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Agustsson AS, Haraldsdottir S, Birgisson H, Lund SH, Ingason AB, Hreinsson JP, Björnsson ES. Effects of aspirin at diagnosis on the survival of colorectal cancer patients: a 20-year population-based study. Scand J Gastroenterol 2025; 60:516-525. [PMID: 40320718 DOI: 10.1080/00365521.2025.2499126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/27/2025]
Abstract
BACKGROUND Previous studies have produced conflicting results regarding whether aspirin affects survival in colorectal cancer (CRC) patients. This study examines the relationship between regular aspirin use and survival in CRC patients within a nationwide cohort. METHODS All patients diagnosed with CRC in Iceland from 2000 to 2019 were identified through the Icelandic Cancer Registry. Clinical variables, including medications, were extracted from medical records. Overall survival (OS) and cancer-specific survival (CSS) were calculated. The follow-up period ended on 1 October 2022. The Charlson comorbidity index was used to assess comorbidity burden, and propensity score matching was employed to balance patient characteristics. RESULTS Of the 2,561 eligible patients, 22% (n = 559) had been taking aspirin before their CRC diagnosis. Aspirin users were generally older and more frequently male (63% vs. 51%), with a higher comorbidity burden (15% vs. 4.7%). The median follow-up period was 51 months (IQR 14-110). Aspirin users were less likely to receive a stage IV diagnosis. After matching, overall survival (OS) was comparable between aspirin and non-users (HR: 0.94, 95% CI (0.83-1.06), p = 0.30). However, cancer-specific survival (CSS) was significantly better for aspirin users (HR: 0.79, 95% CI (0.65-0.95), p = 0.01). This benefit was not observed in patients with stages I-III CRC or those diagnosed due to gastrointestinal bleeding. CONCLUSION Aspirin use was linked to improved CSS but not OS. The findings suggest aspirin's potential role in slowing or hindering progression to stage IV cancer.
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Affiliation(s)
| | - Sigurdis Haraldsdottir
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Department of Medical Oncology, Landspitali University Hospital of Iceland, Reykjavik, Iceland
| | | | - Sigrun H Lund
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Faculty of Physical Science, University of Iceland, Reykjavik, Iceland
| | - Arnar B Ingason
- Department of Surgery, University of Vermont Larner College of Medicine, Burlington, VT, USA
| | - Johann P Hreinsson
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Einar S Björnsson
- Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Department of Internal Medicine, Landspitali University Hospital of Iceland, Reykjavik, Iceland
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Laila UE, Zhao ZL, Liu H, Xu ZX. Aspirin in Cancer Therapy: Pharmacology and Nanotechnology Advances. Int J Nanomedicine 2025; 20:2327-2365. [PMID: 40017626 PMCID: PMC11866938 DOI: 10.2147/ijn.s505636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 02/04/2025] [Indexed: 03/01/2025] Open
Abstract
Aspirin, a non-steroidal anti-inflammatory drug (NSAID), has garnered significant attention for its anti-cancer potential. This review explores the pharmacological properties, chemical dynamics, and evolving therapeutic applications of aspirin, with an emphasis on its integration into advanced cancer therapies. Aspirin demonstrates broad-spectrum efficacy across diverse cancer types by modulating signaling pathways such as COX-dependent and COX-independent mechanisms, including Wnt, NF-κB, β-catenin/TCF, and IL-6/STAT3. Recent advancements highlight the role of nanotechnology in enhancing aspirin's targeted delivery, therapeutic effectiveness, and patient outcomes. Nanoparticle-based formulations, including liposomes, solid lipid nanoparticles, and mesoporous silica nanoparticles, offer improved solubility, stability, and bioavailability, enabling controlled drug release and tumor-specific targeting. These innovations reduce systemic toxicity and enhance therapeutic effects, paving the way for aspirin's integration into personalized cancer treatments. Ongoing clinical studies reinforce its safety profile, underscoring aspirin's role in cancer pharmacotherapy. This review calls for continued research into aspirin's repurposing in combination therapies and novel delivery systems to maximize its therapeutic potential.
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Affiliation(s)
- Umm E Laila
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zi Lon Zhao
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Huai Liu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
| | - Zhi-Xiang Xu
- School of Life Sciences, Henan University, Kaifeng, Henan Province, 475001, People’s Republic of China
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Liu A, Rao W, Watt KD. Lack of progress in cancer-related outcomes after liver transplantation: Mitigating risk and identifying future needs to move this needle. Liver Transpl 2024:01445473-990000000-00483. [PMID: 39724652 DOI: 10.1097/lvt.0000000000000509] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 10/06/2024] [Indexed: 12/28/2024]
Abstract
Malignancy has a crucial impact on long-term survival after liver transplantation. There have been enhanced early detection rates with refined cancer screening and improved prognosis for many cancer diagnoses in the general population with the advent of targeted anticancer therapies. Similar advancements have not occurred in the transplant population over this same timeframe. Individualized strategies to reduce the risk of cancer are needed in this high-risk population. Strict adherence to screening and surveillance specific to the transplant population is required. Lifestyle modifications and medication management (both immunosuppressive and non-immunosuppressive) that may impact cancer risk and outcome are highlighted here. As more effective anticancer therapies evolve, transplant recipients' access to these agents is paramount to truly impact cancer-related outcomes in this population. With adequate immunosuppression, rejection rates with immunotherapy are lower than previously purported. Prospective studies of immunosuppression modifications needed to minimize rejection and maximize cancer response are ongoing and will reduce the fear from oncology and transplant providers alike, allowing utilization of the most optimal therapy available to the individual. This review aims to assess current data to aid in clinical management and identify the need to facilitate further progress in this field.
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Affiliation(s)
- Alex Liu
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Wei Rao
- Department of Medicine, Division of Hepatology, Liver Disease Center and Organ Transplantation Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Kymberly D Watt
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Miret Durazo CI, Zachariah Saji S, Rawat A, Motiño Villanueva AL, Bhandari A, Nurjanah T, Ryali N, Zepeda Martínez IG, Cruz Santiago JA. Exploring Aspirin's Potential in Cancer Prevention: A Comprehensive Review of the Current Evidence. Cureus 2024; 16:e70005. [PMID: 39445288 PMCID: PMC11498354 DOI: 10.7759/cureus.70005] [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] [Accepted: 09/23/2024] [Indexed: 10/25/2024] Open
Abstract
Aspirin, traditionally recognized for its analgesic, anti-inflammatory, antipyretic, and antiplatelet effects, has recently attracted attention for its potential role in cancer prevention. Initially studied for cardiovascular disease prevention, emerging evidence suggests that aspirin may reduce the risk of certain cancers, particularly colorectal cancer (CRC). This narrative review integrates findings from early studies, animal models, epidemiological data, and clinical trials to evaluate aspirin's efficacy as a chemopreventive agent. Aspirin's anticancer effects are primarily attributed to its cyclooxygenase (COX) enzyme inhibition, which decreases prostaglandin E2 (PGE2) levels and disrupts cancer-related signaling pathways. While epidemiological studies support an association between aspirin use and reduced cancer incidence and mortality, especially for CRC and potentially for breast (BC) and prostate cancers (PCa), the risk of adverse effects, such as gastrointestinal (GI) and intracranial bleeding, complicates its use and warrants careful consideration. The decision to use aspirin for cancer prevention should be individualized, balancing its therapeutic benefits against potential adverse effects. It also underscores the necessity for further research to refine dosage guidelines, assess long-term impacts, and explore additional biomarkers to guide personalized cancer prevention strategies.
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Affiliation(s)
| | | | - Akash Rawat
- Department of General Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, IND
| | | | - Amit Bhandari
- Internal Medicine, American University of the Caribbean School of Medicine, Cupecoy, SXM
| | - Tutut Nurjanah
- Department of General Medicine, Universitas Yarsi, Jakarta, IDN
| | - Niharika Ryali
- Department of General Medicine, Gandhi Medical College, Hyderabad, IND
| | | | - Josue A Cruz Santiago
- Department of General Medicine, Universidad Autónoma de Guadalajara, Guadalajara, MEX
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Surandran S, Ahmed S, Walton T, Nikiphorou E, Dey M. Multimorbidity in rheumatoid arthritis: common mechanistic links and impact and challenges in routine clinical practice. Rheumatology (Oxford) 2023; 62:SI260-SI270. [PMID: 37871920 DOI: 10.1093/rheumatology/kead489] [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: 06/01/2023] [Accepted: 09/13/2023] [Indexed: 10/25/2023] Open
Abstract
Early identification and management of multimorbidity in patients with rheumatic and musculoskeletal diseases (RMDs), such as RA, is an integral, but often neglected, aspect of care. The prevalence and incidence of conditions such as osteoporosis, cardiovascular disease, pulmonary disease and malignancies, often co-existing with RA, continues to have significant implications for the management of this patient group. Multimorbidity in RMDs can be associated with inflammatory disease activity and target organ damage. Lifestyle factors, such as smoking and inactivity, further contribute to the burden of disease. Inflammation is the underlying factor, not just in RA but also many comorbidities. The current framework of a treat-to-target approach focuses on achieving early remission and inflammatory activity suppression. We describe how the comorbidity burden in people with RMDs impacts on disease outcome and treatment response. The importance of addressing comorbidity at an early stage and adopting a patient centred approach is critical in modern practice.
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Affiliation(s)
| | - Saad Ahmed
- Department of Rheumatology, Colchester General Hospital, Colchester, UK
| | - Tom Walton
- Department of Rheumatology, Colchester General Hospital, Colchester, UK
| | - Elena Nikiphorou
- Centre for Rheumatic Diseases, King's College London, London, UK
- Rheumatology Department, King's College Hospital, London, UK
| | - Mrinalini Dey
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK
- Department of Rheumatology, Countless of Chester Hospital NHS Foundation Trust, Chester, UK
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Kagan P, Horesh N, Amital H, Tsur AM, Watad A, Cohen AD, Ben-Shabat N. The Risk and Predictors of Malignancies in Ankylosing Spondylitis Patients in Israel-A Retrospective Electronic Data-Based Study. J Clin Med 2023; 12:5153. [PMID: 37568555 PMCID: PMC10419948 DOI: 10.3390/jcm12155153] [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: 07/05/2023] [Revised: 07/29/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
BACKGROUND Previous studies demonstrated unclear and vast variability in the association between Ankylosing Spondylitis (AS) and the risk of cancer. OBJECTIVES To assess the risk of overall and site-specific malignancies for AS patients in Israel, while examining the role of comorbidities and immunomodulatory therapy. METHODS We conducted a retrospective electronic data-based study including all AS patients diagnosed between 2002 and 2018, with no history of cancer prior to enrollment, with 5:1 ratio matched-control by age, gender, and place of residence. The odds Ratios (OR) for site-specific malignancies, comparing AS patients and controls, were calculated using logistic regression. Risk factors for malignancies within the AS cohort were evaluated in the same manner. RESULTS This study comprised 5825 AS patients and 28,356 matched controls. There was a higher overall risk of cancer in AS patients compared to controls (OR = 1.4, 95% CI 1.24-1.6), specifically for solid malignancies (OR = 1.5, 95% CI 1.3-1.7), CNS (OR = 3.72, 95% CI 1.29-10.7), kidney (OR = 2.06, 95% CI 1.12-3.8), and malignancy of unknown primary (OR = 3.06, 95% CI 2.35-3.98). Regarding predictors for malignancy within AS patients, older age at diagnosis (OR = 1.31, 95%,CI 1.25-2.36), diabetes (OR = 1.52, 95% CI 1.18-1.97), IBD (OR = 2.61, 95% CI 1.75-3.89), and treatment with DMARDs (OR = 2.17, 95% CI 1.65-2.83) were associated with a higher risk of solid malignancies, while NSAIDs treatment alone had a protective effect for solid malignancies (OR = 0.78, 95% CI 0.61-0.99). No significant association was found between anti-TNF therapy and the risk of solid or hematologic malignancies within the AS group. CONCLUSION AS is associated with an increased risk of overall and site-specific malignancies, with independently higher risk for older age, comorbidity of DM, IBD, and treatment with DMARDs.
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Affiliation(s)
- Polina Kagan
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
| | - Noy Horesh
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
| | - Howard Amital
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
| | - Avishai M. Tsur
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
- Israel Defense Forces, Medical Corps, Tel Hashomer, Ramat Gan 9112102, Israel
- Department of Military Medicine, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 7610001, Israel
| | - Abdulla Watad
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds LS7 4SA, UK
| | - Arnon D. Cohen
- Chief Physician’s Office, Clalit Health Services, Tel-Aviv 6209813, Israel;
- Siaal Research Center for Family Medicine and Primary Care, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel
| | - Niv Ben-Shabat
- Department of Medicine B, Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5262100, Israel; (P.K.); (N.H.); (H.A.); (A.W.)
