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Ranjan G, Ranjan S, Sunita P, Pattanayak SP. Thiazolidinedione derivatives in cancer therapy: exploring novel mechanisms, therapeutic potentials, and future horizons in oncology. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:4705-4725. [PMID: 39621087 DOI: 10.1007/s00210-024-03661-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 11/20/2024] [Indexed: 04/11/2025]
Abstract
Thiazolidinedione derivatives have shown significant potential as targeted cancer therapies by leveraging their various mechanisms of action. These include suppressing cell proliferation, triggering apoptosis, and influencing signaling pathways associated with tumor development. Their multifaceted effects make them promising candidates for advancing cancer treatment strategies. They have shown significant promise as anti-cancer agents, particularly through their ability to inhibit lipogenesis pathways and apoptosis essential for cancer cell survival and proliferation. This review comprehensively examines the anti-cancer potential of thiazolidinedione derivatives by targeting key aspects of lipid metabolism, apoptosis, and various mechanistic pathways. This review provides an in-depth examination of the anti-cancer potential of TZD derivatives, focusing on their mechanisms of action, therapeutic applications, and future directions in oncology. The anti-tumor effects of TZDs primarily involve the stimulation of peroxisome proliferator-activated receptor gamma (PPAR-γ), suppressing cell proliferation, induction of apoptosis, and inhibition of angiogenesis. Moreover, recent evidence highlights their ability to modulate non-PPAR-γ pathways, such as PI3K/Akt, NF-κB, and MAPK, further expanding their role in overcoming drug resistance and enhancing therapeutic outcomes. This review explores the preclinical (in vitro and in vivo) and clinical research investigating TZD derivatives efficacy in various cancer types. The insights underscore the significance of targeting lipogenesis as a novel anti-cancer strategy, positioning thiazolidinedione derivatives as potent candidates for future cancer therapeutics. As the oncology landscape evolves, TZD derivatives (rosiglitazone, pioglitazone, inolitazone, troglitazone, and 2,4-thiazolidinedione derivatives) represent a promising class of agents with the potential to contribute meaningfully to cancer treatment. By integrating existing knowledge with recent advancements, this study provides valuable insights into the role of thiazolidinedione derivatives in cancer treatment, paving the way for further research and clinical applications.
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Affiliation(s)
- Gaurav Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Shashi Ranjan
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India
| | - Priyashree Sunita
- Department of Surgery, Case Comprehensive Cancer Centre, Case Western Reserve University, Wolstein Research Building 2103 Cornell Rd, Cleveland, OH, 44106, USA
| | - Shakti Prasad Pattanayak
- Department of Pharmacy, School of Health Sciences, Central University of South Bihar, Gaya, 824236, India.
- Department of Biochemistry, School of Medicine, Case Western Reserve University, Woods Building, W437, 2109 Adelbert Road, Cleaveland, OH, 44106, USA.
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Latambale G, Juvale K. Thiazolidinedione derivatives: emerging role in cancer therapy. Mol Divers 2025:10.1007/s11030-024-11093-3. [PMID: 39899123 DOI: 10.1007/s11030-024-11093-3] [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: 08/08/2024] [Accepted: 12/19/2024] [Indexed: 02/04/2025]
Abstract
Cancer remains the leading cause of death worldwide, with the Globocan 2022 study reporting an estimated 9.7 million cancer deaths. Without the selectivity built for tumour cells, chemotherapeutic agents could be toxic to non-cancerous cells. Administration of such non-selective cytotoxic compounds causes severe side effects and could lead to death. Improved cancer treatments are required to overcome the limitations of the current cancer treatment. The potential of thiazolidinedione derivatives as anticancer drugs has recently drawn attention, despite their primary use as insulin sensitizers in the treatment of type 2 diabetes. The ability of thiazolidinedione derivatives to alter important molecular pathways implicated in carcinogenesis, such as cell proliferation, apoptosis, angiogenesis, Raf kinase, EGFR and HER-2 kinases, HDAC, COX-2 enzyme and metastasis, is highlighted in this review, which examines the growing relevance of these compounds in cancer treatment. Thiazolidinediones have anti-inflammatory, antioxidant, and antiproliferative properties in a variety of cancer types, including breast, colon, and prostate cancers, via activating the peroxisome proliferator-activated gamma receptor (PPARγ). In addition to examining the safety profile and difficulties in clinical translation, the paper looks at preclinical and clinical research that points to these medicines potential to improve the effectiveness of immunotherapy and chemotherapy. This review highlights the encouraging therapeutic possibilities and structure-activity relationship insight of TZDs for their anticancer activity and highlights the molecular level facets of the 'glitazone' pharmacophore for its anticancer activity.
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Affiliation(s)
- Ganesh Latambale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India
| | - Kapil Juvale
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V. L. Mehta Road, Vile Parle (W), Mumbai, India.
