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Kayzuka C, Rondon-Pereira VC, Nogueira Tavares C, Pacheco Pachado M, Monica FZ, Tanus-Santos JE, Lacchini R. Epigenetics is involved in the pleiotropic effects of statins. Expert Opin Drug Metab Toxicol 2025; 21:689-701. [PMID: 40208655 DOI: 10.1080/17425255.2025.2491732] [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: 08/31/2024] [Revised: 02/18/2025] [Accepted: 04/07/2025] [Indexed: 04/11/2025]
Abstract
INTRODUCTION Statins have significantly reduced mortality from cardiovascular diseases by lowering serum cholesterol levels. Beyond their lipid-lowering effects, statins improve vascular function, reduce inflammation, decrease reactive oxygen species (ROS) formation, and stabilize atherosclerotic plaques. However, the mechanisms underlying these pleiotropic effects remain unclear. AREA COVERED This narrative review summarizes and discusses epigenetic mechanisms that may explain part of the pleiotropic effects of statins. This approach allows for a reevaluation of statin use beyond its cholesterol-lowering benefits. A structured search was conducted in the PubMed and Scopus databases using specific search terms, including articles published up to August 2024. EXPERT OPINION The pleiotropic effects of statins, including those mediated by the isoprenoid pathway, partially explain their clinical benefits. By inhibiting histone deacetylases (HDACs, the 'erasers') and DNA methyltransferases (DNMTs, the 'writers'), statins promote increased histone acetylation and reduced DNA methylation at gene promoter regions. These epigenetic modifications enhance chromatin accessibility, facilitating gene transcription and protecting the cardiovascular system. Further investigation into these epigenetic mechanisms could support the repositioning of statins for broader therapeutic applications. Statins may have benefits extending beyond their role in managing hypercholesterolemia, as their pleiotropic effects contribute to the prevention of cardiovascular disease-related mortality through mechanisms independent of LDL cholesterol reduction.
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Affiliation(s)
- Cezar Kayzuka
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | | | - Cecilia Nogueira Tavares
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Mayra Pacheco Pachado
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Fabiola Zakia Monica
- Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil
| | - Jose Eduardo Tanus-Santos
- Department of Pharmacology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil
| | - Riccardo Lacchini
- Department of Psychiatric Nursing and Human Sciences, Ribeirao Preto College of Nursing, University of Sao Paulo, Ribeirao Preto, Brazil
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Li J, Pan J, Wang L, Ji G, Dang Y. Colorectal Cancer: Pathogenesis and Targeted Therapy. MedComm (Beijing) 2025; 6:e70127. [PMID: 40060193 PMCID: PMC11885891 DOI: 10.1002/mco2.70127] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 04/29/2025] Open
Abstract
Colorectal cancer (CRC) ranks among the most prevalent malignant neoplasms globally. A growing body of evidence underscores the pivotal roles of genetic alterations and dysregulated epigenetic modifications in the pathogenesis of CRC. In recent years, the reprogramming of tumor cell metabolism has been increasingly acknowledged as a hallmark of cancer. Substantial evidence suggests a crosstalk between tumor cell metabolic reprogramming and epigenetic modifications, highlighting a complex interplay between metabolism and the epigenetic genome that warrants further investigation. Biomarkers associated with the pathogenesis and metabolic characteristics of CRC hold significant clinical implications. Nevertheless, elucidating the genetic, epigenetic, and metabolic landscapes of CRC continues to pose considerable challenges. Here, we attempt to summarize the key genes driving the onset and progression of CRC and the related epigenetic regulators, clarify the roles of gene expression and signaling pathways in tumor metabolism regulation, and explore the potential crosstalk between epigenetic events and tumor metabolic reprogramming, providing a comprehensive mechanistic explanation for the malignant progression of CRC. Finally, by integrating reliable targets from genetics, epigenetics, and metabolic processes that hold promise for translation into clinical practice, we aim to offer more strategies to overcome the bottlenecks in CRC treatment.
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Affiliation(s)
- Jingyuan Li
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Jiashu Pan
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Lisheng Wang
- Department of BiochemistryMicrobiology and ImmunologyFaculty of MedicineUniversity of OttawaOttawaOntarioCanada
- China‐Canada Centre of Research for Digestive DiseasesUniversity of OttawaOttawaOntarioCanada
| | - Guang Ji
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
| | - Yanqi Dang
- Institute of Digestive DiseasesChina‐Canada Center of Research for Digestive DiseasesLonghua HospitalShanghai University of Traditional Chinese MedicineShanghaiChina
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine (Shanghai University of Traditional Chinese Medicine)ShanghaiChina
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Atale N, Wells A. Statins as Secondary Preventive Agent to Limit Breast Cancer Metastatic Outgrowth. Int J Mol Sci 2025; 26:1300. [PMID: 39941069 PMCID: PMC11818786 DOI: 10.3390/ijms26031300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 02/16/2025] Open
Abstract
Metastasis is a leading cause of mortality in breast cancer, as metastatic disease is often aggressive and resistant to conventional treatments. Cancer cells that spread to distant organs can enter a dormant phase for extended periods, sometimes years or decades. During this dormant phase, cancer cells avoid immune and pharmacological response. Thus, new approaches are needed to prevent these disseminated cells from becoming lethal cancers. Statins are known inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase that have been extensively used in patients with cardiovascular diseases to lower cholesterol. However, recent research has demonstrated their potential in anticancer therapies. Epidemiological evidence suggests that statins are associated with a reduction in breast cancer-specific mortality, although they do not appear to affect the incidence of primary tumors. In this review, we discuss the role of statins in metastasis and dormancy, their cytocidal and cytostatic effects and their interactions with different cell types in the tumor microenvironment. The exact mechanisms by which statins reduce mortality without influencing primary tumor growth remain unclear, also warranting further investigation into their potential role in metastasis and tumor dormancy, which could ultimately help patients to improve survival and quality of life.
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Affiliation(s)
- Neha Atale
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;
| | - Alan Wells
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA;
- Research and Development Service, Pittsburgh VA Health System, Pittsburgh, PA 15213, USA
- Cell Biology Program, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
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Zabielska J, Stelmanska E, Szrok-Jurga S, Kobiela J, Czumaj A. Lipids Metabolism Inhibition Antiproliferative Synergy with 5-Fluorouracil in Human Colorectal Cancer Model. Int J Mol Sci 2025; 26:1186. [PMID: 39940954 PMCID: PMC11818398 DOI: 10.3390/ijms26031186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/22/2025] [Accepted: 01/28/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is recognized as the third most lethal cancer worldwide. While existing treatment options demonstrate considerable efficacy, they are often constrained by non-selectivity and substantial side effects. Recent studies indicate that lipid metabolism significantly influences carcinogenesis, highlighting it as a promising avenue for developing targeted anticancer therapies. The purpose of the study was to see if acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and stearoyl-CoA 9-desaturase (SCD1) are good metabolic targets and whether the use of inhibitors of these enzymes together with 5-fluorouracil (5-FU) would have a synergistic effect on CRC cell viability. To confirm that the correct lipid targets were chosen, the expression levels of ACAT1, HMGCR, and SCD1 were examined in CRC patients and cell models. At first, each compound (Avasimibe, Lovastatin, MF-438, and 5-FU was tested separately, and then each inhibitor was paired with 5-FU to assess the synergistic effect on cell viability. Gene expression of selected enzymes significantly increased in tissue samples obtained from CRC patients and cancer cell lines (HT-29). Inhibition of any of the selected enzymes reduced CRC cell growth in a dose-dependent manner. More importantly, the combination of 5-FU + Avasimibe (an ACAT1 inhibitor) and 5-FU + MF-438 (an SCD1 inhibitor) produced a stronger antiproliferative effect than the inhibitors alone. 5-FU combined either with Avasimibe or MF-438 showed a synergistic effect with an HSA score of 47.00 at a dose of 0.3 + 30 µM, respectively (2.66% viability rate vs. 46%; p < 0.001), and 39.34 at a dose of 0.3 + 0.06 µM (46% vs. 10.33%; p < 0.001), respectively. The association of 5-FU with Lovastatin (HMGCR inhibitor) did not significantly impact CRC cell viability in a synergistic manner. Inhibition of lipid metabolism combined with standard chemotherapy is a promising strategy that reduces CRC cell viability and allows for the use of a lower drug dose. The combination of 5-FU and Avasimibe has the greatest therapeutic potential among studied compounds.
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Affiliation(s)
- Judyta Zabielska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.Z.); (E.S.); (S.S.-J.)
| | - Ewa Stelmanska
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.Z.); (E.S.); (S.S.-J.)
| | - Sylwia Szrok-Jurga
- Department of Biochemistry, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland; (J.Z.); (E.S.); (S.S.-J.)
| | - Jarosław Kobiela
- Department of Surgical Oncology, Transplant Surgery and General Surgery, Faculty of Medicine, Medical University of Gdansk, 80-211 Gdansk, Poland;
| | - Aleksandra Czumaj
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-211 Gdansk, Poland
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Fousekis FS, Mpakogiannis K, Filis P, Skamnelos A, Christodoulou DK, Mauri D, Katsanos KH. Exploring Chemoprevention in Colorectal Cancer for Patients with Inflammatory Bowel Disease: Mechanisms of Action and Clinical Aspects. Cancers (Basel) 2025; 17:229. [PMID: 39858011 PMCID: PMC11764170 DOI: 10.3390/cancers17020229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/09/2025] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
Background: Inflammatory bowel diseases (IBDs) have been associated with a higher risk of colorectal cancer (CRC) development and chronic colonic inflammation seems to have a critical role in the pathogenesis of CRC in patients suffering from IBD. In respect to that, surveillance colonoscopy at regular intervals is recommended in patients with colitis. Objective: This review aims to explore the chemopreventive potential of a range of agents, including mesalazine, thiopurines, anti-TNF agents, statins, ursodeoxycholic acid, aspirin, folic acid, and nutraceuticals. Results: These agents target inflammation, oxidative stress, and oncogenic pathways, thereby offering the potential to reduce the risk of CRC in patients with IBD. Anti-TNF agents, such as infliximab and adalimumab, not only reduce colonic inflammation, but also play a protective role against CRC by lessening the carcinogenic effects associated with prolonged inflammatory processes. Furthermore, mesalazine and thiopurines have demonstrated established efficacy, while newer biologics, including interleukin inhibitors, show promising advancements. Although nutraceuticals and dietary interventions require further clinical validation, they offer additional possibilities for non-pharmacological prevention. Conclusion: Despite progress, knowledge gaps persist regarding the long-term safety, optimal dosing, and combined use of these agents. A significant reduction in the incidence of CRC in patients with IBD could be achieved by advancing chemoprevention and personalizing strategies.
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Affiliation(s)
- Fotios S. Fousekis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Konstantinos Mpakogiannis
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Panagiotis Filis
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Alexandros Skamnelos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Dimitrios K. Christodoulou
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
| | - Davide Mauri
- Department of Medical Oncology, School of Health Sciences, Faculty of Medicine, University of Ioannina, 455 00 Ioannina, Greece (D.M.)
| | - Konstantinos H. Katsanos
- Department of Gastroenterology, University Hospital of Ioannina, 455 00 Ioannina, Greece; (K.M.); (A.S.); (D.K.C.); (K.H.K.)
