karin E Smedby
- Department of Medicine, Division of Hematology, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
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Liang PS, Shaukat A, Crockett SD. AGA Clinical Practice Update on Chemoprevention for Colorectal Neoplasia: Expert Review. Clin Gastroenterol Hepatol 2021; 19:1327-1336. [PMID: 33581359 DOI: 10.1016/j.cgh.2021.02.014] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 02/02/2021] [Accepted: 02/08/2021] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this expert review is to describe the role of medications for the chemoprevention of colorectal neoplasia. Neoplasia is defined as precancerous lesions (e.g., adenoma and sessile serrated lesion) or cancer. The scope of this review excludes dietary factors and high-risk individuals with hereditary syndromes or inflammatory bowel disease. METHODS The best practice advice statements are based on a review of the literature to provide practical advice. A formal systematic review and rating of the quality of evidence or strength of recommendation were not performed. BEST PRACTICE ADVICE 1: In individuals at average risk for CRC who are (1) younger than 70 years with a life expectancy of at least 10 years, (2) have a 10-year cardiovascular disease risk of at least 10%, and (3) not at high risk for bleeding, clinicians should use low-dose aspirin to reduce CRC incidence and mortality. BEST PRACTICE ADVICE 2: In individuals with a history of CRC, clinicians should consider using aspirin to prevent recurrent colorectal neoplasia. BEST PRACTICE ADVICE 3: In individuals at average risk for CRC, clinicians should not use non-aspirin NSAIDs to prevent colorectal neoplasia because of a substantial risk of cardiovascular and gastrointestinal adverse events. BEST PRACTICE ADVICE 4: In individuals with type 2 diabetes, clinicians may consider using metformin to prevent colorectal neoplasia. BEST PRACTICE ADVICE 5: In individuals with CRC and type 2 diabetes, clinicians may consider using metformin to reduce mortality. BEST PRACTICE ADVICE 6: Clinicians should not use calcium or vitamin D (alone or together) to prevent colorectal neoplasia. BEST PRACTICE ADVICE 7: Clinicians should not use folic acid to prevent colorectal neoplasia. BEST PRACTICE ADVICE 8: In individuals at average risk for CRC, clinicians should not use statins to prevent colorectal neoplasia. BEST PRACTICE ADVICE 9: In individuals with a history of CRC, clinicians should not use statins to reduce mortality.
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Affiliation(s)
- Peter S Liang
- NYU Langone Health, New York, New York; VA New York Harbor Health Care System, New York, New York.
| | - Aasma Shaukat
- University of Minnesota, Minneapolis, Minnesota; Minneapolis VA Health Care System, Minneapolis, Minnesota
| | - Seth D Crockett
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
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Mukerjee S, Saeedan AS, Ansari MN, Singh M. Polyunsaturated Fatty Acids Mediated Regulation of Membrane Biochemistry and Tumor Cell Membrane Integrity. MEMBRANES 2021; 11:479. [PMID: 34203433 PMCID: PMC8304949 DOI: 10.3390/membranes11070479] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/05/2021] [Accepted: 06/24/2021] [Indexed: 12/25/2022]
Abstract
Particular dramatic macromolecule proteins are responsible for various cellular events in our body system. Lipids have recently recognized a lot more attention of scientists for understanding the relationship between lipid and cellular function and human health However, a biological membrane is formed with a lipid bilayer, which is called a P-L-P design. Our body system is balanced through various communicative signaling pathways derived from biological membrane proteins and lipids. In the case of any fatal disease such as cancer, the biological membrane compositions are altered. To repair the biological membrane composition and prevent cancer, dietary fatty acids, such as omega-3 polyunsaturated fatty acids, are essential in human health but are not directly synthesized in our body system. In this review, we will discuss the alteration of the biological membrane composition in breast cancer. We will highlight the role of dietary fatty acids in altering cellular composition in the P-L-P bilayer. We will also address the importance of omega-3 polyunsaturated fatty acids to regulate the membrane fluidity of cancer cells.