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Shan W, Zuo K, Zuo Z. Hypoglycemic Agents Increase Regulatory Factor X1 to Inhibit Cancer Cell Behaviour in Human Glioblastoma Cells. J Cell Mol Med 2024; 28:e70260. [PMID: 39636301 PMCID: PMC11619449 DOI: 10.1111/jcmm.70260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 08/08/2024] [Accepted: 11/20/2024] [Indexed: 12/07/2024] Open
Abstract
Glioblastoma multiforme is a deadly brain tumour in humans. We have shown that regulatory factor X1 (RFX1), a transcription factor, inhibits the proliferation, migration and invasion of human glioblastoma cells. This study was designed to identify the existing medications that could increase RFX1 in human glioblastoma cells and to determine whether these medications could inhibit the cancer cell behaviours. A bioinformatics approach was used to identify the medications that increased RFX1. The effects of these medications on human glioblastoma cell proliferation, migration and invasion were assayed under cell culture and mouse brain xenograft conditions. Pioglitazone, rosiglitazone and WY-14643 increased RFX1 based on bioinformatics prediction and Western blotting data. These hypoglycemic agents reduced the proliferation, migration and invasion of human glioblastoma cell cultures. These agents reduced metalloproteinase 2 (MMP2) activity in the culture medium. Silencing RFX1 attenuated hypoglycemic agent-induced inhibition of cancer cell behaviours and MMP2 activity. Pioglitazone reduced the xenograft tumour volume and migration distance of U87 human glioblastoma cells in the mouse brain. RFX1-siRNA attenuated these effects. Our results provide additional evidence for RFX1 as a therapeutic target for human glioblastoma and suggest that pioglitazone, rosiglitazone and WY-14643 inhibit cancer cell behaviour of human glioblastoma cells via upregulating RFX1.
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Affiliation(s)
- Weiran Shan
- Department of AnesthesiologyUniversity of VirginiaCharlottesvilleVirginiaUSA
| | - Kendrick Zuo
- Kenneth P. Dietrich School of Arts and SciencesUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Zhiyi Zuo
- Department of AnesthesiologyUniversity of VirginiaCharlottesvilleVirginiaUSA
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Ren L, Zhang T, Zhang J. Recent advances in dietary androgen receptor inhibitors. Med Res Rev 2024; 44:1446-1500. [PMID: 38279967 DOI: 10.1002/med.22019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Revised: 12/07/2023] [Accepted: 01/10/2024] [Indexed: 01/29/2024]
Abstract
As a nuclear transcription factor, the androgen receptor (AR) plays a crucial role not only in normal male sexual differentiation and growth of the prostate, but also in benign prostatic hyperplasia, prostatitis, and prostate cancer. Multiple population-based epidemiological studies demonstrated that prostate cancer risk was inversely associated with increased dietary intakes of green tea, soy products, tomato, and so forth. Therefore, this review aimed to summarize the structure and function of AR, and further illustrate the structural basis for antagonistic mechanisms of the currently clinically available antiandrogens. Due to the limitations of these antiandrogens, a series of natural AR inhibitors have been identified from edible plants such as fruits and vegetables, as well as folk medicines, health foods, and nutritional supplements. Hence, this review mainly focused on recent experimental, epidemiological, and clinical studies about natural AR inhibitors, particularly the association between dietary intake of natural antiandrogens and reduced risk of prostatic diseases. Since natural products offer multiple advantages over synthetic antiandrogens, this review may provide a comprehensive and updated overview of dietary-derived AR inhibitors, as well as their potential for the nutritional intervention against prostatic disorders.
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Affiliation(s)
- Li Ren
- College of Food Science and Engineering, Jilin University, Changchun, China
| | - Tiehua Zhang
- College of Food Science and Engineering, Jilin University, Changchun, China
| | - Jie Zhang
- College of Food Science and Engineering, Jilin University, Changchun, China
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Galal MA, Al-Rimawi M, Hajeer A, Dahman H, Alouch S, Aljada A. Metformin: A Dual-Role Player in Cancer Treatment and Prevention. Int J Mol Sci 2024; 25:4083. [PMID: 38612893 PMCID: PMC11012626 DOI: 10.3390/ijms25074083] [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: 03/06/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies.
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Affiliation(s)
- Mariam Ahmed Galal
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
- Department of Translational Health Sciences, Bristol Medical School, University of Bristol, Bristol BS8 1QU, UK
| | - Mohammed Al-Rimawi
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | | | - Huda Dahman
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Samhar Alouch
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
| | - Ahmad Aljada
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia; (M.A.G.); (M.A.-R.); (H.D.); (S.A.)