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 6997801, Israel
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Tustumi F, Arienzo VP, Sunye IR, Lucas PFS, Colonno BB, Quintas JG, Lisboa EN, Szor DJ. Esophageal Dysbiosis in Achalasia and Cancer Development: A Critical Review. Genes (Basel) 2023; 14:1521. [PMID: 37628573 PMCID: PMC10454429 DOI: 10.3390/genes14081521] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Microorganisms provide various benefits to their human hosts, including assisting with digestion, synthesizing certain vitamins, developing the gastrointestinal and immune systems, regulating metabolism, and protecting against some pathogens. However, microbial imbalances can cause tissue damage and contribute to inflammatory disorders and cancers. Microbial dysbiosis refers to an imbalance or disruption in the normal composition and function of the microbial communities that inhabit various body parts, including the gut, oral cavity, skin, and reproductive tract. Emerging research suggests that microbial dysbiosis plays a significant role in cancer development and progression. This issue is particularly relevant in achalasia, in which food stasis, changes in endoluminal pH, and poor esophageal clearance might contribute to esophageal microbial dysbiosis. This study aimed to evaluate the association between dysbiosis and esophageal cancer development, focused on esophageal dysmotility disorders. METHODS This study is a critical review, gathering the current evidence for the association between dysbiosis and the development of esophageal cancer. RESULTS Studies have shown that microbiota play a role in cancer development, although the mechanisms for how they do so are not yet fully understood. One possible explanation is that microbiota alterations can lead to chronic inflammation, promoting cancer cell growth. Additionally, some bacteria produce toxins that can damage DNA and cause genomic instability, and certain bacterial products can promote tumor growth. CONCLUSION Despite the close relationship between dysbiosis and cancer development in esophageal dysmotility disorders, further investigations are still needed to elucidate the precise mechanisms by which dysbiosis contributes to cancer development and to identify potential therapeutic interventions targeting the microbiota to prevent or treat cancer.
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Affiliation(s)
- Francisco Tustumi
- Department of Health Sciences, Hospital Israelita Albert Einstein, Sao Paulo 05652-900, Brazil (J.G.Q.)
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Newman P, Muscat J. Potential Role of Non-Steroidal Anti-Inflammatory Drugs in Colorectal Cancer Chemoprevention for Inflammatory Bowel Disease: An Umbrella Review. Cancers (Basel) 2023; 15:cancers15041102. [PMID: 36831446 PMCID: PMC9954537 DOI: 10.3390/cancers15041102] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/11/2023] Open
Abstract
Inflammatory Bowel Disease (IBD) is a category of autoimmune diseases that targets the destruction of the gastrointestinal system and includes both Crohn's Disease and Ulcerative Colitis (UC). Patients with IBD are at a higher risk of developing colorectal cancer (CRC) throughout their lives due to chronically increased inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are potential chemopreventative agents that can inhibit the development of CRC in persons without IBD. However, the use of NSAIDs for CRC chemoprevention in IBD patients is further complicated by NSAIDs' induction of damage to the bowel mucosal layer and ulcer formation. There has been a push in new research on chemopreventative properties of certain NSAIDs for IBD. The purpose of this umbrella review is to investigate the potential of low-dose NSAID compounds as chemopreventative agents for patients with IBD. This paper will also suggest future areas of research in the prevention of CRC for patients with IBD.
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Ying J, Zhou H, Wang Z, You Q, Chen J, Lu H, Zhang J. Aspirin increases chemosensitivity of colorectal cancer cells and inhibits the expression of toll-like receptor 4. Cancer Cell Int 2023; 23:6. [PMID: 36647071 PMCID: PMC9843993 DOI: 10.1186/s12935-023-02847-4] [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: 06/20/2022] [Accepted: 01/02/2023] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Chemotherapy resistance is an important bottleneck affecting the efficacy of chemotherapy in colon cancer. Therefore, improving the chemotherapy sensitivity of colorectal cancer cells is of great significance for improving the prognosis of patients with colon cancer. METHODS CCK-8 assay was employed to examine the cell viability of colorectal cancer cell lines. Realtime-PCR and western blot were used to explore toll-like receptor 4 (TLR4) expression in colorectal cancer cell lines. The functions of TLR4 in the stemness of the colorectal cancer cell lines were analyzed by infecting cells with lentivirus containing TLR4 siRNA. RESULTS We found that aspirin could effectively enhance the chemosensitivity of CT26 and HCT116 colorectal cancer cell lines. Aspirin can also inhibit the stemness of colorectal cancer cell including inhibiting the number of clone formation and reducing the volume and number of cell spheres and inducing the down-regulation of stemness-related genes. Besides that, aspirin also lead to down-regulation of TLR4 expression in colorectal cancer cells. The TLR4 positive colorectal cancer cells demonstrated a higher chemotherapy resistance potential than TLR4 negative colorectal cancer cells. In addition, the stemness of TLR4 positive colorectal cancer cells is stronger than TLR4 negative colorectal cancer cells. CONCLUSION The results of our study indicate that aspirin increases chemosensitivity of colorectal cancer cells and inhibits the expression of toll-like receptor 4.
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Affiliation(s)
- Jun Ying
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Haiyang Zhou
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Zhiguo Wang
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Qing You
- grid.73113.370000 0004 0369 1660Department of Gastrointestinal Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Junnan Chen
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Hao Lu
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
| | - Jian Zhang
- grid.73113.370000 0004 0369 1660Division of Colorectal Surgery, Department of Surgery, Second Affiliated Hospital of Naval Medical University, 415 Fengyang Road, Shanghai, 200003 China
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Thiruchenthooran V, Sánchez-López E, Gliszczyńska A. Perspectives of the Application of Non-Steroidal Anti-Inflammatory Drugs in Cancer Therapy: Attempts to Overcome Their Unfavorable Side Effects. Cancers (Basel) 2023; 15:cancers15020475. [PMID: 36672424 PMCID: PMC9856583 DOI: 10.3390/cancers15020475] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/30/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) express anti-tumoral activity mainly by blocking cyclooxygenase-2 involved in the synthesis of prostaglandins. Therefore, in the last few decades, many have attempted to explore the possibilities of applying this group of drugs as effective agents for the inhibition of neoplastic processes. This review summarizes the evidence presented in the literature regarding the anti-tumoral actions of NSAIDs used as monotherapies as well as in combination with conventional chemotherapeutics and natural products. In several clinical trials, it was proven that combinations of NSAIDs and chemotherapeutic drugs (CTDs) were able to obtain suitable results. The combination with phospholipids may resolve the adverse effects of NSAIDs and deliver derivatives with increased antitumor activity, whereas hybrids with terpenoids exhibit superior activity against their parent drugs or physical mixtures. Therefore, the application of NSAIDs in cancer therapy seems to be still an open chapter and requires deep and careful evaluation. The literature's data indicate the possibilities of re-purposing anti-inflammatory drugs currently approved for cancer treatments.
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Affiliation(s)
- Vaikunthavasan Thiruchenthooran
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
| | - Elena Sánchez-López
- Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, University of Barcelona, 08028 Barcelona, Spain
- Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, 08028 Barcelona, Spain
- Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, 08034 Barcelona, Spain
- Correspondence: (E.S.-L.); or (A.G.)
| | - Anna Gliszczyńska
- Department of Food Chemistry and Biocatalysis, Wrocław University of Environmental and Life Sciences, Norwida 25, 50-375 Wrocław, Poland
- Correspondence: (E.S.-L.); or (A.G.)
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Samami E, Aleebrahim-Dehkordi E, Mohebalizadeh M, Yaribash S, Saghazadeh A, Rezaei N. Inosine, gut microbiota, and cancer immunometabolism. Am J Physiol Endocrinol Metab 2023; 324:E1-E8. [PMID: 36416582 DOI: 10.1152/ajpendo.00207.2022] [Citation(s) in RCA: 13] [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] [Indexed: 11/24/2022]
Abstract
This article briefly reviews cancer immunity and the role of gut microbiota in carcinogenesis, followed by an understanding of mechanisms by which inosine is involved in cancer immunometabolism. The immune system plays a paradoxical role in cancer treatment. Antitumor immunity depends on the T-cell priming against tumor antigens, whereas inflammatory mediators trigger the protumor signaling in the tumor microenvironment. Studies link the microbiome with metabolism and immunity-two main factors implicated in carcinogenesis. Gut microbiota has been shown to affect both antitumor immunity and protumor immune signaling. There is mounting evidence that the human microbiome can play a role in the immunotherapeutic effects, both response and resistance. Inosine-5'-monophosphate dehydrogenase (IMPDH) is a highly conservative enzyme widely expressed in mammals. Cell signaling pathways use molecular inosine, a crucial secondary metabolite in purine metabolism and a molecular messenger. Recent research has identified inosine as a critical regulator of immune checkpoint inhibition (ICI) therapeutic response in various tumor types. Some bacterial species were found to produce inosine or its metabolite hypoxanthine and induce T-helper 1 differentiation and effector functions via the inosine-A2AR-cAMP-PKA pathway upon ICI therapy. Also, inosine acts as a substitute carbon source for T-cell metabolism in glucose-restricted environments, i.e., the tumor microenvironment, assisting T-cell proliferation and differentiation while enhancing sensitivity to ICI, reinforcing the notion that inosine metabolism might contribute to antitumor immunity. Also, inosine is a potent agonist of the adenosine receptor, A2AR, and A2AR signaling can affect T-cell responses and antitumor immunity, making the inosine-A2AR pathway blockage a candidate for cancer treatment. Further research is required to investigate inosine as a cancer immunometabolism therapy.
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Affiliation(s)
- Elham Samami
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Elahe Aleebrahim-Dehkordi
- Medical Plants Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Shahrekord, Iran
| | - Mehdi Mohebalizadeh
- Student Research Committee, Urmia University of Medical Sciences, Urmia, Iran
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Urmia, Iran
| | - Shakila Yaribash
- International Campus, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Amene Saghazadeh
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Systematic Review and Meta-analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), Urmia, Iran
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Sugimoto N, Tanaka E, Inoue E, Abe M, Sugano E, Sugitani N, Saka K, Ochiai M, Higuchi Y, Yamaguchi R, Ikari K, Nakajima A, Yamanaka H, Harigai M. Trends in Risks of Malignancies in Japanese Patients with Rheumatoid Arthritis: Analyses from a 14-year Observation of the IORRA Cohort. Mod Rheumatol 2022:6653673. [PMID: 35920098 DOI: 10.1093/mr/roac085] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/16/2022] [Accepted: 08/02/2022] [Indexed: 11/14/2022]
Abstract
OBJECTIVES To investigate the trends in risks of overall and site-specific malignancies in patients with rheumatoid arthritis (RA). METHODS Among Japanese patients with RA enrolled in the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort, all malignancies that occurred from 2000 to 2013 were extracted. The standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for overall and site-specific malignancies were calculated during three periods: pre-biologics, 2000-2004; early biologics, 2005-2009; and recent biologics, 2010-2013. Risk factors for overall and specific malignancies were analyzed using time-dependent Cox regression models. RESULTS Among 11,299 patients with RA (68,483 person-years), 507 malignancies were confirmed. Similar risks were observed versus the general Japanese population for overall malignancies throughout the three periods, with SIRs (95% CIs) of 0.96 (0.80-1.14) in the pre-biologics period, 0.95 (0.82-1.09) in the early biologics period, and 0.87 (0.75-1.01) in the recent biologics period. Significant increased risk for malignant lymphoma was observed throughout the observation period (SIR 4.61, 95% CI 3.58-5.85). The disease activity was a significant risk factor for overall malignancies and lung cancer. CONCLUSION Despite the expanding use of methotrexate and biologics, there were no increases in malignancy risk in Japanese patients with RA.
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Affiliation(s)
- Naoki Sugimoto
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Eiichi Tanaka
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Eisuke Inoue
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Showa University Research Administration Center, Showa University, Tokyo, Japan
| | - Mai Abe
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Eri Sugano
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Naohiro Sugitani
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Kumiko Saka
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Moeko Ochiai
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Yoko Higuchi
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Rei Yamaguchi
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
| | - Katsunori Ikari
- Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan.,Department of Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.,Division of Multidisciplinary Management of Rheumatic Diseases, Tokyo Women's Medical University, Tokyo, Japan
| | - Ayako Nakajima
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Center for Rheumatic Diseases, Mie University Hospital, Tsu, Mie, Japan
| | - Hisashi Yamanaka
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Rheumatology, Sanno Medical Center, Tokyo, Japan.,Department of Rheumatology, International University of Health and Welfare, Narita, Chiba, Japan
| | - Masayoshi Harigai
- Division of Rheumatology, Department of Internal Medicine, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.,Department of Rheumatology, Institute of Rheumatology, Tokyo Women's Medical University Hospital, Tokyo, Japan
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13
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Hall DCN, Benndorf RA. Aspirin sensitivity of PIK3CA-mutated Colorectal Cancer: potential mechanisms revisited. Cell Mol Life Sci 2022; 79:393. [PMID: 35780223 PMCID: PMC9250486 DOI: 10.1007/s00018-022-04430-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/01/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022]
Abstract
PIK3CA mutations are amongst the most prevalent somatic mutations in cancer and are associated with resistance to first-line treatment along with low survival rates in a variety of malignancies. There is evidence that patients carrying PIK3CA mutations may benefit from treatment with acetylsalicylic acid, commonly known as aspirin, particularly in the setting of colorectal cancer. In this regard, it has been clarified that Class IA Phosphatidylinositol 3-kinases (PI3K), whose catalytic subunit p110α is encoded by the PIK3CA gene, are involved in signal transduction that regulates cell cycle, cell growth, and metabolism and, if disturbed, induces carcinogenic effects. Although PI3K is associated with pro-inflammatory cyclooxygenase-2 (COX-2) expression and signaling, and COX-2 is among the best-studied targets of aspirin, the mechanisms behind this clinically relevant phenomenon are still unclear. Indeed, there is further evidence that the protective, anti-carcinogenic effect of aspirin in this setting may be mediated in a COX-independent manner. However, until now the understanding of aspirin's prostaglandin-independent mode of action is poor. This review will provide an overview of the current literature on this topic and aims to analyze possible mechanisms and targets behind the aspirin sensitivity of PIK3CA-mutated cancers.