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Affiliation(s)
- Souvik Mukerjee
- Department of Pharmaceutical Sciences, Guru Ghasidas Vishwavidyalaya (A Central University), Bilaspur 495009, Chhattisgarh, India;
| | - Abdulaziz S. Saeedan
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Mohd. Nazam Ansari
- Department of Pharmacology & Toxicology, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia;
| | - Manjari Singh
- Department of Pharmaceutical Sciences, Assam University, Silchar 788011, Assam, India
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Post-Diagnostic Statin Use Reduces Mortality in South Korean Patients with Dyslipidemia and Gastrointestinal Cancer. J Clin Med 2021; 10:jcm10112361. [PMID: 34072162 PMCID: PMC8198926 DOI: 10.3390/jcm10112361] [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: 05/09/2021] [Revised: 05/25/2021] [Accepted: 05/25/2021] [Indexed: 12/09/2022] Open
Abstract
Background: Statins play a role in lowering serum cholesterol and are known to have pleiotropic effects in a variety of diseases, including cancer. Despite the beneficial effects of statins in dyslipidemia patients, the treatment rate for dyslipidemia in Korea remains low, and evidence supporting the continued use of statins is lacking. The purpose of this study was to evaluate the effect of continued statin use and dosage on patient mortality after diagnosis of dyslipidemia and gastrointestinal (GI) cancer. Methods: We used data from the National Health Insurance Sampling (NHIS) cohort to evaluate patients diagnosed with dyslipidemia from 2002 to 2015. A total of 901 GI cancer patients with dyslipidemia and 62,727 non-cancer dyslipidemia patients were included in the study. During the study period, each patient’s medication possession ratio (MPR) after diagnosis was evaluated as a measure of continued statin use. Statin dosage was measured based on a defined daily dose (DDD). Finally, we used Cox-proportional hazard ratios to identify associations between the continual use of statins and mortality in patients with dyslipidemia and GI cancer. Results: In our study, mortality decreased with increasing MPR and reached significance in MPRs exceeding 50% for GI cancer patients and 75% for dyslipidemia patients compared to patients that did not use statins. Moreover, patients with high MPRs had significantly reduced 5-year mortality compared to non-users, and cause-specific mortality analyses revealed that high MPR was associated with decreased colorectal cancer death. We did not find a significant dose–response relationship between statins and mortality. Conclusion: Our findings suggest that continued statin use after diagnosis is associated with reduced patient mortality. Altogether, these results support the continued use of statins in dyslipidemia patients with and without GI cancer and highlight the importance of patient education by healthcare providers.
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Syn NL, Chua DW, Raphael Chen L, Tan YC, Goh BKP, Chung Cheow P, Jeyaraj PR, Koh Y, Chung A, Yee Lee S, Lucien Ooi L, Tai BC, Yip Chan C, Teo JY. Time-varying prognostic effects of primary tumor sidedness and grade after curative liver resection for colorectal liver metastases. Surg Oncol 2021; 38:101586. [PMID: 33933898 DOI: 10.1016/j.suronc.2021.101586] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 04/07/2021] [Accepted: 04/18/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The veracity of the proportional hazards (PH) requirement is rarely scrutinized in most areas of cancer research, although fulfilment of this assumption underpins widely-used Cox survival models. We sought to critically appraise the existence of prognostic factors with time-dependent effects and to characterize their impact on survival among CLM patients. METHODS Consecutive patients who underwent liver resection with curative intent for CLM at the Singapore General Hospital were identified from a prospectively-maintained database. We evaluated PH of 55 candidate variables, and parameters which departed significantly from proportionality were included in Cox models that incorporated an interaction term to account for time-dependent effects. As sensitivity analyses, we fitted Weibull mixture 'cure' models to handle long plateaus in the tails of survival curves, and also analyzed the restricted mean survival time. RESULTS 318 consecutive patients who underwent curative liver resection for CLM between Jan 2000 and Nov 2016 were included in this analysis. Hazard ratios for tumor grade (poorly-versus well- and moderately-differentiated) were found to decrease from 3.135 (95% CI: 1.637-6.003) at 12 months to 2.048 (95% CI: 1.038-4.042) after 24 months, and ceased to be significant at 26 months. Compared to left-sided tumors, a right-sided tumor location was found to portend worse prognosis for the first 10 months after resection but subsequently confer a survival benefit due to a crossing of survival curves. Corroborating this observation, long-term cure fractions were estimated to be 25.5% (95% CI: 17.4%-33.6%) and 34.2% (95% CI: 17.4%-50.9%) among patients with left-sided and right-sided primary disease respectively. CONCLUSION Primary tumor sidedness and grade appear to exert time-varying prognostic effects in CLM patients undergoing curative liver resection.