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Eslami M, Memarsadeghi O, Davarpanah A, Arti A, Nayernia K, Behnam B. Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines 2024; 12:183. [PMID: 38255288 PMCID: PMC10812960 DOI: 10.3390/biomedicines12010183] [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: 11/26/2023] [Revised: 12/17/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
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Affiliation(s)
- Maryam Eslami
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Omid Memarsadeghi
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Ali Davarpanah
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Afshin Arti
- Department of Biomedical Engineering, Central Tehran Branch, Islamic Azad University, Tehran 1469669191, Iran;
| | - Karim Nayernia
- International Center for Personalized Medicine (P7Medicine), 40235 Dusseldorf, Germany
| | - Babak Behnam
- Department of Regulatory Affairs, Amarex Clinical Research, NSF International, Germantown, MD 20874, USA
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Zhao LY, Mei JX, Yu G, Lei L, Zhang WH, Liu K, Chen XL, Kołat D, Yang K, Hu JK. Role of the gut microbiota in anticancer therapy: from molecular mechanisms to clinical applications. Signal Transduct Target Ther 2023; 8:201. [PMID: 37179402 PMCID: PMC10183032 DOI: 10.1038/s41392-023-01406-7] [Citation(s) in RCA: 137] [Impact Index Per Article: 68.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 02/21/2023] [Accepted: 03/12/2023] [Indexed: 05/15/2023] Open
Abstract
In the past period, due to the rapid development of next-generation sequencing technology, accumulating evidence has clarified the complex role of the human microbiota in the development of cancer and the therapeutic response. More importantly, available evidence seems to indicate that modulating the composition of the gut microbiota to improve the efficacy of anti-cancer drugs may be feasible. However, intricate complexities exist, and a deep and comprehensive understanding of how the human microbiota interacts with cancer is critical to realize its full potential in cancer treatment. The purpose of this review is to summarize the initial clues on molecular mechanisms regarding the mutual effects between the gut microbiota and cancer development, and to highlight the relationship between gut microbes and the efficacy of immunotherapy, chemotherapy, radiation therapy and cancer surgery, which may provide insights into the formulation of individualized therapeutic strategies for cancer management. In addition, the current and emerging microbial interventions for cancer therapy as well as their clinical applications are summarized. Although many challenges remain for now, the great importance and full potential of the gut microbiota cannot be overstated for the development of individualized anti-cancer strategies, and it is necessary to explore a holistic approach that incorporates microbial modulation therapy in cancer.
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Affiliation(s)
- Lin-Yong Zhao
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Jia-Xin Mei
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Gang Yu
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Lei Lei
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University; Frontier Innovation Center for Dental Medicine Plus, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Kai Liu
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiao-Long Chen
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Damian Kołat
- Department of Experimental Surgery, Medical University of Lodz, Lodz, Poland
| | - Kun Yang
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Jian-Kun Hu
- Department of General Surgery & Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
- Gastric Cancer Center, West China Hospital, Sichuan University, Chengdu, China.
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Yu OHY, Suissa S. Metformin and Cancer: Solutions to a Real-World Evidence Failure. Diabetes Care 2023; 46:904-912. [PMID: 37185680 DOI: 10.2337/dci22-0047] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/09/2023] [Indexed: 05/17/2023]
Abstract
The quest to repurpose metformin, an antidiabetes drug, as an agent for cancer prevention and treatment, which began in 2005 with an observational study that reported a reduction in cancer incidence among metformin users, generated extensive experimental, observational, and clinical research. Experimental studies revealed that metformin has anticancer effects via various pathways, potentially inhibiting cancer cell proliferation. Concurrently, multiple nonrandomized observational studies reported remarkable reductions in cancer incidence and outcomes with metformin use. However, these studies were shown, in 2012, to be affected by time-related biases, such as immortal time bias, which tend to greatly exaggerate the benefit of a drug. The observational studies that avoided these biases did not find an association. Subsequently, the randomized trials of metformin for the treatment of type 2 diabetes and as adjuvant therapy for the treatment of various cancers, advanced or metastatic, did not find reductions in cancer incidence or outcomes. Most recently, the largest phase 3 randomized trial of metformin as adjuvant therapy for breast cancer, which enrolled 3,649 women with a 5-year follow-up, found no benefit for disease-free survival or overall survival with metformin. This major failure of observational real-world evidence studies in correctly assessing the effects of metformin on cancer incidence and outcomes was caused by preventable biases which, surprisingly, are still prominent in 2022. Rigorous approaches for observational studies that emulate randomized trials, such as the incident and prevalent new-user designs along with propensity scores, avoid these biases and can provide more accurate real-world evidence for the repurposing of drugs such as metformin.
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Affiliation(s)
- Oriana Hoi Yun Yu
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 2Division of Endocrinology, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
| | - Samy Suissa
- 1Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
- 3Department of Medicine, McGill University, Montreal, Canada
- 4Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
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Hartley A, Ahmad I. The role of PPARγ in prostate cancer development and progression. Br J Cancer 2023; 128:940-945. [PMID: 36510001 PMCID: PMC10006070 DOI: 10.1038/s41416-022-02096-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/16/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.
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Affiliation(s)
- Andrew Hartley
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK
| | - Imran Ahmad
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
- CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
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Scheinberg T, Mak B, Butler L, Selth L, Horvath LG. Targeting lipid metabolism in metastatic prostate cancer. Ther Adv Med Oncol 2023; 15:17588359231152839. [PMID: 36743527 PMCID: PMC9893394 DOI: 10.1177/17588359231152839] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 01/05/2023] [Indexed: 02/04/2023] Open
Abstract
Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.