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Ren YM, Zhuang ZY, Xie YH, Yang PJ, Xia TX, Xie YL, Liu ZH, Kang ZR, Leng XX, Lu SY, Zhang L, Chen JX, Xu J, Zhao EH, Wang Z, Wang M, Cui Y, Tan J, Liu Q, Jiang WH, Xiong H, Hong J, Chen YX, Chen HY, Fang JY. BCAA-producing Clostridium symbiosum promotes colorectal tumorigenesis through the modulation of host cholesterol metabolism. Cell Host Microbe 2024; 32:1519-1535.e7. [PMID: 39106870 DOI: 10.1016/j.chom.2024.07.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 01/21/2024] [Accepted: 07/11/2024] [Indexed: 08/09/2024]
Abstract
Identification of potential bacterial players in colorectal tumorigenesis has been a focus of intense research. Herein, we find that Clostridium symbiosum (C. symbiosum) is selectively enriched in tumor tissues of patients with colorectal cancer (CRC) and associated with higher colorectal adenoma recurrence after endoscopic polypectomy. The tumorigenic effect of C. symbiosum is observed in multiple murine models. Single-cell transcriptome profiling along with functional assays demonstrates that C. symbiosum promotes the proliferation of colonic stem cells and enhances cancer stemness. Mechanistically, C. symbiosum intensifies cellular cholesterol synthesis by producing branched-chain amino acids (BCAAs), which sequentially activates Sonic hedgehog signaling. Low dietary BCAA intake or blockade of cholesterol synthesis by statins could partially abrogate the C. symbiosum-induced cell proliferation in vivo and in vitro. Collectively, we reveal C. symbiosum as a bacterial driver of colorectal tumorigenesis, thus identifying a potential target in CRC prediction, prevention, and treatment.
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Affiliation(s)
- Yi-Meng Ren
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zi-Yan Zhuang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yuan-Hong Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Peng-Jie Yang
- Chinese Academy of Sciences Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China
| | - Tian-Xue Xia
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Yi-Le Xie
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zhu-Hui Liu
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Zi-Ran Kang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Xiao-Xu Leng
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Shi-Yuan Lu
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Lu Zhang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Jin-Xian Chen
- Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jia Xu
- Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - En-Hao Zhao
- Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Zheng Wang
- Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Ming Wang
- Division of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Yun Cui
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Juan Tan
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Wei-Hong Jiang
- Chinese Academy of Sciences Key Laboratory of Synthetic Biology, Institute of Plant Physiology and Ecology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200032, China
| | - Hua Xiong
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Jie Hong
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China
| | - Ying-Xuan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
| | - Hao-Yan Chen
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
| | - Jing-Yuan Fang
- Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, NHC Key Laboratory of Digestive Diseases, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China.
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Hosseini FS, Ahmadi A, Kesharwani P, Hosseini H, Sahebkar A. Regulatory effects of statins on Akt signaling for prevention of cancers. Cell Signal 2024; 120:111213. [PMID: 38729324 DOI: 10.1016/j.cellsig.2024.111213] [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: 03/11/2024] [Revised: 05/01/2024] [Accepted: 05/06/2024] [Indexed: 05/12/2024]
Abstract
Statins, which are primarily used as lipid-lowering drugs, have been found to exhibit anti-tumor effects through modulating and interfering with various signaling pathways. In observational studies, statin use has been associated with a significant reduction in the progression of various cancers, including colon, lung, prostate, pancreas, and esophagus cancer, as well as melanoma and B and T cell lymphoma. The mevalonate pathway, which is affected by statins, plays a crucial role in activating Rho, Ras, and Rab proteins, thereby impacting the proliferation and apoptosis of tumor cells. Statins block this pathway, leading to the inhibition of isoprenoid units, which are critical for the activation of these key proteins, thereby affecting cancer cell behavior. Additionally, statins affect MAPK and Cdk2, which in turn reduce the expression of p21 and p27 cyclin-dependent kinase inhibitors. Akt signaling plays a crucial role in key cancer cell features like proliferation, invasion, and apoptosis by activating multiple effectors in downstream pathways such as FOXO, PTEN, NF-κB, GSK3β, and mTOR. The PI3K/Akt signaling is necessary for many events in the metastatic pathway and has been implicated in the resistance to cytostatic drugs. The Akt/PTEN axis is currently attracting great interest for its role in carcinogenesis. Statins have been shown to activate the purinergic receptor P2X7 and affect Akt signaling, which may have important anti-cancer effects. Hence, targeting Akt shows promise as an effective approach to cancer prevention and therapy. This review aims to provide a comprehensive discussion on the specific impact of statins through Akt signaling in different types of cancer.
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Affiliation(s)
- Fatemeh Sadat Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Abdolreza Ahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Hossein Hosseini
- Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Huang X, Liang N, Zhang F, Lin W, Ma W. Lovastatin-Induced Mitochondrial Oxidative Stress Leads to the Release of mtDNA to Promote Apoptosis by Activating cGAS-STING Pathway in Human Colorectal Cancer Cells. Antioxidants (Basel) 2024; 13:679. [PMID: 38929118 PMCID: PMC11200898 DOI: 10.3390/antiox13060679] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/27/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
Statins are 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase inhibitors widely used in the treatment of hyperlipidemia. The inhibition of HMG-CoA reductase in the mevalonate pathway leads to the suppression of cell proliferation and induction of apoptosis. The cyclic GMP-AMP synthase (cGAS) stimulator of the interferon genes (STING) signaling pathway has been suggested to not only facilitate inflammatory responses and the production of type I interferons (IFN), but also activate other cellular processes, such as apoptosis. It has not been studied, however, whether cGAS-STING activation is involved in the apoptosis induced by statin treatment in human colorectal cancer cells. In this study, we reported that lovastatin impaired mitochondrial function, including the depolarization of mitochondrial membrane potential, reduction of oxygen consumption, mitochondrial DNA (mtDNA) integrity, and mtDNA abundance in human colorectal cancer HCT116 cells. The mitochondrial dysfunction markedly induced ROS production in mitochondria, whereas the defect in mitochondria respiration or depletion of mitochondria eliminated reactive oxygen species (ROS) production. The ROS-induced oxidative DNA damage by lovastatin treatment was attenuated by mitochondrial-targeted antioxidant mitoquinone (mitoQ). Upon DNA damage, mtDNA was released into the cytosol and bound to DNA sensor cGAS, thus activating the cGAS-STING signaling pathway to trigger a type I interferon response. This effect was not activated by nuclear DNA (nuDNA) or mitochondrial RNA, as the depletion of mitochondria compromised this effect, but not the knockdown of retinoic acid-inducible gene-1/melanoma differentiation-associated protein 5 (RIG-I/MDA5) adaptor or mitochondrial antiviral signaling protein (MAVS). Moreover, lovastatin-induced apoptosis was partly dependent on the cGAS-STING signaling pathway in HCT116 cells as the knockdown of cGAS or STING expression rescued cell viability and mitigated apoptosis. Similarly, the knockdown of cGAS or STING also attenuated the antitumor effect of lovastatin in the HCT116 xenograft model in vivo. Our findings suggest that lovastatin-induced apoptosis is at least partly mediated through the cGAS-STING signaling pathway by triggering mtDNA accumulation in the cytosol in human colorectal cancer HCT116 cells.
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Affiliation(s)
- Xiaoming Huang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
- Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
- Tsinghua Berkeley Shenzhen Institute, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China
| | - Ning Liang
- College of Physics and Optoelectronic Engineering, Shenzhen University, Shenzhen 518060, China
- School of Pharmacy, Shenzhen University Medical School, Shenzhen University, Shenzhen 518055, China
| | - Fuming Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Wanjun Lin
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
| | - Wenzhe Ma
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
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Tripathi S, Gupta E, Galande S. Statins as anti-tumor agents: A paradigm for repurposed drugs. Cancer Rep (Hoboken) 2024; 7:e2078. [PMID: 38711272 PMCID: PMC11074523 DOI: 10.1002/cnr2.2078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 03/28/2024] [Accepted: 04/15/2024] [Indexed: 05/08/2024] Open
Abstract
BACKGROUND Statins, frequently prescribed medications, work by inhibiting the rate-limiting enzyme HMG-CoA reductase (HMGCR) in the mevalonate pathway to reduce cholesterol levels. Due to their multifaceted benefits, statins are being adapted for use as cost-efficient, safe and effective anti-cancer treatments. Several studies have shown that specific types of cancer are responsive to statin medications since they rely on the mevalonate pathway for their growth and survival. RECENT FINDINGS Statin are a class of drugs known for their potent inhibition of cholesterol production and are typically prescribed to treat high cholesterol levels. Nevertheless, there is growing interest in repurposing statins for the treatment of malignant neoplastic diseases, often in conjunction with chemotherapy and radiotherapy. The mechanism behind statin treatment includes targeting apoptosis through the BCL2 signaling pathway, regulating the cell cycle via the p53-YAP axis, and imparting epigenetic modulations by altering methylation patterns on CpG islands and histone acetylation by downregulating DNMTs and HDACs respectively. Notably, some studies have suggested a potential chemo-preventive effect, as decreased occurrence of tumor relapse and enhanced survival rate were reported in patients undergoing long-term statin therapy. However, the definitive endorsement of statin usage in cancer therapy hinges on population based clinical studies with larger patient cohorts and extended follow-up periods. CONCLUSIONS The potential of anti-cancer properties of statins seems to reach beyond their influence on cholesterol production. Further investigations are necessary to uncover their effects on cancer promoting signaling pathways. Given their distinct attributes, statins might emerge as promising contenders in the fight against tumorigenesis, as they appear to enhance the efficacy and address the limitations of conventional cancer treatments.
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Affiliation(s)
- Sneha Tripathi
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Ekta Gupta
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
| | - Sanjeev Galande
- Laboratory of Chromatin Biology & EpigeneticsIndian Institute of Science Education and ResearchPuneIndia
- Centre of Excellence in Epigenetics, Department of Life SciencesShiv Nadar Institution of EminenceGautam Buddha NagarIndia
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10
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Firouzjaei AA, Mahmoudi A, Almahmeed W, Teng Y, Kesharwani P, Sahebkar A. Identification and analysis of the molecular targets of statins in colorectal cancer. Pathol Res Pract 2024; 256:155258. [PMID: 38522123 DOI: 10.1016/j.prp.2024.155258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/05/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
Colorectal cancer (CRC) is the third most common cancer in the world. According to several types of research, statins may impact the development and treatment of CRC. This work aimed to use bioinformatics to discover the relationship between statin targets and differentially expressed genes (DEGs) in CRC patients and determine the possible molecular effect of statins on CRC suppression. We used CRC datasets from the GEO database to select CRC-related DEGs. DGIdb and STITCH databases were used to identify gene targets of subtypes of statin. Further, we identified the statin target of CRC DEGs hub genes by using a Venn diagram of CRC DEGs and statin targets. Funrich and enrichr databases were carried out for the KEGG pathway and gene ontology (GO) enrichment analysis, respectively. GSE74604 and GSE10950 were used to identify CRC DEGs. After analyzing datasets,1370 genes were identified as CRC DEGs, and 345 targets were found for statins. We found that 35 genes are CRC DEGs statin targets. We found that statin targets in CRC were enriched in the receptor and metallopeptidase activity for molecular function, cytoplasm and plasma membrane for cellular component, signal transduction, and cell communication for biological process genes were substantially enriched based on FunRich enrichment. Analysis of the KEGG pathways revealed that the overexpressed DEGs were enriched in the IL-17, PPAR, and Toll-like receptor signaling pathways. Finally, CCNB1, DNMT1, AURKB, RAC1, PPARGC1A, CDKN1A, CAV1, IL1B, and HSPD1 were identified as hub CRC DEGs statin targets. The genetic and molecular aspects of our findings reveal that statins might have a therapeutic effect on CRC.