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Affiliation(s)
- Nicholas L Syn
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Darren W Chua
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Lionel Raphael Chen
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore
| | - Yu Chuan Tan
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Brian K P Goh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Peng Chung Cheow
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Prema Raj Jeyaraj
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Yexin Koh
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Alexander Chung
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Ser Yee Lee
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - London Lucien Ooi
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore
| | - Bee Choo Tai
- Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore, Singapore; Biostatistics Core, Investigational Medicine Unit, National University Health System, Singapore
| | - Chung Yip Chan
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Biostatistics & Modelling Domain, Saw Swee Hock School of Public Health, National University of Singapore, Singapore
| | - Jin Yao Teo
- Department of Hepatopancreatobiliary and Transplant Surgery, Singapore General Hospital, Singapore; Duke-NUS Graduate Medical School, Singapore.
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Chen H, Dai S, Fang Y, Chen L, Jiang K, Wei Q, Ding K. Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients. Front Oncol 2021; 11:631943. [PMID: 33767997 PMCID: PMC7986714 DOI: 10.3389/fonc.2021.631943] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/08/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60–70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study. Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence. Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25–3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence. Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.
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Affiliation(s)
- Haiyan Chen
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China
| | - Siqi Dai
- Zhejiang University Cancer Center, Hangzhou, China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yimin Fang
- Zhejiang University Cancer Center, Hangzhou, China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liubo Chen
- Zhejiang University Cancer Center, Hangzhou, China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kai Jiang
- Zhejiang University Cancer Center, Hangzhou, China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qichun Wei
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China
| | - Kefeng Ding
- Zhejiang University Cancer Center, Hangzhou, China.,Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Shizu R, Ishimura M, Nobusawa S, Hosaka T, Sasaki T, Kakizaki S, Yoshinari K. The influence of the long-term chemical activation of the nuclear receptor pregnane X receptor (PXR) on liver carcinogenesis in mice. Arch Toxicol 2021; 95:1089-1102. [PMID: 33398415 DOI: 10.1007/s00204-020-02955-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/12/2020] [Indexed: 12/13/2022]
Abstract
Pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are nuclear receptors that are highly expressed in the liver and activated by numerous chemicals. While CAR activation by its activators, such as phenobarbital (PB), induces hepatocyte proliferation and liver carcinogenesis in rodents, it remains unclear whether PXR activation drives liver cancer. To investigate the influence of PXR activation on liver carcinogenesis, we treated mice with the PXR activator pregnenolone 16α-carbonitrile (PCN) with or without PB following tumor initiation with diethylnitrosamine (DEN). After 20 weeks of treatment, preneoplastic lesions detected by immunostaining with an anti-KRT8/18 antibody were observed in PB-treated but not PCN-treated mice, and PCN cotreatment augmented the formation of preneoplastic lesions by PB. After 35 weeks of treatment, macroscopic observations indicated that PB-treated and PB/PCN-cotreated mice had increased numbers of liver tumors compared to control and PCN-treated mice. In the pathological analyses of liver sections, all the mice in the PB and PB/PCN groups developed carcinoma and/or eosinophilic adenoma, but in the PB/PCN group, the multiplicity of carcinoma and eosinophilic adenoma was significantly reduced and the size of carcinoma showed a tendency to decrease. No mouse in the control or PCN-treated group developed such tumors. Differentially expressed gene (DEG) and gene set enrichment analyses in combination with RNA sequencing suggested the increased expression of genes related to epithelial-mesenchymal transition (EMT) in mice cotreated with PCN and PB compared to those treated with PB alone. Changes in the hepatic mRNA levels of epithelial marker genes supported the results of the transcriptome analyses. In conclusion, the present results suggest that PXR activation does not promote hepatocarcinogenesis in contrast to CAR and rather attenuates CAR-mediated liver cancer development by suppressing the EMT of liver cancer cells in rodents.