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Affiliation(s)
- Tahlia Scheinberg
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown NSW, Australia,Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia,University of Sydney, Camperdown, NSW, Australia
| | - Blossom Mak
- Medical Oncology, Chris O’Brien Lifehouse, Camperdown NSW, Australia,Advanced Prostate Cancer Group, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia,University of Sydney, Camperdown, NSW, Australia
| | - Lisa Butler
- Prostate Cancer Research Group, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia,South Australian Immunogenomics Cancer Institute and Freemason’s Centre for Male Health and Wellbeing, University of Adelaide, South Australia, Australia
| | - Luke Selth
- South Australian Immunogenomics Cancer Institute and Freemason’s Centre for Male Health and Wellbeing, University of Adelaide, South Australia, Australia,Dame Roma Mitchell Cancer Research Labs, Adelaide Medical School, University of Adelaide, Adelaide, South Australia, Australia,Flinders Health and Medical Research Institute, Flinders University, College of Medicine and Public Health, Bedford Park, Australia
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Wang NF, Jue TR, Holst J, Gunter JH. Systematic review of antitumour efficacy and mechanism of metformin activity in prostate cancer models. BJUI COMPASS 2023; 4:44-58. [PMID: 36569495 PMCID: PMC9766874 DOI: 10.1002/bco2.187] [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: 06/08/2022] [Revised: 07/07/2022] [Accepted: 08/08/2022] [Indexed: 12/27/2022] Open
Abstract
Metformin, the first line pharmacotherapy for type 2 diabetes has demonstrated favourable effects in prostate cancer (PCa) across a range of studies evaluating PCa patient outcomes amongst metformin users. However, a lack of rigorously conducted prospective studies has stalled clinical use in this setting. Despite multiple studies evaluating the mechanisms underpinning antitumour effects of metformin in PCa, to date, no reviews have compared these findings. This systematic review and meta-analysis consolidates the mechanisms accounting for the antitumour effect of metformin in PCa and evaluates the antitumour efficacy of metformin in preclinical PCa studies. Data were obtained through Medline and EMBASE, extracted by two independent assessors. Risk of bias was assessed using the TOXR tool. Meta-analysis compared in vivo reductions of PCa tumour volume with metformin. In total, 447 articles were identified with 80 duplicates, and 261 articles excluded based on eligibility criteria. The remaining 106 articles were assessed and 71 excluded, with 35 articles included for systematic review, and eight included for meta-analysis. The mechanisms of action of metformin regarding tumour growth, viability, migration, invasion, cell metabolism, and activation of signalling cascades are individually discussed. The mechanisms by which metformin inhibits PCa cell growth are multimodal. Metformin regulates expression of multiple proteins/genes to inhibit cellular proliferation, cell cycle progression, and cellular invasion and migration. Published in vivo studies also conclusively demonstrate that metformin inhibits PCa growth. This highlights the potential of metformin to be repurposed as an anticancer agent, warranting further investigation of metformin in the setting of PCa.
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Affiliation(s)
- Nan Fang Wang
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Toni Rose Jue
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jeff Holst
- School of Medical SciencesUNSW SydneySydneyNSWAustralia
- Prince of Wales Clinical SchoolUNSW SydneySydneyNSWAustralia
| | - Jennifer H. Gunter
- Australian Prostate Cancer Research Centre‐Queensland, Centre for Genomic and Personalised Health, School of Biomedical Sciences, Faculty of Health, Translational Research InstituteQueensland University of Technology (QUT)BrisbaneQLDAustralia
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Un S, Quan NV, Anh LH, Lam VQ, Takami A, Khanh TD, Xuan TD. Effects of In Vitro Digestion on Anti-α-Amylase and Cytotoxic Potentials of Sargassum spp. Molecules 2022; 27:2307. [PMID: 35408706 PMCID: PMC9000548 DOI: 10.3390/molecules27072307] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 03/30/2022] [Accepted: 03/31/2022] [Indexed: 02/05/2023] Open
Abstract
This is the first study to examine the effects of in vitro digestion on biological activities of Sargassum spp., a broadly known brown seaweed for therapeutic potential. Three fractions (F1-F3) were obtained from hexane extract by column chromatography. Under in vitro simulated digestion, the anti-α-amylase capacity of F1 in oral and intestinal phases increases, while it significantly decreases in the gastric phase. The α-amylase inhibition of F2 promotes throughout all digestive stages while the activity of F3 significantly reduces. The cytotoxic activity of F1 against U266 cell-line accelerates over the oral, gastric, and intestinal stages. The fractions F2 and F3 exhibited the declined cytotoxic potentialities in oral and gastric phases, but they were strengthened under intestinal condition. Palmitic acid and fucosterol may play an active role in antidiabetic and cytotoxic activity against multiple myeloma U266 cell line of Sargassum spp. However, the involvement of other phytochemicals in the seaweed should be further investigated.