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Affiliation(s)
- Ali Ahmadizad Firouzjaei
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Mahmoudi
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Medical Biotechnology and Nanotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Yong Teng
- Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
| | - Amirhossein Sahebkar
- Center for Global health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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11
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Xi C, Palani C, Takezaki M, Shi H, Horuzsko A, Pace BS, Zhu X. Simvastatin-Mediated Nrf2 Activation Induces Fetal Hemoglobin and Antioxidant Enzyme Expression to Ameliorate the Phenotype of Sickle Cell Disease. Antioxidants (Basel) 2024; 13:337. [PMID: 38539870 PMCID: PMC10968127 DOI: 10.3390/antiox13030337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/26/2024] [Accepted: 03/08/2024] [Indexed: 06/04/2024] Open
Abstract
Sickle cell disease (SCD) is a pathophysiological condition of chronic hemolysis, oxidative stress, and elevated inflammation. The transcription factor Nrf2 is a master regulator of oxidative stress. Here, we report that the FDA-approved oral agent simvastatin, an inhibitor of hydroxymethyl-glutaryl coenzyme A reductase, significantly activates the expression of Nrf2 and antioxidant enzymes. Simvastatin also induces fetal hemoglobin expression in SCD patient primary erythroid progenitors and a transgenic mouse model. Simvastatin alleviates SCD symptoms by decreasing hemoglobin S sickling, oxidative stress, and inflammatory stress in erythroblasts. Particularly, simvastatin increases cellular levels of cystine, the precursor for the biosynthesis of the antioxidant reduced glutathione, and decreases the iron content in SCD mouse spleen and liver tissues. Mechanistic studies suggest that simvastatin suppresses the expression of the critical histone methyltransferase enhancer of zeste homolog 2 to reduce both global and gene-specific histone H3 lysine 27 trimethylation. These chromatin structural changes promote the assembly of transcription complexes to fetal γ-globin and antioxidant gene regulatory regions in an antioxidant response element-dependent manner. In summary, our findings suggest that simvastatin activates fetal hemoglobin and antioxidant protein expression, modulates iron and cystine/reduced glutathione levels to improve the phenotype of SCD, and represents a therapeutic strategy for further development.
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Affiliation(s)
- Caixia Xi
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Chithra Palani
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
| | - Mayuko Takezaki
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
| | - Huidong Shi
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Anatolij Horuzsko
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Betty S. Pace
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
| | - Xingguo Zhu
- Department of Pediatrics, Division of Hematology/Oncology, Augusta University, Augusta, GA 30912, USA; (C.X.); (C.P.)
- Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA (A.H.)
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12
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Xu T, Gao S, Yang N, Zhao Q, Zhang Y, Li T, Liu Z, Han B. A personalized biomimetic dual-drug delivery system via controlled release of PTH 1-34 and simvastatin for in situ osteoporotic bone regeneration. Front Bioeng Biotechnol 2024; 12:1355019. [PMID: 38357710 PMCID: PMC10865375 DOI: 10.3389/fbioe.2024.1355019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 01/17/2024] [Indexed: 02/16/2024] Open
Abstract
Patients with osteoporosis often encounter clinical challenges of poor healing after bone transplantation due to their diminished bone formation capacity. The use of bone substitutes containing bioactive factors that increase the number and differentiation of osteoblasts is a strategy to improve poor bone healing. In this study, we developed an in situ dual-drug delivery system containing the bone growth factors PTH1-34 and simvastatin to increase the number and differentiation of osteoblasts for osteoporotic bone regeneration. Our system exhibited ideal physical properties similar to those of natural bone and allowed for customizations in shape through a 3D-printed scaffold and GelMA. The composite system regulated the sustained release of PTH1-34 and simvastatin, and exhibited good biocompatibility. Cell studies revealed that the composite system reduced osteoblast death, and promoted expression of osteoblast differentiation markers. Additionally, by radiographic analysis and histological observation, the dual-drug composite system demonstrated promising bone regeneration outcomes in an osteoporotic skull defect model. In summary, this composite delivery system, comprising dual-drug administration, holds considerable potential for bone repair and may serve as a safe and efficacious therapeutic approach for addressing bone defects in patients with osteoporosis.
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Affiliation(s)
- Tongtong Xu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, Jilin, China
| | - Shang Gao
- Department of Stomatology, Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai, Guangdong, China
| | - Nan Yang
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Qi Zhao
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Jilin University, Changchun, Jilin, China
| | - Yutong Zhang
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
| | - Tieshu Li
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
| | - Zhihui Liu
- Department of Prosthodontics, Hospital of Stomatology, Jilin University, Changchun, China
| | - Bing Han
- School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin, China
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13
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Zhou W, Yan K, Xi Q. BMP signaling in cancer stemness and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:37. [PMID: 38049682 PMCID: PMC10695912 DOI: 10.1186/s13619-023-00181-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
The BMP (Bone morphogenetic protein) signaling pathway plays a central role in metazoan biology, intricately shaping embryonic development, maintaining tissue homeostasis, and influencing disease progression. In the context of cancer, BMP signaling exhibits context-dependent dynamics, spanning from tumor suppression to promotion. Cancer stem cells (CSCs), a modest subset of neoplastic cells with stem-like attributes, exert substantial influence by steering tumor growth, orchestrating therapy resistance, and contributing to relapse. A comprehensive grasp of the intricate interplay between CSCs and their microenvironment is pivotal for effective therapeutic strategies. Among the web of signaling pathways orchestrating cellular dynamics within CSCs, BMP signaling emerges as a vital conductor, overseeing CSC self-renewal, differentiation dynamics, and the intricate symphony within the tumor microenvironment. Moreover, BMP signaling's influence in cancer extends beyond CSCs, intricately regulating cellular migration, invasion, and metastasis. This multifaceted role underscores the imperative of comprehending BMP signaling's contributions to cancer, serving as the foundation for crafting precise therapies to navigate multifaceted challenges posed not only by CSCs but also by various dimensions of cancer progression. This article succinctly encapsulates the diverse roles of the BMP signaling pathway across different cancers, spanning glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG), colorectal cancer, acute myeloid leukemia (AML), lung cancer, prostate cancer, and osteosarcoma. It underscores the necessity of unraveling underlying mechanisms and molecular interactions. By delving into the intricate tapestry of BMP signaling's engagement in cancers, researchers pave the way for meticulously tailored therapies, adroitly leveraging its dualistic aspects-whether as a suppressor or promoter-to effectively counter the relentless march of tumor progression.
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Affiliation(s)
- Wei Zhou
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kun Yan
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Qiaoran Xi
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Joint Graduate Program of Peking-Tsinghua-NIBS, Tsinghua University, Beijing, China.
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14
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He X, Lan H, Jin K, Liu F. Cholesterol in colorectal cancer: an essential but tumorigenic precursor? Front Oncol 2023; 13:1276654. [PMID: 38023258 PMCID: PMC10655112 DOI: 10.3389/fonc.2023.1276654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal human malignancies, and with the growth of societies and lifestyle changes, the rate of people suffering from it increases yearly. Important factors such as genetics, family history, nutrition, lifestyle, smoking, and alcohol can play a significant role in increasing susceptibility to this cancer. On the other hand, the metabolism of several macromolecules is also involved in the fate of tumors and immune cells. The evidence discloses that cholesterol and its metabolism can play a role in the pathogenesis of several cancers because there appears to be an association between cholesterol levels and CRC, and cholesterol-lowering drugs may reduce the risk. Furthermore, changes or mutations of some involved genes in cholesterol metabolism, such as CYP7A1 as well as signaling pathways, such as mitogen-activated protein kinase (MAPK), can play a role in CRC pathogenesis. This review summarized and discussed the role of cholesterol in the pathogenesis of CRC as well as available cholesterol-related therapeutic approaches in CRC.
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Affiliation(s)
- Xing He
- Department of Gastroenterology, Jinhua Wenrong Hospital, Jinhua, Zhejiang, China
| | - Huanrong Lan
- Department of Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, China
| | - Ketao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Fanlong Liu
- Department of Colorectal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
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15
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Piekuś-Słomka N, Mocan LP, Shkreli R, Grapă C, Denkiewicz K, Wesolowska O, Kornek M, Spârchez Z, Słomka A, Crăciun R, Mocan T. Don't Judge a Book by Its Cover: The Role of Statins in Liver Cancer. Cancers (Basel) 2023; 15:5100. [PMID: 37894467 PMCID: PMC10605163 DOI: 10.3390/cancers15205100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/16/2023] [Accepted: 10/20/2023] [Indexed: 10/29/2023] Open
Abstract
Statins, which are inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, are an effective pharmacological tool for lowering blood cholesterol levels. This property makes statins one of the most popular drugs used primarily to prevent cardiovascular diseases, where hyperlipidemia is a significant risk factor that increases mortality. Nevertheless, studies conducted mainly in the last decade have shown that statins might prevent and treat liver cancer, one of the leading causes of cancer-related mortality worldwide. This narrative review summarizes the scientific achievements to date regarding the role of statins in liver tumors. Molecular biology tools have revealed that cell growth and proliferation can be inhibited by statins, which further inhibit angiogenesis. Clinical studies, supported by meta-analysis, confirm that statins are highly effective in preventing and treating hepatocellular carcinoma and cholangiocarcinoma. However, this effect may depend on the statin's type and dose, and more clinical trials are required to evaluate clinical effects. Moreover, their potential hepatotoxicity is a significant caveat for using statins in clinical practice. Nevertheless, this group of drugs, initially developed to prevent cardiovascular diseases, is now a key candidate in hepato-oncology patient management. The description of new drug-statin-like structures, e.g., with low toxicity to liver cells, may bring another clinically significant improvement to current cancer therapies.
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Affiliation(s)
- Natalia Piekuś-Słomka
- Department of Inorganic and Analytical Chemistry, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Jurasza 2, 85-089 Bydgoszcz, Poland;
| | - Lavinia Patricia Mocan
- Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Rezarta Shkreli
- Department of Pharmacy, Faculty of Medical Sciences, Aldent University, 1001-1028 Tirana, Albania;
| | - Cristiana Grapă
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania;
| | - Kinga Denkiewicz
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Oliwia Wesolowska
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Miroslaw Kornek
- Department of Internal Medicine I, University Hospital Bonn of the Rheinische Friedrich-Wilhelms-University, 53127 Bonn, Germany;
| | - Zeno Spârchez
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
| | - Artur Słomka
- Department of Pathophysiology, Nicolaus Copernicus University in Toruń, Ludwik Rydygier Collegium Medicum in Bydgoszcz, 85-094 Bydgoszcz, Poland; (K.D.); (O.W.); (A.S.)
| | - Rareș Crăciun
- 3rd Medical Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania;
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Tudor Mocan
- Department of Gastroenterology, “Octavian Fodor” Institute for Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- UBBMed Department, Babeș-Bolyai University, 400349 Cluj-Napoca, Romania
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16
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Martínez-Iglesias O, Naidoo V, Corzo L, Carrera I, Seoane S, Rodríguez S, Alcaraz M, Muñiz A, Cacabelos N, Cacabelos R. Proteomic and Global DNA Methylation Modulation in Lipid Metabolism Disorders with a Marine-Derived Bioproduct. BIOLOGY 2023; 12:806. [PMID: 37372091 DOI: 10.3390/biology12060806] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023]
Abstract
Dyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.