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Affiliation(s)
- Ryota Shizu
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Mai Ishimura
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Sumihito Nobusawa
- Department of Human Pathology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Takuomi Hosaka
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Takamitsu Sasaki
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
| | - Satoru Kakizaki
- Department of Gastroenterology and Hepatology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma, 371-8511, Japan
| | - Kouichi Yoshinari
- Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
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Matsushita Y, Nakagawa H, Koike K. Lipid Metabolism in Oncology: Why It Matters, How to Research, and How to Treat. Cancers (Basel) 2021; 13:474. [PMID: 33530546 PMCID: PMC7865757 DOI: 10.3390/cancers13030474] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/11/2022] Open
Abstract
Lipids in our body, which are mainly composed of fatty acids, triacylglycerides, sphingolipids, phospholipids, and cholesterol, play important roles at the cellular level. In addition to being energy sources and structural components of biological membranes, several types of lipids serve as signaling molecules or secondary messengers. Metabolic reprogramming has been recognized as a hallmark of cancer, but changes in lipid metabolism in cancer have received less attention compared to glucose or glutamine metabolism. However, recent innovations in mass spectrometry- and chromatography-based lipidomics technologies have increased our understanding of the role of lipids in cancer. Changes in lipid metabolism, so-called "lipid metabolic reprogramming", can affect cellular functions including the cell cycle, proliferation, growth, and differentiation, leading to carcinogenesis. Moreover, interactions between cancer cells and adjacent immune cells through altered lipid metabolism are known to support tumor growth and progression. Characterization of cancer-specific lipid metabolism can be used to identify novel metabolic targets for cancer treatment, and indeed, several clinical trials are currently underway. Thus, we discuss the latest findings on the roles of lipid metabolism in cancer biology and introduce current advances in lipidomics technologies, focusing on their applications in cancer research.
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Affiliation(s)
| | - Hayato Nakagawa
- Department of Gastroenterology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; (Y.M.); (K.K.)
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Hou J, Karin M, Sun B. Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age? Nat Rev Clin Oncol 2021; 18:261-279. [PMID: 33469195 DOI: 10.1038/s41571-020-00459-9] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/25/2020] [Indexed: 02/07/2023]
Abstract
The immune system has crucial roles in cancer development and treatment. Whereas adaptive immunity can prevent or constrain cancer through immunosurveillance, innate immunity and inflammation often promote tumorigenesis and malignant progression of nascent cancer. The past decade has witnessed the translation of knowledge derived from preclinical studies of antitumour immunity into clinically effective, approved immunotherapies for cancer. By contrast, the successful implementation of treatments that target cancer-associated inflammation is still awaited. Anti-inflammatory agents have the potential to not only prevent or delay cancer onset but also to improve the efficacy of conventional therapeutics and next-generation immunotherapies. Herein, we review the current clinical advances and experimental findings supporting the utility of an anti-inflammatory approach to the treatment of solid malignancies. Gaining a better mechanistic understanding of the mode of action of anti-inflammatory agents and designing more effective treatment combinations would advance the clinical application of this therapeutic approach.
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Affiliation(s)
- Jiajie Hou
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.,Department of Liver Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, University of California San Diego School of Medicine, La Jolla, CA, USA.
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.