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Affiliation(s)
- Sovannary Un
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (S.U.); (L.H.A.)
| | - Nguyen Van Quan
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (S.U.); (L.H.A.)
| | - La Hoang Anh
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (S.U.); (L.H.A.)
| | - Vu Quang Lam
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (V.Q.L.); (A.T.)
| | - Akiyoshi Takami
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute 480-1195, Japan; (V.Q.L.); (A.T.)
| | - Tran Dang Khanh
- Agricultural Genetics Institute, Pham Van Dong Street, Hanoi 122000, Vietnam;
- Center for Agricultural Innovation, Vietnam National University of Agriculture, Hanoi 131000, Vietnam
| | - Tran Dang Xuan
- Transdisciplinary Science and Engineering Program, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan; (S.U.); (L.H.A.)
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13
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Cui H, Wang Y, Yang S, He G, Jiang Z, Gang X, Wang G. Antidiabetic Medications and the Risk of Prostate Cancer in Patients with Diabetes Mellitus: A Systematic Review and Meta-analysis. Pharmacol Res 2022; 177:106094. [PMID: 35074527 DOI: 10.1016/j.phrs.2022.106094] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/19/2022] [Indexed: 11/29/2022]
Abstract
BACKGROUND Antidiabetic medications (ADMs) may modify prostate cancer (PCa) risk in patients with diabetes mellitus (DM). Accordingly, the current study assessed the possible associations between ADMs and the risk of PCa in diabetics. METHODS A systematic literature search (PubMed, Embase and Cochrane Library) identified studies evaluating the associations between ADMs and incidence of PCa. A meta-analysis followed PRISMA was performed using odds ratio (OR) with 95% confidence interval (CI) as effect measures. RESULTS In total of 47 studies involving 3,094,152 patients with diabetes were included. Results of meta-analysis of the observational studies suggested no significant association between metformin, thiazolidinediones, sulfonylureas, insulin or dipeptidyl peptidase-4 inhibitors administration and the risk of PCa (All p-values > 0.05). Separate analysis of randomized controlled trials (RCTs) revealed a significant reduction in PCa risk with thiazolidinediones (OR = 0.55, p = 0.04) or glucagon-like peptide-1 receptor agonists (GLP-1RA) administration (OR = 0.53, p = 0.006), whereas no significant association was found in SGLT2 inhibitors (p = 0.3). CONCLUSION Thiazolidinediones or GLP-1RA administration may have benefits in PCa based on RCTs, however, further research is needed to confirm these findings.
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Affiliation(s)
- Haiying Cui
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yao Wang
- Department of Orthopedics, The Second Hospital Jilin University, Changchun 130021, Jilin Province, China
| | - Shuo Yang
- Department of Clinical Nutrition, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Guangyu He
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Zongmiao Jiang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Xiaokun Gang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
| | - Guixia Wang
- Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China.
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14
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The Impact of Metformin Use with Survival Outcomes in Urologic Cancers: A Systematic Review and Meta-Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:5311828. [PMID: 34660791 PMCID: PMC8519697 DOI: 10.1155/2021/5311828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 01/11/2023]
Abstract
Background Conflicting results exist between the potential protective effects of metformin and the prognosis of urologic cancers. This meta-analysis summarized the effects of metformin exposure on the recurrence, progression, cancer-specific survival (CSS), and overall survival (OS) of the three main urologic cancers (kidney cancer, bladder cancer, and prostate cancer). Methods We systematically searched PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure databases (January 2010 to December 2019), which identified studies regarding metformin users and nonusers with urologic cancers and extracted patient data. A random effect model or fixed effect model was used to analyze hazard ratios (HRs) and 95% confidence intervals (CIs). Results Among the 1883 confirmed studies, 27 eligible studies were identified, including 123,212 participants. In prostate cancer, patients using metformin have significant benefits for recurrence (HR = 0.74; 95% CI: 0.61-0.90; P = 0.007; I2 = 56%), CSS (HR = 0.74; 95% CI: 0.61-0.91; P = 0.002; I2 = 79%), and OS (HR = 0.76; 95% CI: 0.65-0.90; P < 0.001; I2 = 86%). Moreover, further subgroup analysis showed that the beneficial effects of metformin may be more significant for patients receiving radical radiotherapy. For kidney cancer, metformin was beneficial for progression (HR = 0.80; 95% CI: 0.65-0.98; P = 0.14; I2 = 46%). Analysis revealed that the effect of metformin on the overall survival of kidney cancer patients may be related to nationality (American: HR = 0.76; 95% CI: 0.59-0.98; P = 0.88; I2 = 0%). For bladder cancer, no obvious benefits of metformin use were identified. However, subgroup analysis indicated that metformin may improve the recurrence of bladder cancer, but this improvement was only found in patients with a median follow-up time of more than 4 years (HR = 0.43; 95% CI: 0.28-0.67; P = 0.61; I2 = 0%).