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Affiliation(s)
- Daniella C N Hall
- Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany
| | - Ralf A Benndorf
- Department of Clinical Pharmacy and Pharmacotherapy, Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 3, 06120, Halle (Saale), Germany.
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14
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Zaman FY, Orchard SG, Haydon A, Zalcberg JR. Non-aspirin non-steroidal anti-inflammatory drugs in colorectal cancer: a review of clinical studies. Br J Cancer 2022; 127:1735-1743. [PMID: 35764787 DOI: 10.1038/s41416-022-01882-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 12/21/2022] Open
Abstract
Colorectal cancer (CRC) chemoprevention is an area of interest. Non-steroidal anti-inflammatory drugs (NSAIDs) are anti-inflammatory agents which have been identified as cancer chemoprevention agents given that inflammation is thought to contribute to tumorigenesis. Most studies have demonstrated that the NSAID, aspirin, plays a beneficial role in the prevention of CRC and colonic adenomas. Non-aspirin NSAIDs (NA-NSAIDs) have also been studied in CRC chemoprevention. There is increasing literature around their role in pre-cancerous polyp prevention and in decreasing CRC incidence and CRC-related outcomes in certain high-risk subgroups. However, the use of NA-NSAIDs may be accompanied by increased risks of toxicity. Further studies are required to establish the associations between concurrent aspirin and NA-NSAID use, and CRC-related outcomes.
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Affiliation(s)
- Farzana Y Zaman
- Department of Medical Oncology, The Alfred Hospital, Alfred Health, Melbourne, VIC, Australia.
| | - Suzanne G Orchard
- School of Public Health and Preventive Medicine, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia
| | - Andrew Haydon
- Department of Medical Oncology, The Alfred Hospital, Alfred Health, Melbourne, VIC, Australia
| | - John R Zalcberg
- Department of Medical Oncology, The Alfred Hospital, Alfred Health, Melbourne, VIC, Australia.,Head of Cancer Research Program, School of Public Health and Preventive Medicine, Faculty of Medicine, Monash University, Melbourne, VIC, Australia
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15
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Shahrivar M, Weibull CE, Ekström Smedby K, Glimelius B, Syk I, Matthiessen P, Nordenvall C, Martling A. Low-dose aspirin use and colorectal cancer survival in 32,195 patients-A national cohort study. Cancer Med 2022; 12:315-324. [PMID: 35717628 PMCID: PMC9844641 DOI: 10.1002/cam4.4859] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 04/28/2022] [Accepted: 05/17/2022] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Results from previous studies indicate that use of aspirin may improve colorectal cancer (CRC) survival. The aim of this study was to assess whether use of aspirin influences overall survival or CRC-specific survival in an unselected cohort of patients diagnosed with CRC. METHODS The study was performed using the Colorectal Cancer Data Base Sweden (CRCBaSe), a mega-linkage originating from the Swedish Colorectal Cancer Register, with additional linkages to other national health care registers. All patients diagnosed with primary CRC stage I-III treated with curative surgery, aged 18-85 years at diagnosis, from 2007 through 2016 were identified. Information on low-dose aspirin use was extracted from the Swedish Prescribed Drug Register. Exposure was defined as dispensed prescription for at least 6 months. Aspirin exposure was analyzed at the time of surgery (yes/no) and as a time-varying exposure during follow-up. Follow-up was restricted to a maximum 6 years, to model 5-year survival. Cox regression models were fitted to estimate hazard ratios (HRs) with 95% confidence intervals (CIs). Adjustments were performed for sex, age, year of diagnosis, Charlson comorbidity index, hypertension, and ASA score as potential confounders. RESULTS A total of 32,195 patients diagnosed with CRC were included. 6764 (21%) were exposed to aspirin at the time of CRC surgery. The median time of follow-up was 4.2 years. Aspirin use at the time of surgery was not associated with all-cause (adjusted HR = 1.03, 95% CI: 0.97-1.08) nor CRC-specific mortality (adjusted HR = 0.99, 95% CI: 0.91-1.07). Aspirin use during follow-up was associated with increased all-cause (adjusted HR = 1.09, 95% CI: 1.04-1.15) but not CRC-specific mortality (adjusted HR = 0.98, 95% CI: 0.91-1.06). A CRC-specific effect associated with aspirin was noted from approximately 3 years following surgery. CONCLUSIONS In this large nation-wide cohort study there was no convincing association between aspirin use after CRC and OS or CRC-specific survival.
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Affiliation(s)
- Mehrnoosh Shahrivar
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
| | - Caroline E. Weibull
- Department of Medicine Solna, Clinical Epidemiology DivisionKarolinska InstitutetStockholmSweden
| | - Karin Ekström Smedby
- Department of Medicine Solna, Clinical Epidemiology DivisionKarolinska InstitutetStockholmSweden
| | - Bengt Glimelius
- Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
| | - Ingvar Syk
- Department of SurgerySkåne University HospitalMalmöSweden
| | - Peter Matthiessen
- Department of Surgery, Faculty of Medicine and HealthÖrebro UniversityÖrebroSweden
| | - Caroline Nordenvall
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden,Department of Pelvic Cancer, GI oncology and colorectal surgery unitKarolinska University HospitalStockholmSweden
| | - Anna Martling
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden,Department of Pelvic Cancer, GI oncology and colorectal surgery unitKarolinska University HospitalStockholmSweden
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16
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Potential Cancer Risk in Patients with Rheumatoid Arthritis: A Longitudinal Korean Population-Based Analysis. J Pers Med 2022; 12:jpm12060965. [PMID: 35743750 PMCID: PMC9224951 DOI: 10.3390/jpm12060965] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/08/2022] [Accepted: 06/10/2022] [Indexed: 12/31/2022] Open
Abstract
The potential link between rheumatoid arthritis (RA) and cancer incidence needs to be validated due to inconsistent results between Asian and Western countries. We explored the long-term association of RA with the overall and organ-specific cancer incidence using nationwide population data. This longitudinal follow-up study (2002–2015) included 3070 patients with RA and 12,280 controls (1:4 propensity score-matched for sex, age, residence, and income) from the Korean National Health Insurance Service-Health Screening Cohort database. A Cox proportional hazard model estimated the hazard ratio for malignancy following adjusting for covariates. Despite the similar overall cancer incidence between RA and control groups, differences in the incidence of organ-specific cancers were noted: the RA group had a 1.63-fold greater likelihood for lung cancer (95% confidence interval 1.11–2.40). In the sex-stratified subgroup analyses, the male RA patients exhibited higher odds of lung and thyroid cancer but a lower probability for colorectal cancer; no such associations were detected in either female patients with RA or age subgroups. In summary, the higher likelihood for lung cancer in Korean RA patients, especially thyroid and lung cancer in male RA patients, seems to be characteristic, which needs to be carefully monitored.
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17
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Ho PH, Hsiao HC, Chen CW, Chen HM, Lim SN, Yeh CT, Kuo CJ, Lin WR. Anticoagulant drugs with or without proton pump inhibitor and colorectal cancer risk: a population-based, case-control study. BMC Gastroenterol 2022; 22:225. [PMID: 35534834 PMCID: PMC9082832 DOI: 10.1186/s12876-022-02314-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 04/27/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Low-dose aspirin and clopidogrel have demonstrated potential chemoprevention for colorectal cancer (CRC). Proton-pump inhibitors (PPI) are commonly prescribed with anticoagulation drugs, but the relationship between PPI and CRC is unclear. Moreover, evidence of CRC risk under direct oral anticoagulant (DOAC) is limited. This study aimed to investigate the effects of anticoagulation drugs combined with or without PPI on the risks of CRC in Taiwan. METHODS A retrospective case-control study of 1,024,227 cases based on the Chang Gung Research Database from 2010 to 2017 was performed. Clinical characteristics, indications, duration of anticoagulation and PPI use, and CRC occurrence data were collected. Logistic regression was employed to adjust for known confounders of CRC risk. RESULTS Monotherapy of clopidogrel decreased the risk of CRC (AOR 0.70; 95% CI 0.60-0.83), while no protective effect was observed in aspirin alone or aspirin plus clopidogrel. DOAC did not affect CRC significantly. The risk of CRC increased in patients with PPI (AOR 1.38; 95% CI 1.28-1.49) and PPI plus DOAC (OR 3.91; 95% CI 1.49-10.27), while PPI plus aspirin decreased the risk of CRC (OR 0.48; 95% CI 0.32-0.73). PPI plus clopidogrel showed no significant effect on the CRC. CONCLUSION This study suggests clopidogrel alone and PPI plus aspirin offer a preventative benefit against CRC in the Taiwanese population studied. The same effect was not observed in DOAC. Moreover, a significant increase in CRC was observed in patients on PPI monotherapy and PPI plus DOAC, suggesting a possible risk.
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Affiliation(s)
- Pei-Huan Ho
- Department of Internal Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Hung-Chun Hsiao
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chun-Wei Chen
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
| | - Hui-Ming Chen
- Center for Big Data Analytics and Statistics, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, 5, Fu-Shin Street, Taoyuan, 333, Taiwan
- Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, 5, Fu-Shin Street, Taoyuan, 333, Taiwan.
- Chang Gung University College of Medicine, Taoyuan, Taiwan.
| | - Wey-Ran Lin
- Liver Research Center, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, 5, Fu-Shin Street, Taoyuan, 333, Taiwan.
- Chang Gung University College of Medicine, Taoyuan, Taiwan.
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18
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Mädge JC, Stallmach A, Kleebusch L, Schlattmann P. Meta-analysis of aspirin-guided therapy of colorectal cancer. J Cancer Res Clin Oncol 2022; 148:1407-1417. [PMID: 35171329 PMCID: PMC9114035 DOI: 10.1007/s00432-022-03942-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/03/2022] [Indexed: 12/03/2022]
Abstract
Abstract Purpose colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide. Some evidence has shown that aspirin can reduce the morbidity and mortality of CRC. The aim of this meta-analysis was to compare standard care of patients with CRC and standard care with the addition of aspirin in terms of the survival benefit. Methods The systematic search was conducted by two independent reviewers in the databases PubMed and Web of Science. Survival data were extracted from studies published before July 2019. We searched for randomised controlled trials, cohort studies and case-control studies. Results We included 27 studies in our meta-analysis. There was a sample size of 237,245 patients overall. Aspirin use after diagnosis was associated with an improvement in CRC-specific survival with a hazard ratio (HR) for cancer-related death of 0.74 (95% CI: 0.62–0.89). Our analysis of overall survival data revealed reduced mortality with an HR of 0.82 (95% CI: 0.74–0.90). Patients with the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutation profited from postdiagnosis aspirin use (HR = 0.74, 95% CI: 0.56–0.97). For a high expression of prostaglandin-endoperoxide synthase 2 (PTGS2) = COX-2, we found an HR of 0.65 (95% CI: 0.52–0.82). Conclusion Aspirin can improve the outcome of patients with CRC. PIK3CA mutation status and high expression of PTGS2 are associated with longer survival. However, randomised controlled trials are needed to investigate postdiagnosis aspirin use in CRC patients taking into account cancer stage and gene expression. Supplementary Information The online version contains supplementary material available at 10.1007/s00432-022-03942-1.
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Affiliation(s)
- Johanna C Mädge
- Department of Medical Statistics, Computer Sciences and Data Sciences, Jena University Hospital, 07743, Jena, Germany.
| | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, 07743, Jena, Germany
| | - Lisa Kleebusch
- Department of Internal Medicine, Thüringen-Kliniken Pößneck, 07381, Pößneck, Germany
| | - Peter Schlattmann
- Department of Medical Statistics, Computer Sciences and Data Sciences, Jena University Hospital, 07743, Jena, Germany
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19
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Shahani SA, Marcotte EL. Landscape of germline cancer predisposition mutations testing and management in pediatrics: Implications for research and clinical care. Front Pediatr 2022; 10:1011873. [PMID: 36225340 PMCID: PMC9548803 DOI: 10.3389/fped.2022.1011873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
As germline genetic testing capacities have improved over the last two decades, increasingly more people are newly diagnosed with germline cancer susceptibility mutations. In the wake of this growth, there remain limitations in both testing strategies and translation of these results into morbidity- and mortality-reducing practices, with pediatric populations remaining especially vulnerable. To face the challenges evoked by an expanding diversity of germline cancer mutations, we can draw upon a model cancer-associated genetic condition for which we have developed a breadth of expertise in managing, Trisomy 21. We can additionally apply advances in other disciplines, such as oncofertility and pharmacogenomics, to enhance care delivery. Herein, we describe the history of germline mutation testing, epidemiology of known germline cancer mutations and their associations with childhood cancer, testing limitations, and future directions for research and clinical care.