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Affiliation(s)
- Olaia Martínez-Iglesias
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Vinogran Naidoo
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Lola Corzo
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Iván Carrera
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Silvia Seoane
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Susana Rodríguez
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Margarita Alcaraz
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Adriana Muñiz
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Natalia Cacabelos
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
| | - Ramón Cacabelos
- EuroEspes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Bergondo, Corunna, Spain
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17
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Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
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18
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Awosika A, E. Omole A, Adabanya U, Anand N, M. Millis R. Statins and Epigenetics: A Putative Mechanism for Explaining Pleiotropic Effects. STATINS - FROM LIPID-LOWERING BENEFITS TO PLEIOTROPIC EFFECTS 2023. [DOI: 10.5772/intechopen.1001141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2025]
Abstract
Statins remain the most efficient hypolipidemic agent and their use is pivotal in primary, secondary, and tertiary treatment of cardiovascular disease, reducing both morbidity and mortality. Statins target 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes conversion of HMG-CoA to mevalonate, the “committed and rate limiting step” in hepatic production of cholesterol. Genetic predilections for hypercholesterolemia are known to be responsible for substantial morbidity and mortality from cardiovascular disease. Environmental or lifestyle factors such as dietary fat and carbohydrate may also contribute to cardiovascular disease mortality by both genetic and epigenetic mechanisms. Besides lipid-lowering, statins have pleiotropic effects which may contribute to their protection against cardiovascular and several other diseases wherein hypercholesterolemia is a risk factor. Evidence is emerging that the clinical outcomes of many diseases are improved when modifications of environmental or lifestyle factors play integral roles in treatment and preventive prescriptions. This chapter is, therefore, intended to inform physicians and other health care professionals about the environment-gene interactions underlying the main and pleiotropic effects of statins which may be employed to improve the efficacy of statin therapies.
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19
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Torres T, Barros S, Neuparth T, Ruivo R, Santos MM. Using zebrafish embryo bioassays to identify chemicals modulating the regulation of the epigenome: a case study with simvastatin. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:22913-22928. [PMID: 36307569 DOI: 10.1007/s11356-022-23683-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 10/11/2022] [Indexed: 06/16/2023]
Abstract
Contaminants of emerging concern have been increasingly associated with the modulation of the epigenome, leading to potentially inherited and persistent impacts on apical endpoints. Here, we address the performance of the OECD Test No. 236 FET (fish embryo acute toxicity) in the identification of chemicals able to modulate the epigenome. Using zebrafish (Danio rerio) embryos, acute and chronic exposures were performed with the pharmaceutical, simvastatin (SIM), a widely prescribed hypocholesterolemic drug reported to induce inter and transgenerational effects. In the present study, the epigenetic effects of environmentally relevant concentrations of SIM (from 8 ng/L to 2000 ng/L) were addressed following (1) an acute embryo assay based on OECD Test No. 236 FET, (2) a chronic partial life-cycle exposure using adult zebrafish (90 days), and (3) F1 embryos obtained from parental exposed animals. Simvastatin induced significant effects in gene expression of key epigenetic biomarkers (DNA methylation and histone acetylation/deacetylation) in the gonads of exposed adult zebrafish and in 80 hpf zebrafish embryos (acute and chronic parental intergenerational exposure), albeit with distinct effect profiles between biological samples. In the chronic exposure, SIM impacted particularly DNA methyltransferase genes in males and female gonads, whereas in F1 embryos SIM affected mostly genes associated with histone acetylation/deacetylation. In the embryo acute direct exposure, SIM modulated the expression of both genes involved in DNA methylation and histone deacetylase. These findings further support the use of epigenetic biomarkers in zebrafish embryos in a high throughput approach to identify and prioritize epigenome-modulating chemicals.
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Affiliation(s)
- Tiago Torres
- Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal
- FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua Do Campo Alegre, 4169-007, Porto, Portugal
| | - Susana Barros
- Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal
- CITAB - Centre for the Research and Technology of Agro-Environmental and Biological Sciences, Quinta de Prados, Ed. Blocos Laboratoriais C1.10, 5000-801, Vila Real, Portugal
| | - Teresa Neuparth
- Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal
| | - Raquel Ruivo
- Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal.
| | - Miguel Machado Santos
- Group of Endocrine Disruptors and Emerging Contaminants, University of Porto, Avenida General Norton de Matos, 4450-208, Matosinhos, S/N, Portugal.
- FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua Do Campo Alegre, 4169-007, Porto, Portugal.
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20
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Feng J, Yao Z, Yang H, Ma J, Zhong X, Qin Y, Li J. Bone marrow-derived mesenchymal stem cells expressing BMP2 suppress glioma stem cell growth and stemness through Bcl-2/Bax signaling. J Cancer Res Ther 2022; 18:2033-2040. [PMID: 36647967 DOI: 10.4103/jcrt.jcrt_1983_21] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Objectives To find an effective molecule that controls glioma stem cell (GSC) proliferation and differentiation for the development of future therapeutic interventions against glioblastoma. Material and Methods Bone marrow-derived mesenchymal stem cells (BMSCs) were infected with a lentiviral vector to express BMP2. Cell viability, cell counting, and tumor sphere formation assays, as well as flow cytometry, immunofluorescence staining, and Western blotting were used to investigate the effects of BMSC-BMP2 on GSCs. Results The results of flow cytometry and the CKK-8 assay showed that BMSC-BMP2 induced GSC apoptosis while inhibiting proliferation. BMSC-BMP2 decreased GSC neurosphere formation and neurospheres' transverse and vertical diameter. Meanwhile, BMSC-BMP2 downregulated GSC Nanog and OCT4 expression levels, suggesting stemness inhibition. Western blotting showed that BMSC-BMP2 increased Bax protein expression and significantly decreased Bcl-2 protein expression. Accordingly, the Bcl-2/Bax ratio increased. Conclusion BMSC-BMP2 could effectively inhibit GSC proliferation, induce GSC apoptosis, and decrease GSC stemness, thereby providing a novel strategy for treating malignant glioma.
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Affiliation(s)
- Jizhen Feng
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Zhigang Yao
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Hongan Yang
- Department of Neurosurgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jiwei Ma
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xiuming Zhong
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yejun Qin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Jiamei Li
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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21
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Simvastatin in the Treatment of Colorectal Cancer: A Review. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2022:3827933. [PMID: 35873646 PMCID: PMC9303163 DOI: 10.1155/2022/3827933] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/26/2022] [Accepted: 05/28/2022] [Indexed: 12/21/2022]
Abstract
Drug repositioning and drug reuse are the heated topics in the field of oncology in recent years. These two concepts refer to seeking effective drugs for cancer that are not originally intended to treat cancer. The survival benefits are then analyzed by combining the re-positioned drugs with conventional cancer treatment methods. Simvastatin is a clinically commonly used hyperlipidemia drug and exerts the effect of preventing cardiovascular diseases. Recent studies have found that simvastatin has great potential in the treatment of colorectal cancer, and a large number of clinical studies have used simvastatin as an adjuvant drug to help treat metastatic colorectal cancer.
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22
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Xia Y, Jin Y, Cui D, Wu X, Song C, Jin W, Huang H. Antitumor Effect of Simvastatin in Combination With DNA Methyltransferase Inhibitor on Gastric Cancer via GSDME-Mediated Pyroptosis. Front Pharmacol 2022; 13:860546. [PMID: 35517821 PMCID: PMC9065610 DOI: 10.3389/fphar.2022.860546] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/28/2022] [Indexed: 11/13/2022] Open
Abstract
Gasdermin E (GSDME) is one of the executors of pyroptosis, a type of programmed lytic cell death, which can be triggered by caspase-3 activation upon stimulation. Silenced GSDME expression due to promoter hypermethylation is associated with gastric cancer (GC), which is confirmed in the present study by bioinformatics analysis and methylation-specific PCR (MSP) test of GC cell lines and clinical samples. GC cell lines and mouse xenograft models were used to investigate the pyroptosis-inducing effect of the common cholesterol-depleting, drug simvastatin (SIM), allied with upregulating GSDME expression by doxycycline (DOX)- inducible Tet-on system or DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine (5-Aza-CdR). Cell viability assessment and xenograft tumour growth demonstrated that the tumour inhibition effects of SIM can be enhanced by elevated GSDME expression. Morphological examinations and assays measuring lactate dehydrogenase (LDH) release and caspase-3/GSDME protein cleavage underlined the stimulation of pyroptosis as an important mechanism. Using short hairpin RNA (shRNA) knockdown of caspase-3 or GSDME, and caspase-3-specific inhibitors, we provided evidence of the requirement of caspase-3/GSDME in the pyroptosis process triggered by SIM. We conclude that reactivating GSDME expression and thereby inducing cancer cell-specific pyroptosis could be a potential therapeutic strategy against GC.
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Affiliation(s)
- Ying Xia
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Pathophysiology, School of Basic Medical Science, Guizhou Medical University, Guiyang, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang, China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Yong Jin
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
| | - Daxiang Cui
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xia Wu
- Guizhou Provincial People’s Hospital, Guiyang, China
| | - Cunfeng Song
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China
- *Correspondence: Cunfeng Song, ; Weilin Jin, ; Hai Huang,
| | - Weilin Jin
- Shanghai Engineering Research Center for Intelligent Diagnosis and Treatment Instrument, Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Institute of Nano Biomedicine and Engineering, Shanghai Jiao Tong University, Shanghai, China
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, China
- *Correspondence: Cunfeng Song, ; Weilin Jin, ; Hai Huang,
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang, China
- School of Clinical Laboratory Science, Guizhou Medical University, Guiyang, China
- *Correspondence: Cunfeng Song, ; Weilin Jin, ; Hai Huang,
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23
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Pashirzad M, Sathyapalan T, Sheikh A, Kesharwani P, Sahebkar A. Cancer stem cells: An overview of the pathophysiological and prognostic roles in colorectal cancer. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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24
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Ding S, Yu B, van Vuuren AJ. Statins significantly repress rotavirus replication through downregulation of cholesterol synthesis. Gut Microbes 2021; 13:1955643. [PMID: 34369301 PMCID: PMC8354672 DOI: 10.1080/19490976.2021.1955643] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Rotavirus is the most common cause of severe diarrhea among infants and young children and is responsible for more than 200,000 pediatric deaths per year. There is currently no pharmacological treatment for rotavirus infection in clinical activity. Although cholesterol synthesis has been proven to play a key role in the infections of multiple viruses, little is known about the relationship between cholesterol biosynthesis and rotavirus replication. The models of rotavirus infected two cell lines and a human small intestinal organoid were used. We investigated the effects of cholesterol biosynthesis, including inhibition, enhancement, and their combinations on rotavirus replication on these models. The knockdown of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was built by small hairpin RNAs in Caco2 cells. In all these models, inhibition of cholesterol synthesis by statins or HMGCR knockdown had a significant inhibitory effect on rotavirus replication. The result was further confirmed by the other inhibitors: 6-fluoromevalonate, Zaragozic acid A and U18666A, in the cholesterol biosynthesis pathway. Conversely, enhancement of cholesterol production increased rotavirus replication, suggesting that cholesterol homeostasis is relevant for rotavirus replication. The effects of all these compounds toward rotavirus were further confirmed with a clinical rotavirus isolate. We concluded that rotavirus replication is dependent on cholesterol biosynthesis. To be specific, inhibition of cholesterol synthesis can downregulate rotavirus replication; on the contrary, rotavirus replication is upregulated. Statin treatment is potentially an effective novel clinical anti-rotavirus strategy.