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15
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Russell N, Grossmann M. Management of bone and metabolic effects of androgen deprivation therapy. Urol Oncol 2021; 39:704-712. [DOI: 10.1016/j.urolonc.2018.10.007] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2017] [Revised: 07/20/2018] [Accepted: 10/03/2018] [Indexed: 12/13/2022]
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16
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Lee MH. Harness the functions of gut microbiome in tumorigenesis for cancer treatment. Cancer Commun (Lond) 2021; 41:937-967. [PMID: 34355542 PMCID: PMC8504147 DOI: 10.1002/cac2.12200] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/16/2021] [Indexed: 11/08/2022] Open
Abstract
It has been shown that gut microbiota dysbiosis leads to physiological changes and links to a number of diseases, including cancers. Thus, many cancer categories and treatment regimens should be investigated in the context of the microbiome. Owing to the availability of metagenome sequencing and multiomics studies, analyses of species characterization, host genetic changes, and metabolic profile of gut microbiota have become feasible, which has facilitated an exponential knowledge gain about microbiota composition, taxonomic alterations, and host interactions during tumorigenesis. However, the complexity of the gut microbiota, with a plethora of uncharacterized host‐microbe, microbe‐microbe, and environmental interactions, still contributes to the challenge of advancing our knowledge of the microbiota‐cancer interactions. These interactions manifest in signaling relay, metabolism, immunity, tumor development, genetic instability, sensitivity to cancer chemotherapy and immunotherapy. This review summarizes current studies/molecular mechanisms regarding the association between the gut microbiota and the development of cancers, which provides insights into the therapeutic strategies that could be harnessed for cancer diagnosis, treatment, or prevention.
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Affiliation(s)
- Mong-Hong Lee
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China.,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China
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17
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Xu Y, Liu Y, He T, Zhang Y, Wang M, Yuan H, Yang M. Biguanides decorated albumin nanoparticles loading nintedanib for synergic enhanced hepatocellular carcinoma therapy. Colloids Surf B Biointerfaces 2021; 207:112020. [PMID: 34403984 DOI: 10.1016/j.colsurfb.2021.112020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/29/2021] [Accepted: 08/01/2021] [Indexed: 12/12/2022]
Abstract
Nintedanib (ND) was known as a triple tyrosine kinase inhibitors, inhibiting angiogenesis and tissue fibrosis. Biguanide group has attracted much attention for its great penetrating ability to the lipid bilayer of cytomembrane and potential anti-cancer efficacy. In this study, a biguanide group (p-biguanidinobenzoic acid, CBH) decorated bovine serum albumin (CBH-AB) was synthesized as a novel functional biomaterial to prepare the ND loaded CBH-AB nanoparticles (ND-CBH-AB NPs). The results of physical and chemical properties showed that ND-CBH-AB NPs possessed high encapsulation efficiency and drug loading efficiency. In vitro cell study indicated that CBH modification on ND-CBH-AB NPs enhanced the cyctotoxicities to HepG2 cells. Furthermore, pharmacokinetic study showed that ND-CBH-AB NPs had good stability in circulation. Finally, pharmacodynamic studies were conducted, the results indicated that ND-CBH-AB NPs exhibited excellent anti-tumor effect and tumor microenvironment regulation effect. Thereby, this work provides a potential function albumin delivery system for hepatocellular carcinoma therapy.
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Affiliation(s)
- Ying Xu
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, China.
| | - Yulong Liu
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, China
| | - Taofeng He
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, China; Humanwell PuraCap Pharmaceuticals (Wuhan) Co., Ltd, Wuhan, 430206, China
| | - Yaqi Zhang
- College of Pharmacy, Jiangsu University, Zhenjiang, 212013, China
| | - Mingyun Wang
- Cancer Center of NanJing GaoChun People's Hospital, Nanjing, 211300, China
| | - Huaqin Yuan
- Cancer Center of NanJing GaoChun People's Hospital, Nanjing, 211300, China
| | - Mi Yang
- Cancer Center of NanJing GaoChun People's Hospital, Nanjing, 211300, China; The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, 210008, China.
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18
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Vihervuori VJ, Talala K, Taari K, Lahtela J, Tammela TLJ, Auvinen A, Raittinen P, Murtola TJ. Antidiabetic Drugs and Prostate Cancer Prognosis in a Finnish Population-Based Cohort. Cancer Epidemiol Biomarkers Prev 2021; 30:982-989. [PMID: 33653815 DOI: 10.1158/1055-9965.epi-19-0580] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Revised: 11/01/2020] [Accepted: 02/22/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Hyperinsulemia and glycemic control may play a role as prostate cancer prognostic factors, whereas use of certain antidiabetic drugs, that is metformin, could improve the prognosis. We examined the link between antidiabetic medication use and prostate cancer survival taking into account simultaneous use of multiple drugs. METHODS The study cohort composed of 6,537 men in The Finnish Randomized Study of Screening for Prostate Cancer with prostate cancer diagnosed 1996 to 2009. Use of medication was attained from the nationwide prescription database of the Social Insurance Institution of Finland. Median follow-up was 9.2 years postdiagnosis. A total of 1,603 (24,5%) men had used antidiabetic medication. A total of 771 men died of prostate cancer during the follow-up. We used multivariable-adjusted Cox regression to evaluate the risk of prostate cancer death and onset of androgen deprivation therapy (ADT) with adjustment for prostate cancer clinical characteristics, comorbidities and use of other drugs. Separate analyses were further adjusted for blood glucose. RESULTS Risk of prostate cancer death was higher among antidiabetic drug users overall (HR = 1.42; 95% CI, 1.18-1.70) compared with nonusers, separately among insulin and metformin users. Adjustment for blood glucose level abolished the risk increase. Risk of ADT initiation was increased among the medication users (HR = 1.26; 95% CI, 1.05-1.49). CONCLUSIONS Men with prostate cancer using antidiabetic medication are generally at increased risk of dying from prostate cancer compared with nonusers. The risk association is driven by underlying diabetes, as adjustment for blood glucose level ameliorates the risk increase. IMPACT Type 2 diabetes should be considered as a risk factor when considering prostate cancer prognosis.