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Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med 2021; 218:e20201606. [PMID: 33601415 PMCID: PMC7754673 DOI: 10.1084/jem.20201606] [Citation(s) in RCA: 534] [Impact Index Per Article: 133.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 10/15/2020] [Accepted: 10/26/2020] [Indexed: 02/05/2023] Open
Abstract
Dysregulation in lipid metabolism is among the most prominent metabolic alterations in cancer. Cancer cells harness lipid metabolism to obtain energy, components for biological membranes, and signaling molecules needed for proliferation, survival, invasion, metastasis, and response to the tumor microenvironment impact and cancer therapy. Here, we summarize and discuss current knowledge about the advances made in understanding the regulation of lipid metabolism in cancer cells and introduce different approaches that have been clinically used to disrupt lipid metabolism in cancer therapy.
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Affiliation(s)
- Xueli Bian
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China
| | - Rui Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ying Meng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Dongming Xing
- Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Daqian Xu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhimin Lu
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
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Rus I, Tertiș M, Barbălată C, Porfire A, Tomuță I, Săndulescu R, Cristea C. An Electrochemical Strategy for the Simultaneous Detection of Doxorubicin and Simvastatin for Their Potential Use in the Treatment of Cancer. BIOSENSORS-BASEL 2021; 11:bios11010015. [PMID: 33401625 PMCID: PMC7823638 DOI: 10.3390/bios11010015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/22/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022]
Abstract
The aim of this study was to develop a disposable, simple, fast, and sensitive sensor for the simultaneous electrochemical detection of doxorubicin (DOX) and simvastatin (SMV), which could be used in preclinical studies for the development of new pharmaceutical formulations for drug delivery. Firstly, the electrochemical behavior of each molecule was analyzed regarding the influence of electrode material, electrolyte solution, and scan rate. After this, the proper electrode material, electrolyte solution, and scan rate for both active substances were chosen, and a linear sweep voltammetry procedure was optimized for simultaneous detection. Two chronoamperometry procedures were tested, one for the detection of DOX in the presence of SMV, and the other one for the detection of DOX and SMV together. Finally, calibration curves for DOX and SMV in the presence of each other were obtained using both electrochemical methods and the results were compared. The use of amperometry allowed for a better limit of detection (DOX: 0.1 μg/mL; SMV: 0.7 μg/mL) than the one obtained in voltammetry (1.5 μg/mL for both drugs). The limits of quantification using amperometry were 0.5 μg/mL for DOX (dynamic range: 0.5-65 μg/mL) and 2 μg/mL for SMV (dynamic range: 2-65 μg/mL), while using voltammetry 1 μg/mL was obtained for DOX (dynamic range: 1-100 μg/mL) and 5 μg/mL for SMV (dynamic range: 5-100 μg/mL). This detection strategy represents a promising tool for the analysis of new pharmaceutical formulations for targeted drug delivery containing both drugs, whose association was proven to bring benefits in the treatment of cancer.
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Affiliation(s)
- Iulia Rus
- Department of Analytical Chemistry, Iuliu Hațieganu University of Medicine and Pharmacy, 4 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (I.R.); (M.T.); (R.S.)
| | - Mihaela Tertiș
- Department of Analytical Chemistry, Iuliu Hațieganu University of Medicine and Pharmacy, 4 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (I.R.); (M.T.); (R.S.)
| | - Cristina Barbălată
- Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.B.); (A.P.); (I.T.)
| | - Alina Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.B.); (A.P.); (I.T.)
| | - Ioan Tomuță
- Department of Pharmaceutical Technology and Biopharmaceutics, Iuliu Hațieganu University of Medicine and Pharmacy, 41 Victor Babes Street, 400012 Cluj-Napoca, Romania; (C.B.); (A.P.); (I.T.)
| | - Robert Săndulescu
- Department of Analytical Chemistry, Iuliu Hațieganu University of Medicine and Pharmacy, 4 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (I.R.); (M.T.); (R.S.)
| | - Cecilia Cristea
- Department of Analytical Chemistry, Iuliu Hațieganu University of Medicine and Pharmacy, 4 Louis Pasteur Street, 400349 Cluj-Napoca, Romania; (I.R.); (M.T.); (R.S.)