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Affiliation(s)
- Shihao Ding
- Department Of Gastroenterology And Hepatology, Na-1001, Erasmus MC – University Medical Center Rotterdam, CA Rotterdam, Netherlands,Department of Endocrinology and Metabolism, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands,Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands,CONTACT Shihao Ding Department Of Gastroenterology And Hepatology, Na-1001, Erasmus MC – University Medical Center Rotterdam, CA Rotterdam, Netherlands
| | - Bingting Yu
- Department Of Gastroenterology And Hepatology, Na-1001, Erasmus MC – University Medical Center Rotterdam, CA Rotterdam, Netherlands
| | - Anneke J. van Vuuren
- Department Of Gastroenterology And Hepatology, Na-1001, Erasmus MC – University Medical Center Rotterdam, CA Rotterdam, Netherlands
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25
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Jiang H, Tang E, Chen Y, Liu H, Zhao Y, Lin M, He L. FDFT1 predicts poor prognosis in stage I-III colon adenocarcinoma and synergizes SQLE to promote tumor progression. Cancer Sci 2021; 113:971-985. [PMID: 34939274 PMCID: PMC8898704 DOI: 10.1111/cas.15248] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 12/12/2021] [Accepted: 12/16/2021] [Indexed: 11/30/2022] Open
Abstract
Colon adenocarcinoma (COAD) is one of the most prevalent malignancies, with poor prognosis and lack of effective treatment targets. Squalene synthase (FDFT1) is an upstream enzyme of squalene epoxidase (SQLE) in cholesterol biosynthesis. In a previous study, we revealed that SQLE promotes colon cancer cell proliferation in vitro and in vivo. Here, we investigate the prognostic value of FDFT1 in stage I‐III COAD and explore the potential underlying mechanisms. Squalene synthase was significantly upregulated in stage I‐III COAD and positively correlated with poor differentiation and advanced tumor stage. High expression of FDFT1 was an independent predictor of overall and relapse‐free survival, and the nomograms based on FDFT1 could effectively identify patients at high risk of poor outcome. Squalene synthase accelerated colon cancer cell proliferation and promoted tumor growth. Lack of FDFT1 resulted in accumulating NAT8 and D‐pantethine to lower reactive oxygen species levels and inhibit colon cancer cell proliferation. Moreover, the combined inhibition of FDFT1 and SQLE induced a greater suppressive effect on cell proliferation and tumor growth than single inhibition. Taken together, these results indicate that FDFT1 predicts poor prognosis in stage I‐III COAD and has the tumor‐promoting effect on COAD through regulating NAT8 and D‐pantethine. Targeting both FDFT1 and SQLE is a more promising therapy than their single inhibition for stage I‐III COAD.
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Affiliation(s)
- Huihong Jiang
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.,Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China
| | - Erjiang Tang
- Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China.,Center for clinical research and translational medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
| | - Ying Chen
- Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China.,Center for clinical research and translational medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
| | - Hailong Liu
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.,Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China
| | - Yun Zhao
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.,The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.,School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Moubin Lin
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.,Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China.,Center for clinical research and translational medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
| | - Luwei He
- Institute of Gastrointestinal Surgery and Translational Medicine, School of Medicine, Tongji University, Shanghai, 200090, China.,Center for clinical research and translational medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China
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26
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Jiang W, Hu JW, He XR, Jin WL, He XY. Statins: a repurposed drug to fight cancer. J Exp Clin Cancer Res 2021; 40:241. [PMID: 34303383 PMCID: PMC8306262 DOI: 10.1186/s13046-021-02041-2] [Citation(s) in RCA: 231] [Impact Index Per Article: 57.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/13/2021] [Indexed: 12/12/2022] Open
Abstract
As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.
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Affiliation(s)
- Wen Jiang
- Department of General Surgery, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, P. R. China
| | - Jin-Wei Hu
- Department of General Surgery, The Affiliated Provincial Hospital of Anhui Medical University, Hefei, 230001, P. R. China
| | - Xu-Ran He
- Department of Finance, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, 230001, P. R. China
| | - Wei-Lin Jin
- Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, P. R. China.
| | - Xin-Yang He
- Department of General Surgery, The First Affiliated Hospital of University of Science and Technology of China (Anhui Provincial Hospital), Hefei, 230001, P. R. China.
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27
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Kinome-wide analysis of the effect of statins in colorectal cancer. Br J Cancer 2021; 124:1978-1987. [PMID: 33742146 PMCID: PMC8184819 DOI: 10.1038/s41416-021-01318-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 01/19/2021] [Accepted: 02/10/2021] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. METHODS CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. RESULTS Kinome analysis can distinguish between non-specific, toxic effects caused by 10 µM of Lovastatin and specific effects on cell signalling caused by 2 µM Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. CONCLUSIONS Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC.
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28
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Tilija Pun N, Jeong CH. Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance. Pharmaceuticals (Basel) 2021; 14:ph14050470. [PMID: 34065757 PMCID: PMC8156779 DOI: 10.3390/ph14050470] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/31/2022] Open
Abstract
Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.
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29
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Kumar A, Misra S, Nair P, Algahtany M. Epigenetics Mechanisms in Ischemic Stroke: A Promising Avenue? J Stroke Cerebrovasc Dis 2021; 30:105690. [PMID: 33684709 DOI: 10.1016/j.jstrokecerebrovasdis.2021.105690] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/15/2021] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
Stroke has emerged as the second most common cause of mortality worldwide and is a major public health problem. It is a multi-factorial disease and genetics plays an important role in its pathophysiology, however, mechanisms of genome involvement in the disease remain unclear. Both genetic and epigenetic mechanisms could play a role in the development of stroke disease. Although epigenetic characteristics may also be heritable, they can be modified during the lifetime under different environmental exposure in response to lifestyle. Recent studies provide clear evidence that epigenetic factors play an important role in the pathological mechanisms leading to an elevated risk of cardiovascular diseases and stroke. Epigenetic changes are reversible therefore; studying epigenetic factors may serve as a marker for disease progression, biomarker for disease diagnosis, and development of novel targets for therapeutic intervention. Identifying the factors which predispose the risk of stroke provides information for the mechanism of stroke and the design of new drug targets where epigenetic modifications play a significant role. Epigenetic modifications play an essential role in a large variety of multifactorial diseases. This review will focus on the evidence that epigenetic mechanisms play a crucial role in the pathophysiology of ischemic stroke.
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Affiliation(s)
- Amit Kumar
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
| | - Shubham Misra
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
| | - Pallavi Nair
- Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
| | - Mubarak Algahtany
- Division of Neurosurgery, Department of Surgery, College of Medicine, King Khalid University, Abha, Saudi Arabia.
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30
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Sphyris N, Hodder MC, Sansom OJ. Subversion of Niche-Signalling Pathways in Colorectal Cancer: What Makes and Breaks the Intestinal Stem Cell. Cancers (Basel) 2021; 13:1000. [PMID: 33673710 PMCID: PMC7957493 DOI: 10.3390/cancers13051000] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/15/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
The intestinal epithelium fulfils pleiotropic functions in nutrient uptake, waste elimination, and immune surveillance while also forming a barrier against luminal toxins and gut-resident microbiota. Incessantly barraged by extraneous stresses, the intestine must continuously replenish its epithelial lining and regenerate the full gamut of specialized cell types that underpin its functions. Homeostatic remodelling is orchestrated by the intestinal stem cell (ISC) niche: a convergence of epithelial- and stromal-derived cues, which maintains ISCs in a multipotent state. Following demise of homeostatic ISCs post injury, plasticity is pervasive among multiple populations of reserve stem-like cells, lineage-committed progenitors, and/or fully differentiated cell types, all of which can contribute to regeneration and repair. Failure to restore the epithelial barrier risks seepage of toxic luminal contents, resulting in inflammation and likely predisposing to tumour formation. Here, we explore how homeostatic niche-signalling pathways are subverted in tumorigenesis, enabling ISCs to gain autonomy from niche restraints ("ISC emancipation") and transform into cancer stem cells capable of driving tumour initiation, progression, and therapy resistance. We further consider the implications of the pervasive plasticity of the intestinal epithelium for the trajectory of colorectal cancer, the emergence of distinct molecular subtypes, the propensity to metastasize, and the development of effective therapeutic strategies.
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Affiliation(s)
- Nathalie Sphyris
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
| | - Michael C. Hodder
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
| | - Owen J. Sansom
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; (N.S.); (M.C.H.)
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1QH, UK
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31
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Alves N, Neuparth T, Barros S, Santos MM. The anti-lipidemic drug simvastatin modifies epigenetic biomarkers in the amphipod Gammarus locusta. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2021; 209:111849. [PMID: 33387775 DOI: 10.1016/j.ecoenv.2020.111849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 12/17/2020] [Accepted: 12/19/2020] [Indexed: 06/12/2023]
Abstract
The adverse effects of certain environmental chemicals have been recently associated with the modulation of the epigenome. Although changes in the epigenetic signature have yet to be integrated into hazard and risk assessment, they are interesting candidates to link environmental exposures and altered phenotypes, since these changes may be passed across multiple non-exposed generations. Here, we addressed the effects of simvastatin (SIM), one of the most prescribed pharmaceuticals in the world, on epigenetic regulation using the amphipod Gammarus locusta as a proxy, to support its integration into hazard and environmental risk assessment. SIM is a known modulator of the epigenome in mammalian cell lines and has been reported to impact G. locusta ecological endpoints at environmentally relevant levels. G. locusta juveniles were exposed to three SIM environmentally relevant concentrations (0.32, 1.6 and 8 µg L-1) for 15 days. Gene transcription levels of selected epigenetic regulators, i.e., dnmt1, dmap1, usp7, kat5 and uhrf1 were assessed, along with the quantification of DNA methylation levels and evaluation of key ecological endpoints: survival and growth. Exposure to 0.32 and 8 µg L-1 SIM induced significant downregulation of DNA methyltransferase 1 (dnmt1), concomitant with global DNA hypomethylation and growth impacts. Overall, this work is the first to validate the basal expression of key epigenetic regulators in a keystone marine crustacean, supporting the integration of epigenetic biomarkers into hazard assessment frameworks.
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Affiliation(s)
- Nélson Alves
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre nº 1021/1055, 4169-007 Porto, Portugal
| | - Teresa Neuparth
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal.
| | - Susana Barros
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal
| | - Miguel M Santos
- CIIMAR - Interdisciplinary Centre of Marine and Environmental Research, Endocrine Disruptors and Emerging Contaminants Group, University of Porto, Avenida General Norton de Matos S/N, 4450-208 Matosinhos, Portugal; FCUP - Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre nº 1021/1055, 4169-007 Porto, Portugal.
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Anti-inflammatory Effects of Statins in Lung Vascular Pathology: From Basic Science to Clinical Trials. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:33-56. [PMID: 33788186 DOI: 10.1007/978-3-030-63046-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
HMG-CoA reductase inhibitors (or statins) are cholesterol-lowering drugs and are among the most widely prescribed medications in the United States. Statins exhibit pleiotropic effects that extend beyond cholesterol reduction including anti-atherosclerotic, antiproliferative, anti-inflammatory, and antithrombotic effects. Over the last 20 years, statins have been studied and examined in pulmonary vascular disorders, including both chronic pulmonary vascular disease such as pulmonary hypertension, and acute pulmonary vascular endothelial injury such as acute lung injury. In both research and clinical settings, statins have demonstrated promising vascular protection through modulation of the endothelium, attenuation of vascular leak, and promotion of endothelial repair following lung inflammation. This chapter provides a summary of the rapidly changing literature, summarizes the anti-inflammatory mechanism of statins on pulmonary vascular disorders, and explores clinical evidence for statins as a potential therapeutic approach to modulation of the endothelium as well as a means to broaden our understanding of pulmonary vasculopathy pathophysiology.
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Mohammadzadeh N, Montecucco F, Carbone F, Xu S, Al-Rasadi K, Sahebkar A. Statins: Epidrugs with effects on endothelial health? Eur J Clin Invest 2020; 50:e13388. [PMID: 32854143 DOI: 10.1111/eci.13388] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 08/13/2020] [Accepted: 08/15/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Epigenetic events involving the methylation of CpG cites in DNA, histone modifications and noncoding RNAs correlated with many essential processes in human cells and diseases, such as cancer and cardiovascular diseases. HMG-CoA reductase inhibitors (statins)-the LDL cholesterol-lowering drugs-are broadly used in cardio- and cerebro-vascular diseases. It is well established that statins exert pleiotropic functions, but how they exert effects on epigenetic modifications independently of HMG-CoA reductase inhibition is not yet clear. Thereby, understanding these mechanisms may pave the way for further clinical application of statin therapy. DESIGN Following and electronic database search, studies reporting substantial effects of statins on epigenetic reprogramming in both cultured cells and in vivo models were retrieved and reviewed. RESULTS Epigenetic mechanisms play an essential role in cellular development and function, and data collected in the past few years have revealed that many of the pleiotropic properties of statins are mediated by epigenetic mechanisms. Furthermore, those 'nonclassical' effects are not limited to CV field but they would extend to other conditions such as malignancies. CONCLUSION This review suggests that the epigenetic effects of statins mediate, at least in part, the pleiotropic actions of these drugs but further validation of such effects in clinical studies is yet to be provided.