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Affiliation(s)
- Ville J Vihervuori
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
| | | | - Kimmo Taari
- Department of Urology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Jorma Lahtela
- Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
| | - Teuvo L J Tammela
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Urology, Tampere University Hospital, Tampere, Finland
| | - Anssi Auvinen
- Faculty of Social Sciences, Tampere University, Tampere, Finland
| | | | - Teemu J Murtola
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.,Department of Urology, Tampere University Hospital, Tampere, Finland.,Department of Surgery, Seinäjoki Central Hospital, Seinäjoki, Finland
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19
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Chou PC, Choi HH, Huang Y, Fuentes-Mattei E, Velazquez-Torres G, Zhang F, Phan L, Lee J, Shi Y, Bankson JA, Wu Y, Wang H, Zhao R, Yeung SCJ, Lee MH. Impact of diabetes on promoting the growth of breast cancer. Cancer Commun (Lond) 2021; 41:414-431. [PMID: 33609419 PMCID: PMC8118590 DOI: 10.1002/cac2.12147] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Accepted: 02/07/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Type II diabetes mellitus (DM2) is a significant risk factor for cancers, including breast cancer. However, a proper diabetic breast cancer mouse model is not well-established for treatment strategy design. Additionally, the precise diabetic signaling pathways that regulate cancer growth remain unresolved. In the present study, we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression. METHODS We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive (Her2+ or ERBB2) breast cancer with DM2 by crossing leptin receptor mutant (Leprdb/+ ) mice with MMTV-ErbB2/neu) mice. The mouse models were administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth. Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism. RESULTS Treatment with metformin/rosiglitazone in MMTV-ErbB2/Leprdb/db mouse model reduced serum insulin levels, prolonged overall survival, decreased cumulative tumor incidence, and inhibited tumor progression. Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized 13 C pyruvate-to-lactate reaction. The tumor cells from MMTV-ErbB2/Leprdb/db transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production. Metformin decreased the expression of Myc and pyruvate kinase isozyme 2 (PKM2), leading to metabolism reprogramming. Moreover, metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles. CONCLUSIONS MMTV-ErbB2/Leprdb/db mouse model was able to recapitulate diabetic HER2+ human breast cancer. Additionally, our results defined the signaling pathways deregulated in HER2+ breast cancer under diabetic condition, which can be intervened by anti-insulin resistance therapy.
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Affiliation(s)
- Ping-Chieh Chou
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Hyun Ho Choi
- Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China.,Research Institute of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China
| | - Yizhi Huang
- Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China.,Research Institute of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China
| | - Enrique Fuentes-Mattei
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Guermarie Velazquez-Torres
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Fanmao Zhang
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Liem Phan
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Jaehyuk Lee
- Department of Imaging Physics, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yanxia Shi
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510060, P. R. China
| | - James A Bankson
- Department of Imaging Physics, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Yun Wu
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Huamin Wang
- Department of Pathology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Ruiying Zhao
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Sai-Ching Jim Yeung
- Department of Emergency Medicine, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Mong-Hong Lee
- Department of Molecular and Cellular Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.,Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China.,Research Institute of Gastroenterology, the Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, 510020, P. R. China
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20
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Nath M, Nath S, Choudhury Y. The impact of thiazolidinediones on the risk for prostate cancer in patients with type 2 diabetes mellitus: A review and meta-analysis. Meta Gene 2021. [DOI: 10.1016/j.mgene.2020.100840] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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21
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Cannarella R, Condorelli RA, Barbagallo F, La Vignera S, Calogero AE. Endocrinology of the Aging Prostate: Current Concepts. Front Endocrinol (Lausanne) 2021; 12:554078. [PMID: 33692752 PMCID: PMC7939072 DOI: 10.3389/fendo.2021.554078] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Benign prostate hyperplasia (BPH), one of the most common diseases in older men, adversely affects quality-of-life due to the presence of low urinary tract symptoms (LUTS). Numerous data support the presence of an association between BPH-related LUTS (BPH-LUTS) and metabolic syndrome (MetS). Whether hormonal changes occurring in MetS play a role in the pathogenesis of BPH-LUTS is a debated issue. Therefore, this article aimed to systematically review the impact of hormonal changes that occur during aging on the prostate, including the role of sex hormones, insulin-like growth factor 1, thyroid hormones, and insulin. The possible explanatory mechanisms of the association between BPH-LUTS and MetS are also discussed. In particular, the presence of a male polycystic ovarian syndrome (PCOS)-equivalent may represent a possible hypothesis to support this link. Male PCOS-equivalent has been defined as an endocrine syndrome with a metabolic background, which predisposes to the development of type II diabetes mellitus, cardiovascular diseases, prostate cancer, BPH and prostatitis in old age. Its early identification would help prevent the onset of these long-term complications.