- Correspondence: ; Tel.: +40-721-375-789
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Wu Z, Qu B, Huang X, Song Y, Gao P, Shi J, Zhou C, Wang Z. The potential adjunctive benefit of adding metformin to standard treatment in inoperable cancer patients: a meta-analysis of randomized controlled trials. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1404. [PMID: 33313149 PMCID: PMC7723600 DOI: 10.21037/atm-20-4441] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Background Recently, there have been several randomized clinical trials (RCTs) conducted to evaluate the efficacy and safety of metformin plus standard treatment in inoperable cancer patients. Our meta-analysis aimed to assess the efficacy of metformin in combination with standard treatment in inoperable cancer patients. Methods PubMed and Embase databases were systematically searched for relevant RCTs investigating the efficacy of adding metformin to standard treatment for cancer patients. The pooled relative risk (RR) for tumor response and safety was calculated to assess the efficacy of combining metformin with standard treatment. Meta-analysis was subsequently performed to pool the hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). Results Ten RCTs comprising 1033 patients were included in our current meta-analysis. In patients with breast cancer, results of meta-analysis showed that the addition of metformin to standard treatment was beneficial to objective response rate (ORR) with 30.3% (33/109) in the metformin plus standard treatment group and 16.1% (18/112) in the placebo group (RR 1.92, 95% CI: 1.19–3.10, P=0.008). OS and PFS were not significantly improved in patients who received metformin plus standard treatment compared with those who received placebo plus standard treatment (OS: HR 1.02, 95% CI: 0.71–1.46, P=0.916; PFS: HR 1.14, 95% CI: 0.86–1.50, P=0.366). For lung cancer patients, meta-analysis results showed adding metformin to standard treatment could benefit ORR (metformin 65.3% vs. placebo 54.6%, RR 1.22, 95% CI: 1.03–1.43, P=0.018) with no significant survival benefit in the metformin group. For patients with pancreatic cancer, the pooled ORR was 17.6% (16/91) in metformin plus standard treatment group and 20% (18/90) in the placebo group, indicating metformin did not benefit ORR (RR 0.85, 95% CI: 0.49–1.49, P=0.576). Besides, the addition of metformin to standard treatment did not increase the incidence rate of adverse effects. Conclusions Our results indicated that addition of metformin to standard treatment was beneficial to ORR in inoperable breast or lung cancer patients without increasing the incidence of adverse effects. However, adding metformin to standard treatment could not benefit OS and PFS.
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Affiliation(s)
- Zhonghua Wu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Bicheng Qu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peng Gao
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Nunes M, Henriques Abreu M, Bartosch C, Ricardo S. Recycling the Purpose of Old Drugs to Treat Ovarian Cancer. Int J Mol Sci 2020; 21:ijms21207768. [PMID: 33092251 PMCID: PMC7656306 DOI: 10.3390/ijms21207768] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 10/13/2020] [Accepted: 10/17/2020] [Indexed: 02/07/2023] Open
Abstract
The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.
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Affiliation(s)
- Mariana Nunes
- Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto/Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal;
- Porto Comprehensive Cancer Center (PCCC), 4200-162 Porto, Portugal; (M.H.A.); (C.B.)
| | - Miguel Henriques Abreu
- Porto Comprehensive Cancer Center (PCCC), 4200-162 Porto, Portugal; (M.H.A.); (C.B.)
- Department of Medical Oncology, Portuguese Oncology Institute of Porto (IPOP), 4200-162 Porto, Portugal
| | - Carla Bartosch
- Porto Comprehensive Cancer Center (PCCC), 4200-162 Porto, Portugal; (M.H.A.); (C.B.)