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Affiliation(s)
- Shilpa A Shahani
- Department of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA, United States
| | - Erin L Marcotte
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States.,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
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20
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Wang Y, Nguyen LH, Mehta RS, Song M, Huttenhower C, Chan AT. Association Between the Sulfur Microbial Diet and Risk of Colorectal Cancer. JAMA Netw Open 2021; 4:e2134308. [PMID: 34767023 PMCID: PMC8590167 DOI: 10.1001/jamanetworkopen.2021.34308] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
IMPORTANCE Sulfur-metabolizing bacteria that reduce dietary sulfur to hydrogen sulfide have been associated with colorectal cancer (CRC). However, there are limited studies investigating the association between diet and sulfur-metabolizing bacteria in the development of CRC. OBJECTIVE To develop a dietary score that correlates with gut sulfur-metabolizing bacteria and to examine its association with CRC risk. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study included data from the Health Professionals Follow-up Study (1986-2014), Nurses' Health Study (1984-2016), and Nurses' Health Study II (1991-2017). Participants were US male health professionals and female registered nurses who were free of inflammatory bowel disease and cancer at baseline, with a subsample of participants who provided stool samples from 2012 to 2014. Statistical analysis was conducted from September 1, 2020, to June 1, 2021. EXPOSURE A dietary pattern, assessed by a food-frequency questionnaire, that most correlated with 43 sulfur-metabolizing bacteria identified through taxonomic and functional profiling of gut metagenome data. MAIN OUTCOMES AND MEASURES Incident CRC. RESULTS Among 214 797 participants comprising 46 550 men (mean [SD] age at baseline, 54.3 [9.7] years) and 168 247 women (mean [SD] age at baseline, 43.0 [9.2] years), 3217 incident cases of CRC (1.5%) were documented during 5 278 048 person-years of follow-up. The sulfur microbial diet, developed in a subsample of 307 men (mean [SD] age, 70.5 [4.3] years) and 212 women (mean [SD] age, 61.0 [3.8] years), was characterized by high intakes of low-calorie beverages, french fries, red meats, and processed meats and low intakes of fruits, yellow vegetables, whole grains, legumes, leafy vegetables, and cruciferous vegetables. After adjustment for other risk factors, greater adherence to the sulfur microbial diet was associated with an increased risk of CRC, with a hazard ratio (HR) of 1.27 (95% CI, 1.12-1.44) comparing the highest vs the lowest quintile of the diet score (linear trend of diet score quintiles; P < .001 for trend). When assessed by anatomical subsites, greater adherence to the sulfur microbial diet was positively associated with distal CRC (HR, 1.25; 95% CI, 1.05-1.50; P = .02 for trend) but not proximal colon cancer (HR, 1.13; 95% CI, 0.93-1.39; P = .19 for trend). CONCLUSIONS AND RELEVANCE Adherence to the sulfur microbial diet was associated with an increased risk of CRC, suggesting a potential mediating role of sulfur-metabolizing bacteria in the associaton between diet and CRC. Further research is needed to confirm these findings and to determine the underlying mechanisms.
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Affiliation(s)
- Yiqing Wang
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Long H. Nguyen
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Raaj S. Mehta
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
- Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
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21
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Yaqub S, Bjørnbeth BA, Angelsen JH, Fristrup CW, Grønbech JE, Hemmingsson O, Isaksson B, Juel IS, Larsen PN, Lindell G, Mortensen FV, Mortensen KE, Rizell M, Sandström P, Sandvik OM, Sparrelid E, Taflin H, Taskén K. Aspirin as secondary prevention in colorectal cancer liver metastasis (ASAC trial): study protocol for a multicentre randomized placebo-controlled trial. Trials 2021; 22:642. [PMID: 34544470 PMCID: PMC8451095 DOI: 10.1186/s13063-021-05587-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 08/31/2021] [Indexed: 12/21/2022] Open
Abstract
Background Colorectal cancer is one the most common cancers in the western world with increasing incidence. Approximately 50% of the patients develop liver metastases. Resection of liver metastases is the treatment of choice although almost half of the resected patients get recurrence in the liver. Methods The ASAC trial is a Scandinavian, multicentre, double-blinded, randomized, placebo-controlled study to determine whether adjuvant treatment with low-dose aspirin (acetylsalicylic acid (ASA)) can improve disease-free survival in patients treated for colorectal cancer liver metastases (CRCLM). Up to 800 patients operated for CRCLM will be randomized to Arm#1 ASA 160 mg once daily or Arm#2 Placebo, for a period of 3 years or until disease recurrence. The patients will be recruited at all major hepatobiliary surgical units in Norway, Sweden and Denmark and have follow-up according to standard of care and the National Guidelines. Discussion The ASAC trial will be the first clinical interventional trial to assess the potential beneficial role of ASA in recurrence of CRCLM and survival. ASA is an inexpensive, well-tolerated and easily accessible drug that will be highly potential as adjuvant drug in secondary prevention of CRCLM if the study shows a beneficial effect. We will also determine the effect of ASA as adjuvant treatment on Health-Related Quality of Life and the cost-effectiveness. Trial registration ClinicalTrials.gov NCT03326791. Registered on 31 October 2017.
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Affiliation(s)
- Sheraz Yaqub
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - Bjørn Atle Bjørnbeth
- Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Oslo, Norway
| | - Jon-Helge Angelsen
- Department of Acute and Digestive Surgery, Haukeland University Hospital, Bergen, Norway.,Departments of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | - Jon Erik Grønbech
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway.,Department of Clinical and Molecular Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway
| | - Oskar Hemmingsson
- Department of Surgical and Perioperative Sciences, Umeå University, Umea, Sweden
| | - Bengt Isaksson
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
| | - Ingebjørg Soterud Juel
- Department of Gastrointestinal Surgery, St. Olav's Hospital, Trondheim University Hospital, Trondheim, Norway
| | | | - Gert Lindell
- Department of Surgery, Skåne University Hospital, Lund, Sweden
| | | | - Kim Erlend Mortensen
- Department of Gastrointestinal Surgery, University Hospital of North, Tromsø, Norway
| | - Magnus Rizell
- Department of Transplantation, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Per Sandström
- Department of Surgery, County Council of Östergötland, Linköping, Sweden.,Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology, Linköping, Sweden
| | - Oddvar Mathias Sandvik
- Department of Gastrointestinal Surgery, Stavanger University Hospital, Stavanger, Norway
| | - Ernesto Sparrelid
- Division of Surgery, Department of Clinical Science, Intervention, and Technology (CLINTEC), Center for Digestive Diseases, Karolinska University Hospital, Karolinska Institute, Stockholm, Sweden
| | - Helena Taflin
- Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Kjetil Taskén
- Institute for Cancer Research, Oslo University Hospital, and Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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22
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Xiao S, Xie W, Fan Y, Zhou L. Timing of Aspirin Use Among Patients With Colorectal Cancer in Relation to Mortality: A Systematic Review and Meta-Analysis. JNCI Cancer Spectr 2021; 5:pkab067. [PMID: 34514327 PMCID: PMC8421810 DOI: 10.1093/jncics/pkab067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 05/25/2021] [Accepted: 07/09/2021] [Indexed: 12/21/2022] Open
Abstract
Background Exposure of aspirin has been associated with reduced risk of colorectal cancer (CRC) incidence, but aspirin use in relation to CRC patients' mortality remains undetermined. It is necessary to quantify the association between aspirin use and CRC mortality. Methods Two authors independently searched the electronic databases (PubMed, Embase, and the Cochrane Library) from 1947 through April 25, 2020. All observational studies assessing the association between different timing of aspirin use and CRC mortality were included. The effect size on study outcomes was calculated using random-effect model and presented as risk ratio (RR) with 95% confidence interval (CI). Heterogeneity, publication bias, and quality of included studies were also assessed. Results A total of 34 studies were included in this systematic review and meta-analysis. Prediagnosis aspirin use was not associated with CRC-specific mortality (RR = 0.91, 95% CI = 0.79 to 1.05) and all-cause mortality (RR = 0.87, 95% CI = 0.57 to 1.31). A statistically significant association between continued aspirin use and improvement in both CRC-specific mortality (RR = 0.76, 95% CI = 0.70 to 0.81) and all-cause mortality (RR = 0.83, 95% CI = 0.74 to 0.93) was observed. Postdiagnosis use of aspirin was associated only with reduced all-cause mortality (RR = 0.80, 95% CI = 0.69 to 0.94). Conclusions Continued aspirin use before and after CRC diagnosis has the most advantage regarding the improvement of CRC mortality. Nevertheless, further prospective trials and mechanistic studies are highly warranted.
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Affiliation(s)
- Shiyu Xiao
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Wenhui Xie
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing, China
| | - Yihan Fan
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
| | - Liya Zhou
- Department of Gastroenterology, Peking University Third Hospital, Beijing, China
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23
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Wang X, Liu Q, Halfdanarson ÓÖ, Zoega H, Sadr-Azodi O, Engstrand L, Fall K, Brusselaers N. Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study. Br J Cancer 2021; 125:893-900. [PMID: 34253872 PMCID: PMC8438017 DOI: 10.1038/s41416-021-01480-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/09/2021] [Accepted: 06/30/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality. METHODS We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure. RESULTS Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32-1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0-I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40-1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24-1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality. CONCLUSION PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.
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Affiliation(s)
- Xinchen Wang
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Qing Liu
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Óskar Ö Halfdanarson
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Helga Zoega
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
- Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, NSW, Australia
| | - Omid Sadr-Azodi
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Lars Engstrand
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Katja Fall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden
- Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Nele Brusselaers
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
- Global Health Institute, Antwerp University, Antwerpen, Belgium.
- Department of Head and Skin, Ghent University, Ghent, Belgium.
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24
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Thoms HC, Stark LA. The NF-κB Nucleolar Stress Response Pathway. Biomedicines 2021; 9:biomedicines9091082. [PMID: 34572268 PMCID: PMC8471347 DOI: 10.3390/biomedicines9091082] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/09/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
The nuclear organelle, the nucleolus, plays a critical role in stress response and the regulation of cellular homeostasis. P53 as a downstream effector of nucleolar stress is well defined. However, new data suggests that NF-κB also acts downstream of nucleolar stress to regulate cell growth and death. In this review, we will provide insight into the NF-κB nucleolar stress response pathway. We will discuss apoptosis mediated by nucleolar sequestration of RelA and new data demonstrating a role for p62 (sequestosome (SQSTM1)) in this process. We will also discuss activation of NF-κB signalling by degradation of the RNA polymerase I (PolI) complex component, transcription initiation factor-IA (TIF-IA (RRN3)), and contexts where TIF-IA-NF-κB signalling may be important. Finally, we will discuss how this pathway is targeted by aspirin to mediate apoptosis of colon cancer cells.
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25
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Elwood PC, Morgan G, Delon C, Protty M, Galante J, Pickering J, Watkins J, Weightman A, Morris D. Aspirin and cancer survival: a systematic review and meta-analyses of 118 observational studies of aspirin and 18 cancers. Ecancermedicalscience 2021; 15:1258. [PMID: 34567243 PMCID: PMC8426031 DOI: 10.3332/ecancer.2021.1258] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Despite the accumulation of research papers on aspirin and cancer, there is doubt as to whether or not aspirin is an acceptable and effective adjunct treatment of cancer. The results of several randomised trials are awaited, and these should give clear evidence on three common cancers: colon, breast and prostate. The biological effects of aspirin appear likely however to be of relevance to cancer generally, and to metastatic spread, rather than just to one or a few cancers, and there is already a lot of evidence, mainly from observational studies, on the association between aspirin and survival in a wide range of cancers. AIMS In order to test the hypothesis that aspirin taking is associated with an increase in the survival of patients with cancer, we conducted a series of systematic literature searches to identify clinical studies of patients with cancer, some of whom took aspirin after having received a diagnosis of cancer. RESULTS Three literature searches identified 118 published observational studies in patients with 18 different cancers. Eighty-one studies report on aspirin and cancer mortality and 63 studies report on all-cause mortality. Within a total of about a quarter of a million patients with cancer who reported taking aspirin, representing 20%-25% of the total cohort, we found aspirin to be associated with a reduction of about 20% in cancer deaths (pooled hazard ratio (HR): 0.79; 95% confidence intervals: 0.73, 0.84 in 70 reports and a pooled odds ratio (OR): 0.67; 0.45, 1.00 in 11 reports) with similar reductions in all-cause mortality (HR: 0.80; 0.74, 0.86 in 56 studies and OR: 0.57; 0.36, 0.89 in seven studies). The relative safety of aspirin taking was examined in the studies and the corresponding author of every paper was written to asking for additional information on bleeding. As expected, the frequency of bleeding increased in the patients taking aspirin, but fatal bleeding was rare and no author reported a significant excess in fatal bleeds associated with aspirin. No author mentioned cerebral bleeding in the patients they had followed. CONCLUSIONS There is a considerable body of evidence suggestive of about a 20% reduction in mortality in patients with cancer who take aspirin, and the benefit appears not to be restricted to one or a few cancers. Aspirin, therefore, appears to deserve serious consideration as an adjuvant treatment of cancer, and patients with cancer, and their carers, have a right to be informed of the available evidence.