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Affiliation(s)
| | - Fabrizio Montecucco
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Federico Carbone
- IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, Genoa, Italy
- First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, Genoa, Italy
| | - Suowen Xu
- Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | | | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
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Reeskamp LF, Venema A, Pereira JPB, Levin E, Nieuwdorp M, Groen AK, Defesche JC, Grefhorst A, Henneman P, Hovingh GK. Differential DNA methylation in familial hypercholesterolemia. EBioMedicine 2020; 61:103079. [PMID: 33096472 PMCID: PMC7581877 DOI: 10.1016/j.ebiom.2020.103079] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 08/28/2020] [Accepted: 10/07/2020] [Indexed: 01/01/2023] Open
Abstract
Background Familial hypercholesterolemia (FH) is a monogenic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C). A FH causing genetic variant in LDLR, APOB, or PCSK9 is not identified in 12–60% of clinical FH patients (FH mutation-negative patients). We aimed to assess whether altered DNA methylation might be associated with FH in this latter group Methods In this study we included 78 FH mutation-negative patients and 58 FH mutation-positive patients with a pathogenic LDLR variant. All patients were male, not using lipid lowering therapies and had LDL-C levels >6 mmol/L and triglyceride levels <3•5 mmol/L. DNA methylation was measured with the Infinium Methylation EPIC 850 K beadchip assay. Multiple linear regression analyses were used to explore DNA methylation differences between the two groups in genes related to lipid metabolism. A gradient boosting machine learning model was applied to investigate accumulated genome-wide differences between the two groups. Findings Candidate gene analysis revealed one significantly hypomethylated CpG site in CPT1A (cg00574958) in FH mutation-negative patients, while no differences in methylation in other lipid genes were observed. The machine learning model did distinguish the two groups with a mean Area Under the Curve (AUC)±SD of 0•80±0•17 and provided two CpG sites (cg26426080 and cg11478607) in genes with a possible link to lipid metabolism (PRDM16 and GSTT1). Interpretation FH mutation-negative patients are characterized by accumulated genome wide DNA methylation differences, but not by major DNA methylation alterations in known lipid genes compared to FH mutation-positive patients. Funding ZonMW grant (VIDI no. 016.156.445)
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Affiliation(s)
- Laurens F Reeskamp
- Department of Vascular Medicine, Amsterdam UMC, Location AMC, Meibergdreef 9, Amsterdam 1105AZ, The Netherlands
| | - Andrea Venema
- Department of Clinical Genetics, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Joao P Belo Pereira
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands; HORAIZON BV, Delft, The Netherlands
| | - Evgeni Levin
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands; HORAIZON BV, Delft, The Netherlands
| | - Max Nieuwdorp
- Department of Vascular Medicine, Amsterdam UMC, Location AMC, Meibergdreef 9, Amsterdam 1105AZ, The Netherlands; Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Albert K Groen
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Joep C Defesche
- Department of Clinical Genetics, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Aldo Grefhorst
- Department of Experimental Vascular Medicine, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Peter Henneman
- Department of Clinical Genetics, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - G Kees Hovingh
- Department of Vascular Medicine, Amsterdam UMC, Location AMC, Meibergdreef 9, Amsterdam 1105AZ, The Netherlands.
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Barbalata CI, Tefas LR, Achim M, Tomuta I, Porfire AS. Statins in risk-reduction and treatment of cancer. World J Clin Oncol 2020; 11:573-588. [PMID: 32879845 PMCID: PMC7443827 DOI: 10.5306/wjco.v11.i8.573] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/18/2020] [Accepted: 06/10/2020] [Indexed: 02/06/2023] Open
Abstract
Statins, which are competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, reduce cholesterol blood levels and the risk of developing cardiovascular diseases and their related complications. In addition to this main activity, statins show pleiotropic effects such as antioxidant, anti-inflammatory and antiproliferative properties, with applications in many pathologies. Based on their antiproliferative properties, in vitro and in vivo studies have investigated their effects on various types of cancer (i.e., breast cancer, prostate cancer, colorectal cancer, ovarian cancer, lung cancer) with different genetic and molecular characteristics. Many positive results were obtained, but they were highly dependent on the physiochemical properties of the statins, their dose and treatment period. Combined therapies of statins and cytotoxic drugs have also been tested, and synergistic or additive effects were observed. Moreover, observational studies performed on patients who used statins for different pathologies, revealed that statins reduced the risk of developing various cancers, and improved the outcomes for cancer patients. Currently, there are many ongoing clinical trials aimed at exploring the potential of statins to lower the mortality and the disease-recurrence risk. All these results are the foundation of new treatment directions in cancer therapy.
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Affiliation(s)
- Cristina I Barbalata
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Lucia R Tefas
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Marcela Achim
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Ioan Tomuta
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
| | - Alina S Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, “Iuliu-Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca 400012, Romania
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Dongoran RA, Wang KH, Lin TJ, Yuan TC, Liu CH. Anti-Proliferative Effect of Statins Is Mediated by DNMT1 Inhibition and p21 Expression in OSCC Cells. Cancers (Basel) 2020; 12:E2084. [PMID: 32731382 PMCID: PMC7463937 DOI: 10.3390/cancers12082084] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/23/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022] Open
Abstract
Statins, also known as HMG-CoA reductase inhibitors, are a class of cholesterol-lowering drugs and their anti-cancer effects have been studied in different types of malignant diseases. In the present study, we investigated the anti-proliferative effects of statins, including cerivastatin and simvastatin, on oral squamous cell carcinoma (OSCC) cells. Our data showed that statins inhibited the proliferation of three OSCC cell lines in a dose-dependent manner and this growth inhibition was confirmed through G0/G1 cell cycle arrest. Accordingly, we found the upregulation of p21 and downregulation of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, in the statin-treated cells. Importantly, we clearly showed that statins were able to inhibit the expression of DNA methyltransferase 1 (DNMT1) and further promote the expression of p21. Taken together, our data demonstrated that the anti-proliferative effect of statins is mediated by suppressing DNMT1 expression, thus promoting p21 expression and leading to G0/G1 cell cycle arrest in OSCC cells.
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Affiliation(s)
- Rachmad Anres Dongoran
- Ph.D. Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (R.A.D.); (T.-J.L.)
- Indonesian Food and Drug Authority (Indonesian FDA), Jakarta 10560, Indonesia
| | - Kai-Hung Wang
- Department of Medical Research, Tzu Chi Hospital, Hualien 97004, Taiwan;
| | - Tsung-Jen Lin
- Ph.D. Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (R.A.D.); (T.-J.L.)
| | - Ta-Chun Yuan
- Department of Life Science, College of Science and Engineering, National Dong Hwa University, Hualien 97401, Taiwan
| | - Chin-Hung Liu
- Ph.D. Program in Pharmacology and Toxicology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan; (R.A.D.); (T.-J.L.)
- Department of Pharmacology, School of Medicine, Tzu Chi University, Hualien 97004, Taiwan
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37
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Tabuso M, Christian M, Kimani PK, Gopalakrishnan K, Arasaradnam RP. KRAS Status is Associated with Metabolic Parameters in Metastatic Colorectal Cancer According to Primary Tumour Location. Pathol Oncol Res 2020; 26:2537-2548. [PMID: 32594310 PMCID: PMC7471139 DOI: 10.1007/s12253-020-00850-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 06/11/2020] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is characterized by complex interplay between macroenvironmental factors and tumour microenvironment, leading to variable outcomes in CRC patients. To date, there is still a need to identify macroenvironment/microenvironment factors that could define subgroup of patients that would benefit from specific anti-cancer treatment in order to improve patient selection for individualized targeted-based therapy. Aim of this study was to evaluate associations between metabolic parameters and KRAS status in metastatic CRC (mCRC) according to a new tumour site classification. Retrospective data were extracted from a total of 201 patients diagnosed with mCRC between 2012 and 2017 extracted from an established CRC database at our tertiary institute. Clinical-pathological data, including age, gender, BMI, hypertension, diabetes, pre-CRC diagnosis serum lipid levels and KRAS status were recorded. Categorical characteristics were compared using chi-squared test. Continuous characteristics were compared using Mann-Whitney U test. Log rank test was used to compare hazards for survival. In all comparisons, a two-sided P value <0.05 was considered statistically significant. Out of 201 patients, 170 patients with complete serum lipid profile were included in the analysis. In recto-sigmoid cancers there was a statistically significant association between high cholesterol:high-density lipoprotein (chol:HDL) ratio and KRAS mutation (OR 2.69, 95% CI 1.1–6.4, p = 0,02). In non recto-sigmoid cancers, high cholesterol was associated with KRAS WT (OR 0.39, CI 0.15–0.97, p = 0.04). In 22 patients with KRAS mutated recto-sigmoid cancer stage IV at diagnosis normal chol:HDL ratio was associated with a trend to better survival (p = 0.06). High chol:HDL ratio was significantly associated with KRAS mutated metastatic recto-sigmoid cancers. A subgroup of mCRC patients with KRAS mutated recto-sigmoid cancer may benefit from optimal lipid lowering treatment.
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Affiliation(s)
- M Tabuso
- Department of Gastroenterology, University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK. .,Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK.
| | - M Christian
- School of Science and Technology, Nottingham Trent University, Nottingham, NG11 8NS, UK
| | - P K Kimani
- Warwick Medical School, University of Warwick, Coventry, CV4 7AL, UK
| | - K Gopalakrishnan
- Department of Pathology, University Hospitals of Coventry and Warwickshire NHS Trust, Clifford Bridge Road, Coventry, CV2 2DX, UK
| | - R P Arasaradnam
- Department of Gastroenterology, University Hospital Coventry and Warwickshire, Clifford Bridge Road, Coventry, CV2 2DX, UK.,The University of Warwick, School of life Sciences, Coventry, CV4 7AL, UK.,Faculty of Health and Life Sciences, University of Coventry, Priory Street, Coventry, CV1 5BF, UK.,University of Leicester, Leicester, LE1 7RH, UK
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38
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Khamis A, Boutry R, Canouil M, Mathew S, Lobbens S, Crouch H, Andrew T, Abderrahmani A, Tamanini F, Froguel P. Histone deacetylase 9 promoter hypomethylation associated with adipocyte dysfunction is a statin-related metabolic effect. Clin Epigenetics 2020; 12:68. [PMID: 32410704 PMCID: PMC7222462 DOI: 10.1186/s13148-020-00858-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 04/28/2020] [Indexed: 12/14/2022] Open
Abstract
Background Adipogenesis, the process whereby preadipocytes differentiate into mature adipocytes, is crucial for maintaining metabolic homeostasis. Cholesterol-lowering statins increase type 2 diabetes (T2D) risk possibly by affecting adipogenesis and insulin resistance but the (epi)genetic mechanisms involved are unknown. Here, we characterised the effects of statin treatment on adipocyte differentiation using in vitro human preadipocyte cell model to identify putative effective genes. Results Statin treatment during adipocyte differentiation caused a reduction in key genes involved in adipogenesis, such as ADIPOQ, GLUT4 and ABCG1. Using Illumina’s Infinium ‘850K’ Methylation EPIC array, we found a significant hypomethylation of cg14566882, located in the promoter of the histone deacetylase 9 (HDAC9) gene, in response to two types of statins (atorvastatin and mevastatin), which correlates with an increased HDAC9 mRNA expression. We confirmed that HDAC9 is a transcriptional repressor of the cholesterol efflux ABCG1 gene expression, which is epigenetically modified in obesity and prediabetic states. Thus, we assessed the putative impact of ABCG1 knockdown in mimicking the effect of statin in adipogenesis. ABCG1 KD reduced the expression of key genes involved in adipocyte differentiation and decreased insulin signalling and glucose uptake. In human blood cells from two cohorts, ABCG1 expression was impaired in response to statins, confirming that ABCG1 is targeted in vivo by these drugs. Conclusions We identified an epigenetic link between adipogenesis and adipose tissue insulin resistance in the context of T2D risk associated with statin use, which has important implications as HDAC9 and ABCG1 are considered potential therapeutic targets for obesity and metabolic diseases.