- Department of Pathology, Portuguese Oncology Institute of Porto (IPOP), 4200-162 Porto, Portugal
- Cancer Biology & Epigenetics Group, Research Center—Portuguese Oncology Institute of Porto (CI-IPOP), 4200-162 Porto, Portugal
| | - Sara Ricardo
- Differentiation and Cancer Group, Institute for Research and Innovation in Health (i3S) of the University of Porto/Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), 4200-135 Porto, Portugal;
- Porto Comprehensive Cancer Center (PCCC), 4200-162 Porto, Portugal; (M.H.A.); (C.B.)
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
- Department of Sciences, University Institute of Health Sciences (IUCS), CESPU, CRL, 4585-116 Gandra, Portugal
- Correspondence: ; Tel.: +351-225-570-700
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Feng JL, Qin X. Does adherence to lipid-lowering medications improve cancer survival? A nationwide study of breast and colorectal cancer, and melanoma. Br J Clin Pharmacol 2020; 87:1847-1858. [PMID: 33084072 DOI: 10.1111/bcp.14573] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 09/14/2020] [Accepted: 09/17/2020] [Indexed: 12/18/2022] Open
Abstract
AIMS Inconclusive findings of lipid-lowering medications (LLMs) on cancer survival benefit require more evidence. We tested the hypothesis that adherence to this drug is associated with reduced cancer-specific mortality in a homogeneous population who had used this drug before cancer diagnosis. METHODS The Australian Cancer Database was linked to the Pharmaceutical Benefits Scheme database, and to the National Death Index (up to 2015). Medication adherence was calculated by proportion of days covered. Cox regression models with time-varying covariates were used to derive multivariable-adjusted cause-specific hazard ratio (HR) and 95% confidence interval (CI) for the associations between adherence to LLMs, statins, lipophilic, and hydrophilic statins and cancer-specific mortality. RESULTS From 2003 to 2013, 3 separate cohorts of 20 046, 11 719 and 6430 female patients with newly diagnosed breast, colorectal cancer, and melanoma respectively were identified. The 1-year adherence was similar at 1-year prediagnosis in the 3 cohorts, on average 82%. Each 10% increase in 1-year adherence to LLMs was inversely associated with cancer-specific mortality among women with breast cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), colorectal cancer (fully adjusted HR = 0.92, 95% CI 0.91-0.93), or melanoma (fully adjusted HR = 0.97, 95% CI 0.94-1.00). The reductions in cancer-specific mortality were more pronounced for women who adhered to lipophilic than hydrophilic statins in all 3 cancers albeit not statistically significant for melanoma. CONCLUSION Among LLM users, adherence to this drug is associated with a decrease in cancer-specific mortality. If confirmed, LLMs could be considered as an adjuvant cancer therapy to improve prognosis in cancer survivors.
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Affiliation(s)
- Jia-Li Feng
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.,Prevention Division, Queensland Health, Brisbane, QLD, Australia
| | - Xiwen Qin
- Centre for Medicine Use and Safety (CMUS), Faculty of Pharmacy and Pharmaceutical Science, Monash University, Melbourne, VIC, Australia.,School of Population and Global Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth, WA, Australia
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Boegemann M, Schlack K, Rink M, Bernhardt S, Moran M, Hubbe M, Bergmann L, Schmid M, Strauss A. Effect of comorbidities/comedications on sunitinib outcomes for metastatic renal cell carcinoma: the STAR-TOR registry. Future Oncol 2020; 16:2939-2948. [PMID: 33021843 DOI: 10.2217/fon-2020-0548] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Aim: Examine the effects of baseline hypertension (HTN) and statin or proton pump inhibitor (PPI) use on sunitinib treatment outcomes in STAR-TOR, a real-world registry. Materials & methods: Presence or absence of HTN and use or nonuse of statins or PPIs were determined at registry entry. End points included overall survival (OS) and progression-free survival (PFS). Results: Data were from 557 patients. Presence or absence of HTN did not affect OS or PFS. PFS (median [95% CI]) was longer in statin users (9.4 [6.5-13.6] months) versus nonusers (6.9 [5.7-8.2] months) (p = 0.0442). OS was shorter in PPI users (20.2 [14.9-28.3] months) versus nonusers (25.7 [22.7-33.0] months) (p = 0.0212). Conclusion: Comorbidities and comedications may affect real-world sunitinib treatment outcomes. Clinical Trial Registration: NCT00700258 (ClinicalTrials.gov).