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Affiliation(s)
- Peter C Elwood
- Division of Population Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - Gareth Morgan
- Division of Population Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | | | - Majd Protty
- Cardiff Lipidomics Group, Cardiff University, UK
| | - Julieta Galante
- University of Cambridge, Cambridge, UK
- National Institute for Health Research (NIHR) Applied Research Collaboration East of England, Cambridge, UK
| | - Janet Pickering
- Division of Population Medicine, Cardiff University, Cardiff CF14 4XN, UK
| | - John Watkins
- Division of Population Medicine, Cardiff University, Cardiff CF14 4XN, UK
- Public Health Wales, Cardiff, UK
| | - Alison Weightman
- Specialist Unit for Review Evidence, Cardiff University, Cardiff, UK
| | - Delyth Morris
- University Library Service, Cardiff University, Cardiff, UK
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26
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Figueiredo JC, Jacobs EJ, Newton CC, Guinter MA, Cance WG, Campbell PT. Associations of Aspirin and Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs With Colorectal Cancer Mortality After Diagnosis. J Natl Cancer Inst 2021; 113:833-840. [PMID: 33528005 DOI: 10.1093/jnci/djab008] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Revised: 09/21/2020] [Accepted: 01/14/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. METHODS This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided. RESULTS Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99). CONCLUSIONS Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.
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Affiliation(s)
- Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Eric J Jacobs
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Christina C Newton
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - Mark A Guinter
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
| | - William G Cance
- Office of the Chief Medical and Scientific Officer, American Cancer Society, Atlanta, GA, USA
| | - Peter T Campbell
- Department of Population Science, American Cancer Society, Atlanta, GA, USA
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27
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Meyerhardt JA, Shi Q, Fuchs CS, Meyer J, Niedzwiecki D, Zemla T, Kumthekar P, Guthrie KA, Couture F, Kuebler P, Bendell JC, Kumar P, Lewis D, Tan B, Bertagnolli M, Grothey A, Hochster HS, Goldberg RM, Venook A, Blanke C, O’Reilly EM, Shields AF. Effect of Celecoxib vs Placebo Added to Standard Adjuvant Therapy on Disease-Free Survival Among Patients With Stage III Colon Cancer: The CALGB/SWOG 80702 (Alliance) Randomized Clinical Trial. JAMA 2021; 325:1277-1286. [PMID: 33821899 PMCID: PMC8025124 DOI: 10.1001/jama.2021.2454] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 02/10/2021] [Indexed: 12/21/2022]
Abstract
Importance Aspirin and cyclooxygenase 2 (COX-2) inhibitors have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies. The effect of celecoxib, a COX-2 inhibitor, as treatment for nonmetastatic colon cancer is unknown. Objective To determine if the addition of celecoxib to adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) improves disease-free survival in patients with stage III colon cancer. Design, Setting, and Participants Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group 80702 was a 2 × 2 factorial design, phase 3 trial conducted at 654 community and academic centers throughout the United States and Canada. A total of 2526 patients with stage III colon cancer were enrolled between June 2010 and November 2015 and were followed up through August 10, 2020. Interventions Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 vs 6 months with or without 3 years of celecoxib (400 mg orally daily; n = 1263) vs placebo (n = 1261). This report focuses on the results of the celecoxib randomization. Main Outcomes and Measures The primary end point was disease-free survival, measured from the time of randomization until documented recurrence or death from any cause. Secondary end points included overall survival, adverse events, and cardiovascular-specific events. Results Of the 2526 patients who were randomized (mean [SD] age, 61.0 years [11 years]; 1134 women [44.9%]), 2524 were included in the primary analysis. Adherence with protocol treatment, defined as receiving celecoxib or placebo for more than 2.75 years or continuing treatment until recurrence, death, or unacceptable adverse events, was 70.8% for patients treated with celecoxib and 69.9% for patients treated with placebo. A total of 337 patients randomized to celecoxib and 363 to placebo experienced disease recurrence or died, and with 6 years' median follow-up, the 3-year disease-free survival was 76.3% for celecoxib-treated patients vs 73.4% for placebo-treated patients (hazard ratio [HR] for disease recurrence or death, 0.89; 95% CI, 0.76-1.03; P = .12). The effect of celecoxib treatment on disease-free survival did not vary significantly according to assigned duration of adjuvant chemotherapy (P for interaction = .61). Five-year overall survival was 84.3% for celecoxib vs 81.6% for placebo (HR for death, 0.86; 95% CI, 0.72-1.04; P = .13). Hypertension (any grade) occurred while treated with FOLFOX in 14.6% of patients in the celecoxib group vs 10.9% of patients in the placebo group, and a grade 2 or higher increase in creatinine levels occurred after completion of FOLFOX in 1.7% vs 0.5% of patients, respectively. Conclusions and Relevance Among patients with stage III colon cancer, the addition of celecoxib for 3 years, compared with placebo, to standard adjuvant chemotherapy did not significantly improve disease-free survival. Trial Registration ClinicalTrials.gov Identifier: NCT01150045.
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Affiliation(s)
- Jeffrey A. Meyerhardt
- Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, Massachusetts
| | - Qian Shi
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota
| | - Charles S. Fuchs
- Yale Cancer Center, Yale School of Medicine, Smilow Cancer Hospital, New Haven, Connecticut
| | - Jeffrey Meyer
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota
| | - Donna Niedzwiecki
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina
| | - Tyler Zemla
- Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota
| | - Priya Kumthekar
- Feinberg School of Medicine, Northwestern Medicine, Chicago, Illinois
| | - Katherine A. Guthrie
- SWOG Statistics and Data Management Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | - Philip Kuebler
- Columbus NCI Community Oncology Research Program, Columbus, Ohio
| | | | | | | | - Benjamin Tan
- Siteman Cancer Center, Washington University School of Medicine in St Louis, St Louis, Missouri
| | - Monica Bertagnolli
- Office of the Alliance Group Chair, Brigham and Women’s Hospital, Boston, Massachusetts
| | - Axel Grothey
- West Cancer Center & Research Institute, Germantown, Tennessee
| | | | | | | | - Charles Blanke
- SWOG Cancer Research Network Group Chair’s Office, Oregon Health and Science University Knight Cancer Institute
| | - Eileen M. O’Reilly
- Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, New York
| | - Anthony F. Shields
- Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
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28
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Abstract
BACKGROUND The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients. AREAS OF UNCERTAINTY We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry. DATA SOURCES We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described. THERAPEUTIC INNOVATIONS Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine. CONCLUSIONS Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.
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29
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Zheng L, Lv W, Zhou Y, Lin X, Yao J. Progress on the Mechanism for Aspirin's Anti-tumor Effects. Curr Drug Targets 2020; 22:105-111. [PMID: 33050859 DOI: 10.2174/1389450121999201013152931] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/04/2020] [Accepted: 08/13/2020] [Indexed: 02/06/2023]
Abstract
Since its discovery more than 100 years ago, aspirin has been widely used for its antipyretic, analgesic, anti-inflammatory, and anti-rheumatic activities. In addition to these applications, it is increasingly becoming clear that the drug also has great potential in the field of cancer. Here, we briefly review the current insights on aspirin's anti-tumor effects. These are multiple and vary from inhibiting the major cellular mTOR pathways, acting as a calorie-restricted mimetic by inhibition of energy production, suppressing platelet aggregation and granule release, inhibiting the immune escape of tumor cells, to decreasing inflammatory responses. We consider these five mechanisms of action the most significant for aspirin's anti-tumor effects, whereby the anti-tumor effect may ultimately stem from its inhibition of energy metabolism, platelet function, and inflammatory response. As such, aspirin can play an important role to reduce the occurrence, proliferation, and metastasis of various types of tumors. However, most of the collected data are still based on epidemiological investigations. More direct and effective evidence is needed, and the side effects of aspirin intake need to be solved before this drug can be widely applied in cancer treatment.
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Affiliation(s)
- Lin Zheng
- Department of Clinical Laboratory, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan 528300, Guangdong, China
| | - Weibiao Lv
- Department of Clinical Laboratory, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan 528300, Guangdong, China
| | - Yuanqing Zhou
- Department of Clinical Laboratory, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan 528300, Guangdong, China
| | - Xu Lin
- Medical Research Center, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde Foshan), Foshan, Guangdong, China
| | - Jie Yao
- Department of Clinical Laboratory, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan 528300, Guangdong, China
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30
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Wang X, Li T. Ropivacaine inhibits the proliferation and migration of colorectal cancer cells through ITGB1. Bioengineered 2020; 12:44-53. [PMID: 33345684 PMCID: PMC8806321 DOI: 10.1080/21655979.2020.1857120] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
To study whether ropivacaine inhibits the proliferation and migration of colon cancer cells through ITGB1 (Integrin beta-1). First, the effect of ropivacaine on cell proliferation and migration was detected by MTT and Transwell. DAPI staining, annexin V staining and Western blot were used to detect the expression of apoptosis-related proteins to investigate the effect of ropivacaine on cell apoptosis. Using bioinformatics software to predict the potential drug targets of ropivacaine. RT-PCR, Western blot and immunofluorescence verify the distribution and expression of the drug target ITGB1, and detect its downstream-related proteins to further prove that ropivacaine affects colon cancer cells by acting on ITGB1 protein. 1. Ropivacaine significantly inhibited the proliferation of colon cancer cells and promoted their apoptosis 2. Ropivacaine could interact with ITGB1 protein, and inhibited the expression of ITGB1 protein in colon cancer cells, thereby affecting its downstream signaling pathway. Ropivacaine regulates the function of colon cancer cells by targeting the expression of ITGB1 protein and affecting the activation of its downstream signaling pathways. Abbreviation: Integrin beta-1 (ITGB1); 3-(45)-dimethylthiahiazo (-z-y1)-35-di- phenytetrazoliumromide (MTT); 4. 6-diamimo-2-phenyl indole (DAPI); Reverse transcrption PCR (RT-PCR); Colorectal cancer (CRC); Local anesthetics (LA); voltage-gated sodium channel (VGSC); dulbecco s modifed eade medium (DMEM); propidium iodide (PI); dodecyl sulf ate, sodium salt-Polyacrylamide gel electrophoresis (SDS-PAGE); Polyvinylidene Fluoride (PVDF); BCL2 associated X (Bax); Focal Adhesion Kinase (FAK); extracellular signal-regulated kmase (ERK); alpha serme threcnime-proteim kinase (AKT); Glyceraldehyde-3-phosphate dehydrogenase (GAPDH); Tris-buffered salme with 0.1% Tween 20 (TBST); Similarty ensemble approach (SEA)
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Affiliation(s)
- Xiao Wang
- Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University , Beijing, China
| | - Tianzuo Li
- Department of Anesthesiology, Beijing Shijitan Hospital, Capital Medical University , Beijing, China
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31
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Chapelle N, Martel M, Toes-Zoutendijk E, Barkun AN, Bardou M. Recent advances in clinical practice: colorectal cancer chemoprevention in the average-risk population. Gut 2020; 69:2244-2255. [PMID: 32989022 PMCID: PMC7677480 DOI: 10.1136/gutjnl-2020-320990] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 04/15/2020] [Accepted: 05/21/2020] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. Its development is a multistep process that spans more than 15 years, thereby providing an opportunity for prevention and early detection. The high incidence and mortality rates emphasise the need for prevention and screening. Many countries have therefore introduced CRC screening programmes. It is expected, and preliminary evidence in some countries suggests, that this screening effort will decrease CRC-related mortality rates. CRC prevention involves a healthy lifestyle and chemoprevention-more specifically, oral chemoprevention that can interfere with progression from a normal colonic mucosa to adenocarcinoma. This preventive effect is important for individuals with a genetic predisposition, but also in the general population. The ideal chemopreventive agent, or combination of agents, remains unknown, especially when considering safety during long-term use. This review evaluates the evidence across 80 meta-analyses of interventional and observational studies of CRC prevention using medications, vitamins, supplements and dietary factors. This review suggests that the following factors are associated with a decreased incidence of CRC: aspirin, non-steroidal anti-inflammatory drugs, magnesium, folate, a high consumption of fruits and vegetables, fibre and dairy products. An increased incidence of CRC was observed with frequent alcohol or meat consumption. No evidence of a protective effect for tea, coffee, garlic, fish and soy products was found. The level of evidence is moderate for aspirin, β-carotene and selenium, but is low or very low for all other exposures or interventions.
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Affiliation(s)
- Nicolas Chapelle
- Institut des Maladies de l'appareil digestif, Department of Gastroenterology, Hepatology, Nutrition and Medical Oncology, Service de Gastroenterologie, Nantes, France
| | - Myriam Martel
- Department of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada
| | | | - Alan N Barkun
- Department of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada
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Lobb IT, Morin P, Martin K, Thoms HC, Wills JC, Lleshi X, Olsen KCF, Duncan RR, Stark LA. A Role for the Autophagic Receptor, SQSTM1/p62, in Trafficking NF-κB/RelA to Nucleolar Aggresomes. Mol Cancer Res 2020; 19:274-287. [PMID: 33097627 DOI: 10.1158/1541-7786.mcr-20-0336] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 09/18/2020] [Accepted: 10/16/2020] [Indexed: 11/16/2022]
Abstract
Elevated NF-κB activity is a contributory factor in many hematologic and solid malignancies. Nucleolar sequestration of NF-κB/RelA represses this elevated activity and mediates apoptosis of cancer cells. Here, we set out to understand the mechanisms that control the nuclear/nucleolar distribution of RelA and other regulatory proteins, so that agents can be developed that specifically target these proteins to the organelle. We demonstrate that RelA accumulates in intranucleolar aggresomes in response to specific stresses. We also demonstrate that the autophagy receptor, SQSTM1/p62, accumulates alongside RelA in these nucleolar aggresomes. This accumulation is not a consequence of inhibited autophagy. Indeed, our data suggest nucleolar and autophagosomal accumulation of p62 are in active competition. We identify a conserved motif at the N-terminus of p62 that is essential for nucleoplasmic-to-nucleolar transport of the protein. Furthermore, using a dominant-negative mutant deleted for this nucleolar localization signal (NoLS), we demonstrate a role for p62 in trafficking RelA and other aggresome-related proteins to nucleoli, to induce apoptosis. Together, these data identify a novel role for p62 in trafficking nuclear proteins to nucleolar aggresomes under conditions of cell stress, thus maintaining cellular homeostasis. They also provide invaluable information on the mechanisms that regulate the nuclear/nucleolar distribution of RelA that could be exploited for therapeutic purpose. IMPLICATIONS: The data open up avenues for the development of a unique class of therapeutic agents that act by targeting RelA and other aberrantly active proteins to nucleoli, thus killing cancer cells.