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Affiliation(s)
- Amna Khamis
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK.,Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France
| | - Raphael Boutry
- Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France
| | - Mickaël Canouil
- Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France
| | - Sumi Mathew
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Stephane Lobbens
- Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France
| | - Hutokshi Crouch
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Toby Andrew
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Amar Abderrahmani
- Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France
| | - Filippo Tamanini
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
| | - Philippe Froguel
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK. .,Université de Lille, Inserm UMR1283, CNRS-UMR 8199 - EGID, Lille, Lille University Hospital, F-59000, Lille, France.
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Wu G, Huang F, Chen Y, Zhuang Y, Huang Y, Xie Y. High Levels of BMP2 Promote Liver Cancer Growth via the Activation of Myeloid-Derived Suppressor Cells. Front Oncol 2020; 10:194. [PMID: 32195173 PMCID: PMC7064622 DOI: 10.3389/fonc.2020.00194] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 02/05/2020] [Indexed: 12/16/2022] Open
Abstract
Bone morphogenetic protein 2 (BMP2) signaling had significant roles in diverse pathological processes, such as cancer. Nevertheless, the interaction between BMP2 and carcinoma development remained largely unknown. In particular, the roles that BMP2 play in the development of liver cancer remained controversial, and mechanisms were unclear. BMP2 with strong osteogenic potential had been manufactured into various bone materials. However, cancer risk concerns were raised in recent years. Thus, we focused on analyzing the effects of exogenous BMP2 on the growth of liver cancer and the detailed mechanisms. We found that both intravenous injection of rhBMP2 and in vivo implantation of rhBMP2 materials could lead to the expansion of myeloid-derived suppressor cells (MDSCs) in peripheral blood and subsequently enhanced the infiltration of MDSCs into tumor in vivo. Furthermore, BMP2 signaling-activated MDSCs could secrete IL6 to enhance cell proliferation of liver cancer cells in vitro and facilitate liver cancer growth in vivo. Our study indicated that increased concentration of BMP2 within the peripheral blood could enhance liver cancer growth via the activation of MDSCs. In this study, the roles that BMP2 played in liver cancer growth were further confirmed and the detailed mechanisms about how BMP2 enhanced liver cancer growth were also elucidated.
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Affiliation(s)
- Gui Wu
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Fei Huang
- Central Lab, First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yaoqing Chen
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yuehong Zhuang
- Department of Human Anatomy and Embryology, Institute of Neuroscientific Study, Fujian Medical University, Fuzhou, China
| | - Yunpeng Huang
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
| | - Yun Xie
- Department of Orthopedics, First Affiliated Hospital, Fujian Medical University, Fuzhou, China
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40
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Luput L, Sesarman A, Porfire A, Achim M, Muntean D, Casian T, Patras L, Rauca VF, Drotar DM, Stejerean I, Tomuta I, Vlase L, Dragos N, Toma VA, Licarete E, Banciu M. Liposomal simvastatin sensitizes C26 murine colon carcinoma to the antitumor effects of liposomal 5-fluorouracil in vivo. Cancer Sci 2020; 111:1344-1356. [PMID: 31960547 PMCID: PMC7156830 DOI: 10.1111/cas.14312] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 12/17/2019] [Accepted: 12/24/2019] [Indexed: 02/07/2023] Open
Abstract
5-Fluorouracil-based therapy remains the main approach in colorectal cancer, even though there are still some drawbacks, such as chemoresistance. In this study we combined 5-fluorouracil encapsulated in long-circulating liposomes with simvastatin, also encapsulated in long-circulating liposomes, that was previously proved to exert antitumor actions on the same tumor model. The production of angiogenic/inflammatory proteins was assessed by protein array and the production of markers for tumor aggressiveness (Bcl-2, Bax, and nuclear factor [NF]-κB) were determined by western blot analysis. Intratumor oxidative stress was evaluated through measurement of malondialdehyde level by HPLC, and through spectrophotometric analysis of catalytic activity of catalase and of total antioxidant capacity. Immunohistochemical analysis of tumors for CD31 expression was assessed. Intratumor activity of MMP-2 by gelatin zymography was also carried out. Our results revealed that combined therapies based on liposomal formulations exerted enhanced antitumor activities compared with combined treatment with free drugs. Sequential treatment with liposomal simvastatin and liposomal 5-fluorouracil showed the strongest antitumor activity in C26 colon carcinoma in vivo, mainly through inhibition of tumor angiogenesis. Important markers for cancer progression (Bcl-2, Bax, NF-κB, and intratumor antioxidants) showed that liposomal simvastatin might sensitize C26 cells to liposomal 5-fluorouracil treatment in both regimens tested. The outcome of simultaneous treatment with liposomal formulations was superior to sequential treatment with both liposomal types as the invasive capacity of C26 tumors was strongly increased after the latest treatment. The antitumor efficacy of combined therapy in C26 colon carcinoma might be linked to the restorative effects on proteins balance involved in tumor angiogenesis.
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Affiliation(s)
- Lavinia Luput
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Alina Sesarman
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Alina Porfire
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Marcela Achim
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Dana Muntean
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Tibor Casian
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Laura Patras
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Valentin Florian Rauca
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Denise Minerva Drotar
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Ioana Stejerean
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Ioan Tomuta
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Laurian Vlase
- Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy "Iuliu Hatieganu", Cluj-Napoca, Romania
| | - Nicolae Dragos
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Taxonomy and Ecology Department, Institute of Biological Research, Cluj-Napoca, Romania
| | - Vlad Alexandru Toma
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania.,Department of Experimental Biology and Biochemistry, Institute of Biological Research Cluj-Napoca, branch of NIRDBS Bucharest, Cluj-Napoca, Romania
| | - Emilia Licarete
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
| | - Manuela Banciu
- Department of Molecular Biology and Biotechnology, Faculty of Biology and Geology, Babes-Bolyai University, Cluj-Napoca, Romania.,Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences, Babes-Bolyai University, Cluj-Napoca, Romania
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41
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Miura T, Ishiguro M, Ishikawa T, Okazaki S, Baba H, Kikuchi A, Yamauchi S, Matsuyama T, Uetake H, Kinugasa Y. Methylation of bone morphogenetic protein 2 is associated with poor prognosis in colorectal cancer. Oncol Lett 2019; 19:229-238. [PMID: 31897134 PMCID: PMC6924114 DOI: 10.3892/ol.2019.11091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Accepted: 10/07/2019] [Indexed: 12/29/2022] Open
Abstract
The present study investigated aberrant methylation in colorectal cancer (CRC) and its impact on characteristics and prognosis of patients with CRC. Bone morphogenetic protein 2 (BMP2) was identified as a target gene in oligonucleotide microarray expression profiling in a previous study. Subsequently, the BMP2 methylation status was assessed in 498 patients with stage I–III CRC using methylation-specific polymerase chain reaction, and the association between BMP2 methylation status, patient characteristics and prognosis was assessed. BMP2 methylation was observed in 302/498 (60.6%) patients and was associated with positive lymph nodes and venous invasion (P<0.05). In the stage III subgroup, overall survival (OS) was significantly worse in the methylated BMP2 group compared with in the unmethylated BMP2 group (P=0.012). BMP2 methylation was identified as an independent factor for poor OS in stage III patients (P=0.041). Notably, in the left-sided stage III CRC subgroup, relapse-free survival and OS were significantly worse in the methylated BMP2 group than in the unmethylated group (P=0.048 and P=0.031, respectively). In conclusion, DNA hypermethylation of BMP2 was a poor prognostic factor in patients with stage III disease, particularly in those with left-sided stage III CRC. BMP2 methylation may be a biomarker for prognosis prediction and treatment decision-making.
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Affiliation(s)
- Tomiyuki Miura
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Megumi Ishiguro
- Department of Translational Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Toshiaki Ishikawa
- Department of Specialized Surgeries, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Satoshi Okazaki
- Department of Specialized Surgeries, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Hironobu Baba
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Akifumi Kikuchi
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Shinichi Yamauchi
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Takatoshi Matsuyama
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Hiroyuki Uetake
- Department of Specialized Surgeries, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
| | - Yusuke Kinugasa
- Department of Gastrointestinal Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519, Japan
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42
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Fong W, To KKW. Drug repurposing to overcome resistance to various therapies for colorectal cancer. Cell Mol Life Sci 2019; 76:3383-3406. [PMID: 31087119 PMCID: PMC11105507 DOI: 10.1007/s00018-019-03134-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 04/06/2019] [Accepted: 05/06/2019] [Indexed: 02/06/2023]
Abstract
Emergence of novel treatment modalities provides effective therapeutic options, apart from conventional cytotoxic chemotherapy, to fight against colorectal cancer. Unfortunately, drug resistance remains a huge challenge in clinics, leading to invariable occurrence of disease progression after treatment initiation. While novel drug development is unfavorable in terms of time frame and costs, drug repurposing is one of the promising strategies to combat resistance. This approach refers to the application of clinically available drugs to treat a different disease. With the well-established safety profile and optimal dosing of these approved drugs, their combination with current cancer therapy is suggested to provide an economical, safe and efficacious approach to overcome drug resistance and prolong patient survival. Here, we review both preclinical and clinical efficacy, as well as cellular mechanisms, of some extensively studied repurposed drugs, including non-steroidal anti-inflammatory drugs, statins, metformin, chloroquine, disulfiram, niclosamide, zoledronic acid and angiotensin receptor blockers. The three major treatment modalities in the management of colorectal cancer, namely classical cytotoxic chemotherapy, molecular targeted therapy and immunotherapy, are covered in this review.
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Affiliation(s)
- Winnie Fong
- Faculty of Medicine, School of Pharmacy, Room 801N, Lo Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of Hong Kong, Area 39, Shatin, New Territories, Hong Kong SAR, China
| | - Kenneth K W To
- Faculty of Medicine, School of Pharmacy, Room 801N, Lo Kwee-Seong Integrated Biomedical Sciences Building, The Chinese University of Hong Kong, Area 39, Shatin, New Territories, Hong Kong SAR, China.