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Affiliation(s)
- Martin Boegemann
- Klinik für Urologie und Kinderurologie, Universitätsklinikum Münster, Münster, Germany, & West German Cancer Center, University Hospital of Muenster, Muenster, Germany
| | - Katrin Schlack
- Klinik für Urologie und Kinderurologie, Universitätsklinikum Münster, Münster, Germany, & West German Cancer Center, University Hospital of Muenster, Muenster, Germany
| | - Michael Rink
- Klinik und Poliklinik für Urologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | | | | | - Lothar Bergmann
- Medizinische Klinik 2, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Marianne Schmid
- Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany
| | - Arne Strauss
- Klinik für Urologie, Universitätsmedizin Göttingen, Göttingen, Germany
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Hossain MA, Liu G, Dai B, Si Y, Yang Q, Wazir J, Birnbaumer L, Yang Y. Reinvigorating exhausted CD8 + cytotoxic T lymphocytes in the tumor microenvironment and current strategies in cancer immunotherapy. Med Res Rev 2020; 41:156-201. [PMID: 32844499 DOI: 10.1002/med.21727] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 06/26/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Immunotherapy has revolutionized the treatment of cancer in recent years and achieved overall success and long-term clinical benefit in patients with a wide variety of cancer types. However, there is still a large proportion of patients exhibiting limited or no responses to immunotherapeutic strategy, some of which were even observed with hyperprogressive disease. One major obstacle restricting the efficacy is that tumor-reactive CD8+ T cells, which are central for tumor control, undergo exhaustion, and lose their ability to eliminate cancer cells after infiltrating into the strongly immunosuppressive tumor microenvironment. Thus, as a potential therapeutic rationale in the development of cancer immunotherapy, targeting or reinvigorating exhausted CD8+ T cells has been attracting much interest. Hitherto, both intrinsic and extrinsic mechanisms that govern CD8+ T-cell exhaustion have been explored. Specifically, the transcriptional and epigenetic landscapes have been depicted utilizing single-cell RNA sequencing or mass cytometry (CyTOF). In addition, cellular metabolism dictating the tumor-infiltrating CD8+ T-cell fate is currently under investigation. A series of clinical trials are being carried out to further establish the current strategies targeting CD8+ T-cell exhaustion. Taken together, despite the proven benefit of immunotherapy in cancer patients, additional efforts are still needed to fully circumvent limitations of exhausted T cells in the treatment. In this review, we will focus on the current cellular and molecular understanding of metabolic changes, epigenetic remodeling, and transcriptional regulation in CD8+ T-cell exhaustion and describe hypothetical treatment approaches based on immunotherapy aiming at reinvigorating exhausted CD8+ T cells.
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Affiliation(s)
- Md Amir Hossain
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Guilai Liu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Beiying Dai
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Yaxuan Si
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Qitao Yang
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Junaid Wazir
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
| | - Lutz Birnbaumer
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, Durham, North Carolina, USA.,Institute of Biomedical Research (BIOMED), Catholic University of Argentina, Buenos Aires, Argentina
| | - Yong Yang
- Center for New Drug Safety Evaluation and Research, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, China.,Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China
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Barbalata CI, Tefas LR, Achim M, Tomuta I, Porfire AS. Statins in risk-reduction and treatment of cancer. World J Clin Oncol 2020; 11:573-588. [PMID: 32879845 PMCID: PMC7443827 DOI: 10.5306/wjco.v11.i8.573] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/18/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.
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Affiliation(s)
- Cristina I Barbalata
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Lucia R Tefas
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Marcela Achim
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Ioan Tomuta
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Alina S Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
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