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Affiliation(s)
- Ian T Lobb
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Pierre Morin
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Kirsty Martin
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, Edinburgh, Scotland
| | - Hazel C Thoms
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
| | | | - Xhordi Lleshi
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Karl C F Olsen
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland
| | - Rory R Duncan
- Institute of Biological Chemistry, Biophysics and Bioengineering, Heriot Watt University, Edinburgh, Scotland
| | - Lesley A Stark
- Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland.
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Clark CM, Newark AC, Fokar A, Maxwell JH. Aspirin use predicts prolonged survival in patients with oropharyngeal cancer: Nationwide Veterans Affairs database study. Head Neck 2020; 43:247-254. [PMID: 32959950 DOI: 10.1002/hed.26481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 08/06/2020] [Accepted: 09/11/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Single-institution studies suggest that aspirin reduces the risk of death in head and neck cancer. The aim of this study was to investigate the effect of aspirin use on overall survival (OS) in veterans with oropharyngeal cancer (OPC). METHODS A total of 23 083 veterans with OPC were identified between 2005 and 2018 from the Veterans Health Administration Corporate Data Warehouse. Records were queried for clinical-demographic data, aspirin prescriptions, and outcomes. Three-year OS was estimated. A Cox model was used to estimate hazard ratios (HR) for aspirin use. RESULTS Among the 23 083 identified veterans, 17 206 veterans met inclusion criteria. 21.8% used aspirin. Three-year OS was prolonged for aspirin users (66%) compared to nonaspirin users (54%; P < .001). Adjusted HR for death for nonaspirin users was 1.75 (95% confidence interval (CI) [1.60-1.91]). The average treatment effect of aspirin on survival using inverse probability weighting was 10% (95% CI [0.08-0.11]). CONCLUSION Aspirin use following OPC diagnosis was independently associated with improved 3-year OS among veterans nationwide.
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Affiliation(s)
- Christine M Clark
- Department of Otolaryngology - Head and Neck Surgery, MedStar Georgetown University Hospital, Washington, DC, USA
| | | | - Ali Fokar
- Department of Surgery, Washington DC Veterans Affairs Medical Center, Washington, DC, USA
| | - Jessica H Maxwell
- Department of Otolaryngology - Head and Neck Surgery, MedStar Georgetown University Hospital, Washington, DC, USA.,Department of Surgery, Washington DC Veterans Affairs Medical Center, Washington, DC, USA
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Dunbar K, Valanciute A, Lima ACS, Vinuela PF, Jamieson T, Rajasekaran V, Blackmur J, Ochocka-Fox AM, Guazzelli A, Cammareri P, Arends MJ, Sansom OJ, Myant KB, Farrington SM, Dunlop MG, Din FVN. Aspirin Rescues Wnt-Driven Stem-like Phenotype in Human Intestinal Organoids and Increases the Wnt Antagonist Dickkopf-1. Cell Mol Gastroenterol Hepatol 2020; 11:465-489. [PMID: 32971322 PMCID: PMC7797380 DOI: 10.1016/j.jcmgh.2020.09.010] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/17/2020] [Accepted: 09/18/2020] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Aspirin reduces colorectal cancer (CRC) incidence and mortality. Understanding the biology responsible for this protective effect is key to developing biomarker-led approaches for rational clinical use. Wnt signaling drives CRC development from initiation to progression through regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell populations. Here, we investigated whether aspirin can rescue these proinvasive phenotypes associated with CRC progression in Wnt-driven human and mouse intestinal organoids. METHODS We evaluated aspirin-mediated effects on phenotype and stem cell markers in intestinal organoids derived from mouse (ApcMin/+ and Apcflox/flox) and human familial adenomatous polyposis patients. CRC cell lines (HCT116 and Colo205) were used to study effects on motility, invasion, Wnt signaling, and EMT. RESULTS Aspirin rescues the Wnt-driven cystic organoid phenotype by promoting budding in mouse and human Apc deficient organoids, which is paralleled by decreased stem cell marker expression. Aspirin-mediated Wnt inhibition in ApcMin/+ mice is associated with EMT inhibition and decreased cell migration, invasion, and motility in CRC cell lines. Chemical Wnt activation induces EMT and stem-like alterations in CRC cells, which are rescued by aspirin. Aspirin increases expression of the Wnt antagonist Dickkopf-1 in CRC cells and organoids derived from familial adenomatous polyposis patients, which contributes to EMT and cancer stem cell inhibition. CONCLUSIONS We provide evidence of phenotypic biomarkers of response to aspirin with an increased epithelial and reduced stem-like state mediated by an increase in Dickkopf-1. This highlights a novel mechanism of aspirin-mediated Wnt inhibition and potential phenotypic and molecular biomarkers for trials.
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Affiliation(s)
- Karen Dunbar
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Asta Valanciute
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Ana Cristina Silva Lima
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Paz Freile Vinuela
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Thomas Jamieson
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom
| | - Vidya Rajasekaran
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - James Blackmur
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Anna-Maria Ochocka-Fox
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Alice Guazzelli
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Patrizia Cammareri
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Mark J Arends
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom
| | - Kevin B Myant
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Susan M Farrington
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Malcolm G Dunlop
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom
| | - Farhat V N Din
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom; Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
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Wang Q, Li XL, Mei Y, Ye JC, Fan W, Cheng GH, Zeng MS, Feng GK. The anti-inflammatory drug dimethyl itaconate protects against colitis-associated colorectal cancer. J Mol Med (Berl) 2020; 98:1457-1466. [PMID: 32840638 DOI: 10.1007/s00109-020-01963-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 07/05/2020] [Accepted: 08/11/2020] [Indexed: 01/15/2023]
Abstract
Colorectal cancer (CRC) is the third most common diagnosed cancer of which risk factors include unhealthy diet, smoking, and chronic inflammation. Weakening the inflammatory response emerges as an effective therapeutic strategy to prevent the progression of CRC. Inflammatory macrophages produce substantial amounts of immunoregulatory metabolite itaconate, which is synthesized by the immune response gene 1 (Irg1). In this study, we use a membrane-permeable itaconate derivative, dimethyl itaconate (DI), for the protection against CRC in mouse model. DI decreased the high inflammatory state of ulcerative colitis and reduced the colitis-associated cancer (CAC) risk. Mechanistically, DI inhibited the secretion of the cytokines IL-1β and CCL2 from intestinal epithelial cells, and therefore reduced the recruitment of macrophages into tumor microenvironment. Meanwhile, the decrease of macrophage infiltration was accompanied by a decrease of myeloid-derived suppressor cell (MDSC) infiltration and the differentiation of T cell subsets into cytotoxic T cells. We showed that itaconate derivative limits inflammatory response, indicating a negative feedback loop that involves an inflammatory agent and itaconate. Our findings demonstrate the potential application of DI for the prevention of colitis-associated CRC. KEY MESSAGES: Dimethyl itaconate (DI) suppresses ulcerative colitis and colitis-associated colorectal cancer DI decreases infiltration of macrophages and myeloid-derived suppressor cells into tumor DI weakens the inflammatory response via inhibiting the secretion of IL-1β and CCL2.
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Affiliation(s)
- Qian Wang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center/Cancer Hospital, 651 Dongfeng East Road, Guangzhou, 510060, China.,Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China
| | - Xin Ling Li
- Nuclear Medicine Department, Radiation Oncology Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Yan Mei
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center/Cancer Hospital, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Jia-Chong Ye
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center/Cancer Hospital, 651 Dongfeng East Road, Guangzhou, 510060, China
| | - Wei Fan
- Nuclear Medicine Department, Radiation Oncology Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
| | - Guang-Hui Cheng
- Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, 130033, China.
| | - Mu-Sheng Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center/Cancer Hospital, 651 Dongfeng East Road, Guangzhou, 510060, China.
| | - Guo-Kai Feng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center/Cancer Hospital, 651 Dongfeng East Road, Guangzhou, 510060, China.
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Hao Y, Wang Y, Qi M, He X, Zhu Y, Hong J. Risk Factors for Recurrent Colorectal Polyps. Gut Liver 2020; 14:399-411. [PMID: 31547641 PMCID: PMC7366149 DOI: 10.5009/gnl19097] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 05/22/2019] [Accepted: 06/05/2019] [Indexed: 12/12/2022] Open
Abstract
The recurrence of colorectal polyps is caused by various factors and leads to the carcinogenesis of colorectal cancer, which ranks third in incidence and fourth in mortality among cancers worldwide. The potential risk factors for colorectal polyp recurrence have been demonstrated in multiple trials. However, an article that pools and summarizes the various results is needed. This review enumerates and analyzes some risk factors in terms of patient characteristics, procedural operations, polyp characteristics, and dietary aspects to propose some effective prophylactic measures. This review aimed to provide a reference for clinical application and guide patients to prevent colorectal polyp recurrence in a more effective manner.
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Affiliation(s)
- Yuanzhen Hao
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China
| | - Yining Wang
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China.,Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, Shangha
| | - Miao Qi
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China.,Joint Programme of Nanchang University and Queen Mary University of London, Nanchang, China
| | - Xin He
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Ying Zhu
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Junbo Hong
- Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, China
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Wang H, Wang L, Xie Z, Zhou S, Li Y, Zhou Y, Sun M. Nitric Oxide (NO) and NO Synthases (NOS)-Based Targeted Therapy for Colon Cancer. Cancers (Basel) 2020; 12:E1881. [PMID: 32668616 PMCID: PMC7408898 DOI: 10.3390/cancers12071881] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/10/2020] [Accepted: 07/10/2020] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal malignancies worldwide and CRC therapy remains unsatisfactory. In recent decades, nitric oxide (NO)-a free-radical gas-plus its endogenous producer NO synthases (NOS), have attracted considerable attention. NO exerts dual effects (pro- and anti-tumor) in cancers. Endogenous levels of NO promote colon neoplasms, whereas exogenously sustained doses lead to cytotoxic functions. Importantly, NO has been implicated as an essential mediator in many signaling pathways in CRC, such as the Wnt/β-catenin and extracellular-signal-regulated kinase (ERK) pathways, which are closely associated with cancer initiation, metastasis, inflammation, and chemo-/radio-resistance. Therefore, NO/NOS have been proposed as promising targets in the regulation of CRC carcinogenesis. Clinically relevant NO-donating agents have been developed for CRC therapy to deliver a high level of NO to tumor sites. Notably, inducible NOS (iNOS) is ubiquitously over-expressed in inflammatory-associated colon cancer. The development of iNOS inhibitors contributes to targeted therapies for CRC with clinical benefits. In this review, we summarize the multifaceted mechanisms of NO-mediated networks in several hallmarks of CRC. We review the clinical manifestation and limitations of NO donors and NOS inhibitors in clinical trials. We also discuss the possible directions of NO/NOS therapies in the immediate future.
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Affiliation(s)
- Hao Wang
- College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China;
| | - Liye Wang
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Zuoxu Xie
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Shuang Zhou
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Yan Li
- Department of Pharmacological and Pharmaceutical Science, College of Pharmacy, University of Houston, Houston, TX, 77204, USA; (L.W.); (Z.X.); (S.Z.); (Y.L.)
| | - Yue Zhou
- Department of Statistics, North Dakota University, Fargo, ND 58105, USA;
| | - Meiyan Sun
- College of Laboratory Medicine, Jilin Medical University, Jilin 132013, China;
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Shimura T, Toden S, Komarova NL, Boland C, Wodarz D, Goel A. A comprehensive in vivo and mathematic modeling-based kinetic characterization for aspirin-induced chemoprevention in colorectal cancer. Carcinogenesis 2020; 41:751-760. [PMID: 31904094 PMCID: PMC7351132 DOI: 10.1093/carcin/bgz195] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2019] [Revised: 10/22/2019] [Indexed: 12/21/2022] Open
Abstract
Accumulating evidence suggests that aspirin has anti-tumorigenic properties in colorectal cancer (CRC). Herein, we undertook a comprehensive and systematic series of in vivo animal experiments followed by 3D-mathematical modeling to determine the kinetics of aspirin's anti-cancer effects on CRC growth. In this study, CRC xenografts were generated using four CRC cell lines with and without PIK3CA mutations and microsatellite instability, and the animals were administered with various aspirin doses (0, 15, 50, and 100 mg/kg) for 2 weeks. Cell proliferation, apoptosis and protein expression were evaluated, followed by 3D-mathematical modeling analysis to estimate cellular division and death rates and their impact on aspirin-mediated changes on tumor growth. We observed that aspirin resulted in a dose-dependent decrease in the cell division rate, and a concomitant increase in the cell death rates in xenografts from all cell lines. Aspirin significantly inhibited cell proliferation as measured by Ki67 staining (P < 0.05-0.01). The negative effect of aspirin on the rate of tumor cell proliferation was more significant in xenograft tumors derived from PIK3CA mutant versus wild-type cells. A computational model of 3D-tumor growth suggests that the growth inhibitory effect of aspirin on the tumor growth kinetics is due to a reduction of tumor colony formation, and that this effect is sufficiently strong to be an important contributor to the reduction of CRC incidence in aspirin-treated patients. In conclusion, we provide a detailed kinetics of aspirin-mediated inhibition of tumor cell proliferation, which support the epidemiological data for the observed protective effect of aspirin in CRC patients.