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43
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Dietary vegetable intake is inversely associated with ATP-binding cassette protein A1 (ABCA1) DNA methylation levels among Japanese women. Nutrition 2019; 65:1-5. [DOI: 10.1016/j.nut.2019.02.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/21/2019] [Accepted: 02/14/2019] [Indexed: 11/20/2022]
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Li Y, He X, Ding Y, Chen H, Sun L. Statin uses and mortality in colorectal cancer patients: An updated systematic review and meta-analysis. Cancer Med 2019; 8:3305-3313. [PMID: 31069997 PMCID: PMC6558478 DOI: 10.1002/cam4.2151] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/01/2019] [Accepted: 03/19/2019] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) remains one of the most common types of cancer and a leading cause of death worldwide. Previous studies indicated that statins may have a potential protective effect on CRC. METHODS We conducted this meta-analysis to systematically assess the overall and cancer-specific survival benefit of statin uses on CRC patients. Related references were identified through PubMed, the Cochrane Library, Web of Science, EMBASE, and SCOPUS from inception to August 2017. Adjusted hazard ratios (HRs) were adopted to calculate summary hazard ratios (HRs) with 95% confidence intervals (95% CIs), using a random-effects model. RESULTS Total fourteen studies involving 130 994 patients were included in this meta-analysis. Six studies reported the association between pre-diagnosis statin uses and CRC mortality, while 11 studies investigated mortality in patients using statins after CRC diagnosis. For pre-diagnosis statin uses, the pooled HR of all-cause mortality (ACM) was 0.85 (95% CI, 0.79-0.92) and the pooled HR of cancer-specific mortality (CSM) was 0.82 (95% CI, 0.79-0.86). In terms of post-diagnosis statin uses, the pooled HR of ACM was 0.86 (95% CI, 0.76-0.98), and the pooled HR of CSM was 0.79 (95% CI, 0.70-0.89). For post-diagnosis statin uses, there is no difference in ACM when stratified by KRAS gene (KRAS) mutation status. Results of ACM and CSM did not markedly alter in other subgroup analyses. CONCLUSION Our meta-analysis demonstrates that both pre-diagnosis and post-diagnosis statin uses are associated with reduced ACM and CSM for CRC patients.
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Affiliation(s)
- Yue Li
- Department of Gastroenterology, Zhejiang University Medical School, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xingkang He
- Department of Gastroenterology, Zhejiang University Medical School, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yu'e Ding
- Department of Gastroenterology, Zhejiang University Medical School, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Hongyang Chen
- Department of Gastroenterology, Zhejiang University Medical School, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Leimin Sun
- Department of Gastroenterology, Zhejiang University Medical School, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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45
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Nishikawa S, Menju T, Takahashi K, Miyata R, Chen-Yoshikawa TF, Sonobe M, Yoshizawa A, Sabe H, Sato T, Date H. Statins may have double-edged effects in patients with lung adenocarcinoma after lung resection. Cancer Manag Res 2019; 11:3419-3432. [PMID: 31114376 PMCID: PMC6497483 DOI: 10.2147/cmar.s200819] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 03/21/2019] [Indexed: 01/14/2023] Open
Abstract
Purpose: The epithelial to mesenchymal transition (EMT) is pivotal for driving metastasis and recurrence in lung cancer. Some in vitro reports have shown that statins suppress EMT by inactivating mutant p53 functions. Several clinical trials of conventional treatments with statins have been performed, but the effect of these drugs on prognosis is still uncertain. The purpose of this study is to examine the impact of statins on EMT and the prognosis of patients with lung adenocarcinoma. Materials and methods: Morphological changes were evaluated and EMT markers (E-cadherin, vimentin) were analyzed by Western blotting in p53-overexpressing H1650 and mutant p53-harboring H1975 lung adenocarcinoma cells, with and without simvastatin administration. The invasive ability of these cells was analyzed in a Matrigel chemoinvasion assay. A total of 250 lung adenocarcinoma specimens were also collected from patients who underwent surgery in our institute. EMT markers in these tumor specimens were evaluated by immunostaining and p53 mutation status was determined by direct sequencing. Associations among EMT status, p53 mutation status, and statin use were evaluated, and prognosis was analyzed using a marginal structural model. Results: Mutant p53 induced EMT and increased the invasive ability of H1650 cells. Simvastatin restored the epithelial phenotype and decreased the invasive ability of both H1650 and H1975 cells. Statin administration was associated with inactivation of EMT only in patients with mutant p53, which was consistent with the in vitro results. Moreover, in patients with mutant p53, statin users had significantly better survival than non-statin users. In contrast, statins significantly worsened the prognosis of patients with wild type p53 (HR 2.10, 95% CI 1.14–3.85). Conclusion: Statins suppress EMT and change the prognosis of patients with lung adenocarcinoma in a p53 mutation-dependent manner.
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Affiliation(s)
- Shigeto Nishikawa
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshi Menju
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koji Takahashi
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ryo Miyata
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | - Makoto Sonobe
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Akihiko Yoshizawa
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Hisataka Sabe
- Department of Molecular Biology, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Tosiya Sato
- Department of Biostatistics, Kyoto University School of Public Health, Kyoto, Japan
| | - Hiroshi Date
- Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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46
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Statins Do Not Directly Inhibit the Activity of Major Epigenetic Modifying Enzymes. Cancers (Basel) 2019; 11:cancers11040516. [PMID: 30974899 PMCID: PMC6521159 DOI: 10.3390/cancers11040516] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/16/2019] [Accepted: 04/04/2019] [Indexed: 01/27/2023] Open
Abstract
The potential anticancer effects of statins-a widely used class of cholesterol lowering drugs-has generated significant interest, as has the use of epigenetic modifying drugs such as HDAC and DNMT inhibitors. We set out to investigate the effect of statin drugs on epigenetic modifications in multiple cell lines, including hepatocellular carcinoma, breast carcinoma, leukemic macrophages, cervical adenocarcinoma, and insulin-secreting cells, as well as liver extracts from statin-treated C57B1/6J mice. Cells or cell extracts were treated with statins and with established epigenetic modulators, and HDAC, HAT, and DNMT activities were quantified. We also examined histone acetylation by immunoblotting. Statins altered neither HDAC nor HAT activity. Accordingly, acetylation of histones H3 and H4 was unchanged with statin treatment. However, statins tended to increase DNMT activity. These results indicate that direct inhibition of the major classes of epigenetic modifying enzymes, as previously reported elsewhere, is unlikely to contribute to any anticancer effects of statins. This study concerned global effects on epigenetic enzyme activities and histone acetylation; whether statins influence epigenetic modifications in certain genomic regions, cannot be ruled out and remains to be investigated.
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47
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Lin L, Liu Y, Pan C, Zhang J, Zhao Y, Shao R, Huang Z, Su Y, Shi M, Bin J, Liao Y, Li N, Wang C, Liao W. Gastric cancer cells escape metabolic stress via the DLC3/MACC1 axis. Am J Cancer Res 2019; 9:2100-2114. [PMID: 31037159 PMCID: PMC6485279 DOI: 10.7150/thno.29538] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/21/2019] [Indexed: 12/16/2022] Open
Abstract
Metabolic stress usually occurs in rapidly growing gastric cancer (GC) when the energy demand exceeds the supply. Interestingly, cancer cells can somehow escape this stress. Some small Rho GTPases regulating cell migration can be activated by metabolic stress. DLC3 is a RhoA-specific GTPase-activating protein of unclear function in cancer. We hypothesized that it participated in metabolic stress escape. Methods: Metabolic stress in GC cells was induced by glucose deprivation, and DLC3 expression was detected. Based on the prognostic value, cell viability, motility and glycolysis were detected in DLC3 differently expressed GC cells in vitro and in vivo. DLC3 downstream targets were screened and verified. Chemotactic ability was evaluated to study DLC3 and its downstream signaling on metabolic stress escape. In addition, therapeutic strategies targeting DLC3 were explored. Results: DLC3 expression was lowered by metabolic stress in GC cells. DLC3 downregulation indicated poor cancer prognosis, and silencing DLC3 promoted GC cell proliferation and invasion. MACC1, an oncogene promoting GC growth and metastasis, was proved to be the downstream target of DLC3. Low DLC3 expression and high MACC1 expression indicated high recurrence rate after GC resection. DLC3 transcriptionally inhibited MACC1 expression via RhoA/JNK/AP-1 signaling, and subsequently suppressed GC cell glycolysis and survival under metabolic stress. The DLC3/MACC1 axis modulated the chemotaxis of GC cells from energy deficient area to glucose abundant area. Finally, lovastatin was found to be a promising therapeutic drug targeting the DLC3/MACC1 axis. Conclusions: The DLC3/MACC1 axis modulates GC glycolysis and chemotaxis to escape glucose deprivation. Lovastatin may inhibit GC by targeting the DLC3/MACC1 axis.
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48
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Pennel KAF, Park JH, McMillan DC, Roseweir AK, Edwards J. Signal interaction between the tumour and inflammatory cells in patients with gastrointestinal cancer: Implications for treatment. Cell Signal 2018; 54:81-90. [PMID: 30453014 DOI: 10.1016/j.cellsig.2018.11.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 11/15/2018] [Accepted: 11/15/2018] [Indexed: 12/12/2022]
Abstract
Over the last 15 years there has been a change in how we understand the impact of the interaction between the tumour and the host on cancer outcomes. From the simplistic view that the make-up of tumours cells largely determines their aggressiveness to a more complex view that the interaction between the products of tumour and host cell signal transduction pathways is crucial in determining whether the tumour cell is eliminated or survives in the host. Of the host cells, those with an immune/inflammatory function are most well documented to inhibit or promote tumour cell proliferation and dissemination. It is only in the last few years that there has been greater recognition of the impact of intracellular, cellular and systemic immune/inflammatory phenotypes on patient outcomes independent of current tumour staging and that these phenotypes are useful in informing oncological research and practice. In the present review we will examine the importance of inflammatory phenotypes at the intra-cellular, cellular and systemic levels on outcomes in patients with gastrointestinal cancer with focus on colorectal cancer. Based on these phenotypes we will examine and discuss the prospects for therapeutic intervention.
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Affiliation(s)
- Kathryn A F Pennel
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom.
| | - James H Park
- Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Donald C McMillan
- Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Antonia K Roseweir
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine - University of Glasgow, Royal Infirmary, Glasgow G31 2ER, United Kingdom
| | - Joanne Edwards
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of MVLS, University of Glasgow, United Kingdom
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The Involvement of PPARs in the Peculiar Energetic Metabolism of Tumor Cells. Int J Mol Sci 2018; 19:ijms19071907. [PMID: 29966227 PMCID: PMC6073339 DOI: 10.3390/ijms19071907] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/10/2018] [Accepted: 06/24/2018] [Indexed: 12/13/2022] Open
Abstract
Energy homeostasis is crucial for cell fate, since all cellular activities are strongly dependent on the balance between catabolic and anabolic pathways. In particular, the modulation of metabolic and energetic pathways in cancer cells has been discussed in some reports, but subsequently has been neglected for a long time. Meanwhile, over the past 20 years, a recovery of the study regarding cancer metabolism has led to an increasing consideration of metabolic alterations in tumors. Cancer cells must adapt their metabolism to meet their energetic and biosynthetic demands, which are associated with the rapid growth of the primary tumor and colonization of distinct metastatic sites. Cancer cells are largely dependent on aerobic glycolysis for their energy production, but are also associated with increased fatty acid synthesis and increased rates of glutamine consumption. In fact, emerging evidence has shown that therapeutic resistance to cancer treatment may arise from the deregulation of glucose metabolism, fatty acid synthesis, and glutamine consumption. Cancer cells exhibit a series of metabolic alterations induced by mutations that lead to a gain-of-function of oncogenes, and a loss-of-function of tumor suppressor genes, including increased glucose consumption, reduced mitochondrial respiration, an increase of reactive oxygen species, and cell death resistance; all of these are responsible for cancer progression. Cholesterol metabolism is also altered in cancer cells and supports uncontrolled cell growth. In this context, we discuss the roles of peroxisome proliferator-activated receptors (PPARs), which are master regulators of cellular energetic metabolism in the deregulation of the energetic homeostasis, which is observed in cancer. We highlight the different roles of PPAR isotypes and the differential control of their transcription in various cancer cells.
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50
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Affiliation(s)
- Maurizio Bifulco
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Naples, Italy
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