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Affiliation(s)
- Tadanobu Shimura
- Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Shusuke Toden
- Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | | | - Crichard Boland
- Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Dominik Wodarz
- Department of Population Health and Disease Prevention Program in Public Health Susan and Henry Samueli College of Health Sciences and Department of Mathematics, University of California, Irvine, CA, USA
| | - Ajay Goel
- Center for Gastrointestinal Research, Center from Translational Genomics and Oncology, Baylor Scott and White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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Lin JL, Lin JX, Zheng CH, Li P, Xie JW, Wang JB, Lu J, Chen QY, Cao LL, Lin M, Huang CM. Relationship between aspirin use of esophageal, gastric and colorectal cancer patient survival: a meta-analysis. BMC Cancer 2020; 20:638. [PMID: 32646396 PMCID: PMC7350580 DOI: 10.1186/s12885-020-07117-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 06/26/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Many studies have found that use of aspirin can lengthen survival in patients with gastrointestinal cancer. The aim of this study was to assess the survival benefit of aspirin use compared with non-aspirin use for patients with esophageal, gastric or colorectal cancer. METHODS We searched online databases, including PubMed, the Cochrane Library, Embase and www.clinicaltrials.gov for studies that were conducted, before April 30th, 2020, to identify relevant studies. Overall survival and cancer-specific survival of esophageal, gastric and colorectal cancers among aspirin users were compared with those among non-aspirin users. Data extraction and quality evaluation were independently conducted by 2 investigators. A meta-analysis was performed to calculate the pooled risk ratios (RRs) for overall survival and cancer-specific survival by using either a fixed-effects model or a random-effects model. RESULTS A total of 18 studies were included in this meta-analysis, with more than 74,936 patients. There were no significant differences between postdiagnosis aspirin use and overall survival for esophageal and gastric cancers. For colorectal cancer, a benefit that was associated with postdiagnosis aspirin use was observed for overall survival and cancer-specific survival [HR = 0.83, 95%CI(0.75, 0.9.);HR = 0.78, 95%CI(0.66, 0.92), respectively. However, a prediagnosis of aspirin use did not provide a benefit for overall or cancer-specific survival in colorectal cancer. HR values for overall and cancer-specific survival benefits for colorectal cancer associated with both prediagnosis and postdiagnosis aspirin were as follows: HR = 0.75, 95%CI(0.61, 0.92) and HR = 0.78, 95%CI(0.73, 0.85), respectively. In addition, the survival benefit of postdiagnosis aspirin use appeared to be confined to patients with mutated PIK3CA tumors [HR = 0.78, 95%CI(0.50, 0.99)] and was positive for PTGS2 (COX-2) expression [HR = 0.75, 95%CI(0.43, 1.30)]. CONCLUSIONS These findings provide further indications that postdiagnosis aspirin use improves overall survival and cancer-specific survival in colorectal cancer, especially for patients who are positive for PTGS2 (COX-2) expression and PIK3CA-mutated tumors. However, aspirin therapy does not improve overall survival in esophageal and gastric cancers, although the meta-analysis was mainly limited to retrospective studies.
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Affiliation(s)
- Ju-Li Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Jian-Xian Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Chao-Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jian-Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Jia-Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Qi-Yue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Long-Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Mi Lin
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China
| | - Chang-Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, No.29 Xinquan Road, Fuzhou, 350001, Fujian Province, China.
- Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian Province, China.
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, Fujian Province, China.
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Giorli G, Rouette J, Yin H, Lapi F, Simonetti M, Cricelli C, Pollak M, Azoulay L. Prediagnostic use of low-dose aspirin and risk of incident metastasis and all-cause mortality among patients with colorectal cancer. Br J Clin Pharmacol 2020; 86:2266-2273. [PMID: 32352592 DOI: 10.1111/bcp.14329] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/24/2022] Open
Abstract
AIMS Previous studies suggest that the use of low-dose aspirin before a colorectal cancer (CRC) diagnosis may be associated with a decreased risk of CRC progression. Data supporting this association, however, have been inconsistent. We evaluate whether the use of prediagnostic low-dose aspirin is associated with a lower risk of metastases and all-cause mortality in CRC patients. METHODS Using a large Italian population-based primary care database, we identified a cohort of 7478 patients newly diagnosed with nonmetastatic CRC between 2000 and 2013. Use of prediagnostic low-dose aspirin was compared with no use of low-dose aspirin. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of incident metastasis and of all-cause mortality associated with prediagnostic low-dose aspirin use, both overall and by duration of use. RESULTS There were 314 incident metastatic events and 2189 deaths during a mean follow-up time of 4.4 and 4.7 years, respectively. Overall prediagnostic use of low-dose aspirin was not associated with a decreased risk of incident metastasis (HR 0.88; 95% CI 0.63-1.22) or all-cause mortality (HR 1.09; 95% CI 0.96-1.22) in CRC patients. Cumulative duration of aspirin use was not associated with a decreased risk of incident metastasis (P-trend = .22) or all-cause mortality (P-trend = .38). These findings remained consistent in sensitivity analyses. CONCLUSION In this real-world, population-based study, the prediagnostic use of low-dose aspirin was not associated with a decreased risk of incident metastasis or all-cause mortality in CRC patients.
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Affiliation(s)
- Giovanni Giorli
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada.,Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.,Department of Statistics and Quantitative Methods, Unit of Biostatistics and Epidemiology, University of Milano-Bicocca, Milan, Italy.,Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Julie Rouette
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada.,Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
| | - Hui Yin
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
| | - Francesco Lapi
- Health Search, Italian College of General Practitioners and Primary Care - SIMG, Florence, Italy
| | - Monica Simonetti
- Health Search, Italian College of General Practitioners and Primary Care - SIMG, Florence, Italy
| | - Claudio Cricelli
- Health Search, Italian College of General Practitioners and Primary Care - SIMG, Florence, Italy
| | - Michael Pollak
- Segal Cancer Center, Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Canada.,Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
| | - Laurent Azoulay
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada.,Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.,Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada
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Oh HH, Joo YE. Novel biomarkers for the diagnosis and prognosis of colorectal cancer. Intest Res 2020; 18:168-183. [PMID: 31766836 PMCID: PMC7206347 DOI: 10.5217/ir.2019.00080] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/05/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is among the most common malignancies and remains a major cause of cancer-related death worldwide. Despite recent advances in surgical and multimodal therapies, the overall survival of advanced CRC patients remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. The underlying mechanisms of action resulting in cancer progression are beginning to unravel. The reported molecular and biochemical mechanisms that might contribute to the phenotypic changes in favor of carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, and immune surveillance inhibition. These events may contribute to the development and progression of cancer. A biomarker is a molecule that can be detected in tissue, blood, or stool samples to allow the identification of pathological conditions such as cancer. Thus, it would be beneficial to identify reliable and practical molecular biomarkers that aid in the diagnostic and therapeutic processes of CRC. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. Despite that, the identification of diagnostic, prognostic, and/or predictive biomarkers remains challenging, and previously identified biomarkers might be insufficient to be clinically applicable or offer high patient acceptability. Here, we discuss recent advances in the development of molecular biomarkers for their potential usefulness in early and less-invasive diagnosis, treatment, and follow-up of CRC.
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Affiliation(s)
- Hyung-Hoon Oh
- Department of Internal Medicine, 3rd Fleet Medical Corps, Republic of Korea Navy, Yeongam, Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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43
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Ke TM, Lin LC, Huang CC, Chien YW, Ting WC, Yang CC. High neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio predict poor survival in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy. Medicine (Baltimore) 2020; 99:e19877. [PMID: 32332656 PMCID: PMC7220521 DOI: 10.1097/md.0000000000019877] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
This study explored the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in rectal cancer patients receiving neoadjuvant concurrent chemoradiotherapy (CCRT).Between January 2006 and December 2016, 184 patients with newly-diagnosed rectal cancer receiving neoadjuvant CCRT were enrolled. Risk of overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method and Cox proportional hazard models. Stratified survival analyses were also performed between post-neoadjuvant pathological (yp) stage.The mean follow-up time was 72.73 ± 36.82 months. High- and low-NLR patients differed significantly in both 5-year DFS (P = .026) and OS (P = .016). High- and low-PLR patients differed significantly in 5-year DFS (P = .011) but not OS (P = .185). Multivariate analyses revealed worse 5-year DFS (adjusted HR [aHR] = 2.8; 95% CI: 1.473-5.41; P = .002) and 5-year OS (aHR = 1.871; 95%CI: 1.029-3.4; P = .04) in the high-NLR group after adjusting for covariates. After adjustments, the high-PLR group had inferior 5-year DFS (aHR = 2.274; 95%CI: 1.473-5.419; P = .038) but not 5-year OS (aHR = 1.156; 95%CI: 0.650-2.056; P = .622). Further stratified analysis indicated that yp stage II and III patients with high NLR had worse 5-year DFS (aHR = 2.334; 95% CI: 1.158-4.725; P = .018) and OS (aHR = 2.226; 95% CI: 1.165-4.251; P = .015). Additionally, yp stage II and III patients with high PLR had inferior 5-year DFS (aHR = 2.012; 95% CI: 1.049-3.861; P = .036).Pre-CCRT NLR and PLR are independent prognostic factors for rectal cancer patients and could be used as a potential biomarker to identify high-risk patients for more intense treatment and care.
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Affiliation(s)
- Te-Min Ke
- Dali District public health center, Taichung
- Department of Public Health College of Medicine, National Cheng Kung University
| | - Li-Ching Lin
- Department of Radiation Oncology, Chi Mei Medical Center
- Department of Optometry, Chung Hwa University of Medical Technology, Tainan
- School of Medicine, Taipei Medical University, Taipei
| | - Chun-Che Huang
- Department of Healthcare Administration, I-Shou University, Kaohsiung
| | - Yu-Wen Chien
- Department of Public Health College of Medicine, National Cheng Kung University
| | - Wei-Chen Ting
- Department of radiation oncology, Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital, Pingtung
| | - Ching-Chieh Yang
- Department of Radiation Oncology, Chi Mei Medical Center
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan Taiwan
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Koulis C, Yap R, Engel R, Jardé T, Wilkins S, Solon G, Shapiro JD, Abud H, McMurrick P. Personalized Medicine-Current and Emerging Predictive and Prognostic Biomarkers in Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12040812. [PMID: 32231042 PMCID: PMC7225926 DOI: 10.3390/cancers12040812] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/24/2020] [Accepted: 03/24/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and is heterogeneous both morphologically and molecularly. In an era of personalized medicine, the greatest challenge is to predict individual response to therapy and distinguish patients likely to be cured with surgical resection of tumors and systemic therapy from those resistant or non-responsive to treatment. Patients would avoid futile treatments, including clinical trial regimes and ultimately this would prevent under- and over-treatment and reduce unnecessary adverse side effects. In this review, the potential of specific biomarkers will be explored to address two key questions—1) Can the prognosis of patients that will fare well or poorly be determined beyond currently recognized prognostic indicators? and 2) Can an individual patient’s response to therapy be predicted and those who will most likely benefit from treatment/s be identified? Identifying and validating key prognostic and predictive biomarkers and an understanding of the underlying mechanisms of drug resistance and toxicity in CRC are important steps in order to personalize treatment. This review addresses recent data on biological prognostic and predictive biomarkers in CRC. In addition, patient cohorts most likely to benefit from currently available systemic treatments and/or targeted therapies are discussed in this review.
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Affiliation(s)
- Christine Koulis
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Correspondence: ; Tel.: +61-03-9508-3547
| | - Raymond Yap
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
| | - Rebekah Engel
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
| | - Thierry Jardé
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton 3168, VIC, Australia
| | - Simon Wilkins
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3000, VIC, Australia
| | - Gemma Solon
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
| | - Jeremy D. Shapiro
- Cabrini Haematology and Oncology Centre, Cabrini Health, Malvern 3144, VIC, Australia;
| | - Helen Abud
- Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, VIC, Australia; (T.J.); (H.A.)
- Monash Biomedicine Discovery Institute, Stem Cells and Development Program, Monash University, Clayton 3800, VIC, Australia
| | - Paul McMurrick
- Cabrini Monash University Department of Surgery, Cabrini Health, Malvern 3144, VIC, Australia; (R.Y.); (R.E.); (S.W.); (G.S.); (P.M.)
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Chen Z, Wang C, Dong H, Wang X, Gao F, Zhang S, Zhang X. Aspirin has a better effect on PIK3CA mutant colorectal cancer cells by PI3K/Akt/Raptor pathway. Mol Med 2020; 26:14. [PMID: 32000660 PMCID: PMC6993447 DOI: 10.1186/s10020-020-0139-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/22/2020] [Indexed: 12/21/2022] Open
Abstract
Background Aspirin, as a non-steroidal anti-inflammatory drug, can improve the survival rate of patients with colorectal cancer, while aspirin is effective in patients with PIK3CA mutant colorectal cancer (CRC). However, the mechanism of aspirin in the treatment of PIK3CA mutated CRC patients remains unclear. Methods In this study, immunohistochemistry was used to detect the expression levels of PI3K and Raptor in colorectal cancer patients with PIK3CA mutation and PIK3CA wild-type patients. To demonstrate that aspirin has a better effect on the CRC of PIK3CA mutations in association with the PI3K/Akt/Raptor pathway, we used aspirin to treat PIK3CA mutant CRC cells (HCT-116 and RKO). Subsequently, the CCK8 assay and flow cytometry assay were used to detect the apoptosis of PIK3CA mutant CRC cells before and after aspirin use. Western blot was used to detect the changes of PI3K/Akt/Raptor-associated protein, autophagy protein microtubule associated protein 1 light chain 3 alpha (MAP1LC3A, LC3), beclin 1 (BECN1) and apoptosis protein BCL2-associated X protein/ BCL2 apoptosis regulator (Bax/Bcl2), Caspase 3 after treatment of CRC cells with PIK3CA mutation by aspirin. Results Phosphoinositide-3-kinase (PI3K) and regulatory associated protein of MTOR complex 1 (Raptor) protein expression levels were higher in PIK3CA-mutant patients than in IK3CA wild-type patients. The expression of Bax/Bcl2 increased after treatment indicates that aspirin can induce apoptosis of PIK3CA-mutant CRC cells. The expression level of MAP1LC3 (LC3) in cells increases with the concentration of aspirin demonstrates that aspirin can induce autophagy in CRC cells. After 48 h of treatment with aspirin, the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1) and ribosomal protein S6 kinase B1 (S6K1) was reduced, cell proliferation has been inhibited. After treatment with aspirin, as phosphorylation of PI3K and Protein kinase B (PKB, Akt) was decreased, Raptor expression was also decreased. Conclusion Aspirin can regulate the proliferation, apoptosis and autophagy of CRC cells through the PI3K/Akt/Raptor pathway, affecting PIK3CA-mutant CRC.
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Affiliation(s)
- Zhihang Chen
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Chun Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, 430000, China
| | - Hao Dong
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Xing Wang
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Feng Gao
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Sen Zhang
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China
| | - Xiaolong Zhang
- Department of Colorectal and Anal Surgery, the First Affiliated Hospital, Guangxi Medical University, Nanning, 530021, China.
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Olgen S, Kotra LP. Drug Repurposing in the Development of Anticancer Agents. Curr Med Chem 2019; 26:5410-5427. [PMID: 30009698 DOI: 10.2174/0929867325666180713155702] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 06/14/2018] [Accepted: 06/28/2018] [Indexed: 01/07/2023]
Abstract
BACKGROUND Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established. OBJECTIVE This review provides an overview of anticancer drug development strategies which is one of the important areas of drug restructuring. METHODS Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anticancer agents are evaluated in this review. RESULTS AND CONCLUSION Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development.
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Affiliation(s)
- Sureyya Olgen
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey
| | - Lakshmi P Kotra
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, M5S 3M2, Canada.,Center for Molecular Design and Preformulations, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, M5G 1L7 Canada.,Multi-Organ Transplant Program, Toronto General Hospital, Toronto, Ontario, M5G 1L7 Canada
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Renzi C, Kaushal A, Emery J, Hamilton W, Neal RD, Rachet B, Rubin G, Singh H, Walter FM, de Wit NJ, Lyratzopoulos G. Comorbid chronic diseases and cancer diagnosis: disease-specific effects and underlying mechanisms. Nat Rev Clin Oncol 2019; 16:746-761. [PMID: 31350467 DOI: 10.1038/s41571-019-0249-6] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2019] [Indexed: 02/06/2023]
Abstract
An earlier diagnosis is a key strategy for improving the outcomes of patients with cancer. However, achieving this goal can be challenging, particularly for the growing number of people with one or more chronic conditions (comorbidity/multimorbidity) at the time of diagnosis. Pre-existing chronic diseases might affect patient participation in cancer screening, help-seeking for new and/or changing symptoms and clinicians' decision-making on the use of diagnostic investigations. Evidence suggests, for example, that pre-existing pulmonary, cardiovascular, neurological and psychiatric conditions are all associated with a more advanced stage of cancer at diagnosis. By contrast, hypertension and certain gastrointestinal and musculoskeletal conditions might be associated with a more timely diagnosis. In this Review, we propose a comprehensive framework that encompasses the effects of disease-specific, patient-related and health-care-related factors on the diagnosis of cancer in individuals with pre-existing chronic illnesses. Several previously postulated aetiological mechanisms (including alternative explanations, competing demands and surveillance effects) are integrated with newly identified mechanisms, such as false reassurances, or patient concerns about appearing to be a hypochondriac. By considering specific effects of chronic diseases on diagnostic processes and outcomes, tailored early diagnosis initiatives can be developed to improve the outcomes of the large proportion of patients with cancer who have pre-existing chronic conditions.
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Affiliation(s)
- Cristina Renzi
- ECHO (Epidemiology of Cancer Healthcare and Outcomes) Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK.
- Cancer Survival Group, Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.
| | - Aradhna Kaushal
- ECHO (Epidemiology of Cancer Healthcare and Outcomes) Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK
| | - Jon Emery
- Centre for Cancer Research and Department of General Practice, University of Melbourne, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
| | - Willie Hamilton
- St Luke's Campus, University of Exeter Medical School, Exeter, UK
| | - Richard D Neal
- Leeds Institute of Health Sciences, University of Leeds, Leeds, UK
| | - Bernard Rachet
- Cancer Survival Group, Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Greg Rubin
- Institute of Health and Society, Sir James Spence Institute, Newcastle University, Royal Victoria Infirmary, Newcastle upon Tyne, UK
| | - Hardeep Singh
- Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX, USA
| | - Fiona M Walter
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Niek J de Wit
- Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht University, Utrecht, Netherlands
| | - Georgios Lyratzopoulos
- ECHO (Epidemiology of Cancer Healthcare and Outcomes) Research Group, Department of Behavioural Science and Health, Institute of Epidemiology & Health Care, University College London, London, UK
- The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
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Mohammed A, Janakiram NB, Madka V, Zhang Y, Singh A, Biddick L, Li Q, Lightfoot S, Steele VE, Lubet RA, Suen CS, Miller MS, Sei S, Rao CV. Intermittent Dosing Regimens of Aspirin and Naproxen Inhibit Azoxymethane-Induced Colon Adenoma Progression to Adenocarcinoma and Invasive Carcinoma. Cancer Prev Res (Phila) 2019; 12:751-762. [PMID: 31530543 PMCID: PMC6849393 DOI: 10.1158/1940-6207.capr-19-0312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 07/17/2019] [Accepted: 09/10/2019] [Indexed: 12/24/2022]
Abstract
Chronic use of aspirin and related drugs to reduce cancer risk is limited by unwanted side effects. Thus, we assessed the efficacy associated with different dosing regimens of aspirin and naproxen. Azoxymethane (AOM)-rat colon cancer model was used to establish the pharmacodynamic efficacy of aspirin and naproxen under different dosing regimens. Colon tumors were induced in rats (36/group) by two weekly doses of AOM. At the early adenoma stage, rats were fed diets containing aspirin (700 and 1,400 ppm) or naproxen (200 and 400 ppm), either continuously, 1 week on/1 week off, or 3 weeks on/3 weeks off, or aspirin (2,800 ppm) 3 weeks on/3 weeks off. All rats were euthanized 48 weeks after AOM treatment and assessed for efficacy and biomarkers in tumor tissues. Administration of aspirin and naproxen produced no overt toxicities. Administration of different treatment regimens of both agents had significant inhibitory effects with clear dose-response effects. Aspirin suppressed colon adenocarcinoma multiplicity (both invasive and noninvasive) by 41% (P < 0.003) to 72% (P < 0.0001) and invasive colon adenocarcinomas by 67%-91% (P < 0.0001), depending on the treatment regimen. Naproxen doses of 200 and 400 ppm inhibited invasive adenocarcinoma multiplicity by 53%-88% (P < 0.0001), depending on the dosing regimen. Colonic tumor biomarker analysis revealed that proliferation (proliferating cell nuclear antigen and p21), apoptosis (p53 and Caspase-3), and proinflammatory mediators (IL1β and prostaglandin E2) were significantly correlated with the tumor inhibitory effects of aspirin and naproxen. Overall, our results suggest that intermittent dosing regimens with aspirin or naproxen demonstrated significant efficacy on the progression of adenomas to adenocarcinomas, without gastrointestinal toxicities.
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Affiliation(s)
- Altaf Mohammed
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- DoD/VA, Extremity Trauma & Amputation Center of Excellence, WRNMMC, Bethesda, Maryland
| | - Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Yuting Zhang
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Anil Singh
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
- VA Medical Center, Oklahoma City, Oklahoma
| | - Laura Biddick
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Qian Li
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Stanley Lightfoot
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma
| | - Vernon E Steele
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Ronald A Lubet
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Chen S Suen
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Mark Steven Miller
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Shizuko Sei
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, NCI, Rockville, Maryland
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, Stephenson Cancer Center and University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
- VA Medical Center, Oklahoma City, Oklahoma
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Chao G, Ye F, Yuan Y, Zhang S. Berberine ameliorates non-steroidal anti-inflammatory drugs-induced intestinal injury by the repair of enteric nervous system. Fundam Clin Pharmacol 2019; 34:238-248. [PMID: 31520444 DOI: 10.1111/fcp.12509] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 08/07/2019] [Accepted: 09/09/2019] [Indexed: 12/28/2022]
Abstract
The study was to detect the role of GDNF, PGP9.5 (a neuronal marker), and GFAP (EGCs' marker) in the mechanism of non-steroidal anti-inflammatory drugs (NSAIDs) related to intestinal injury and to clarify the protective effect of berberine in the treatment of NSAID-induced small intestinal disease. Forty male SD rats were divided randomly into five groups (A-E): Group A: control group; Group B: model group received diclofenac sodium 7.5 mg/(kg*day) for 5 days; Group C-E: berberine low, medium and high dose groups were treated by 7.5 mg/(kg*day) diclofenac sodium for 5 days then received berberine 25 mg/(kg*day), 50 mg/(kg*day), and 75 mg/(kg*day), respectively, between the sixth and eighth day. Intestinal mucosa was taken on the ninth day to observe the general, histological injuries, and to measure the intestinal epithelial thickness. Then, immunohistochemistry was performed to detect the expression of PGP9.5 and GFAP, and Western blot was performed to detect GDNF expression. The histological score and the general score in the model group were, respectively, 5.75 ± 1.04 and 4.83 ± 0.92. Scores in berberine medium and high berberine group were lower compared with the model group (P < 0.05). The intestinal epithelial thickness in the model group was lower than in the control group and the berberine groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the model group and the three berberine groups were significantly lower than in the control groups (P < 0.05). PGP9.5, GFAP, and GDNF content in the control group and the three berberine groups were higher compared with the model groups (P < 0.05). Berberine can protect the intestinal mucosa of NSAID users, and the mechanism is associated with the reparation of the enteric nervous system via upregulating the expression of PGP9.5, GFAP, and GDNF.
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Affiliation(s)
- Guanqun Chao
- Department of General Practice, Sir Run Run Shaw Hospital, Zhejiang University, China
| | - Fangxu Ye
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
| | - Yuan Yuan
- Department of Gastroenterology, The First Affiliated Hospital, Henan Chinese Medical University, China
| | - Shuo Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Zhejiang Chinese Medical University, China
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Blaylock RL. Accelerated cancer aggressiveness by viral oncomodulation: New targets and newer natural treatments for cancer control and treatment. Surg Neurol Int 2019; 10:199. [PMID: 31768279 PMCID: PMC6826277 DOI: 10.25259/sni_361_2019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 06/19/2019] [Indexed: 12/12/2022] Open
Abstract
An infectious etiology for a number of cancers has been entertained for over 100 years and modern studies have confirmed that a number of viruses are linked to cancer induction. While a large number of viruses have been demonstrated in a number of types of cancers, most such findings have been dismissed in the past as opportunistic infections, especially with persistent viruses with high rates of infectivity of the world’s populations. More recent studies have clearly shown that while not definitely causing these cancers, these viruses appear capable of affecting the biology of these tumors in such a way as to make them more aggressive and more resistant to conventional treatments. The term oncomodulatory viruses has been used to describe this phenomenon. A number of recent studies have shown a growing number of ways these oncomodulatory viruses can alter the pathology of these tumors by affecting cell-signaling, cell metabolism, apoptosis mechanisms, cell-cell communication, inflammation, antitumor immunity suppression, and angiogenesis. We are also learning that much of the behavior of tumors depends on cancer stem cells and stromal cells within the tumor microenvironment, which participate in extensive, dynamic crosstalk known to affect tumor behavior. Cancer stem cells have been found to be particularly susceptible to infection by human cytomegalovirus. In a number of studies, it has been shown that while only a select number of cells are actually infected with the virus, numerous viral proteins are released into cancer and stromal cells in the microenvironment and these viral proteins are known to affect tumor behavior and aggressiveness.
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