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22
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Roy S, Malone S, Grimes S, Morgan SC. Impact of Concomitant Medications on Biochemical Outcome in Localised Prostate Cancer Treated with Radiotherapy and Androgen Deprivation Therapy. Clin Oncol (R Coll Radiol) 2020; 33:181-190. [PMID: 32994091 DOI: 10.1016/j.clon.2020.09.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 08/11/2020] [Accepted: 09/14/2020] [Indexed: 02/07/2023]
Abstract
AIMS Several classes of concomitant medications have been shown to affect oncological outcomes in patients with prostate cancer (PCa). We assessed the association between the use of commonly prescribed concomitant medications and biochemical relapse-free survival (bRFS) in patients with localised PCa treated with radiotherapy and androgen deprivation therapy (ADT). MATERIALS AND METHODS A secondary pooled analysis of two phase III randomised trials was carried out. In the first trial, patients with localised PCa with clinical stage T1b-T3, prostate-specific antigen <30 ng/ml and Gleason score ≤7 were treated with radical radiotherapy and 6 months of ADT starting 4 months before or concomitantly with radiotherapy. In the second trial, patients with high-risk PCa were treated with radical radiotherapy and 36 months of ADT with randomisation to three-dimensional conformal or intensity-modulated radiotherapy. Information on concomitant medications was collected from the medical record. Univariable and multivariable Cox regression was used to identify factors associated with bRFS. RESULTS Overall, 486 patients were evaluable. The median follow-up was 125 months; 10-year bRFS was 83.7%. On univariable analysis, receipt of metformin was significantly associated with worse bRFS. Ten-year bRFS was 73% and 85% for patients with and without concomitant metformin (adjusted hazard ratio 2.11, 95% confidence interval 1.03-4.33). Similar evidence of an association was observed with sulfonamide-based α1-receptor blockers (adjusted hazard ratio 2.72, 95% confidence interval 1.31-5.66). However, no such association was seen with receipt of quinazoline-based α1-receptor blockers (adjusted hazard ratio 1.09, 95% confidence interval 0.42-2.82). There was no significant association between bRFS and receipt of all other medication classes considered. CONCLUSIONS In this population of patients with localised PCa treated with radiotherapy and ADT, receipt of concomitant metformin and sulfonamide-based α1-receptor blockers was associated with inferior biochemical outcome. Randomised trials are required to assess the true effect of these medications on oncological outcomes in localised PCa.
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Affiliation(s)
- S Roy
- Radiation Medicine Program, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - S Malone
- Radiation Medicine Program, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Canada
| | - S Grimes
- Radiation Medicine Program, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
| | - S C Morgan
- Radiation Medicine Program, The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada; Division of Radiation Oncology, University of Ottawa, Ottawa, Ontario, Canada.
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Elhodaky M, Hong LK, Kadkol S, Diamond AM. Selenium-binding protein 1 alters energy metabolism in prostate cancer cells. Prostate 2020; 80:962-976. [PMID: 32511787 PMCID: PMC7473137 DOI: 10.1002/pros.24028] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE The broad goal of the research described in this study was to investigate the contributions of selenium-binding protein 1 (SBP1) loss in prostate cancer development and outcome. METHODS SBP1 levels were altered in prostate cancer cell lines and the consequences on oxygen consumption, expression of proteins associated with energy metabolism, and cellular transformation and migration were investigated. The effects of exposing cells to the SBP1 reaction products, H2 O2 and H2 S were also assessed. In silico analyses identified potential HNF4α binding sites within the SBP1 promoter region and this was investigated using an inhibitor specific for that transcription factor. RESULTS Using in silico analyses, it was determined that the promoter region of SBP1 contains putative binding sites for the HNF4α transcription factor. The potential for HNF4α to regulate SBP1 expression was supported by data indicating that HNF4α inhibition resulted in a dose-response increase in the levels of SBP1 messenger RNA and protein, identifying HNF4α as a novel negative regulator of SBP1 expression in prostate cancer cells. The consequences of altering the levels of SBP1 were investigated by ectopically expressing SBP1 in PC-3 prostate cancer cells, where SBP1 expression attenuated anchorage-independent cellular growth and migration in culture, both properties associated with transformation. SBP1 overexpression reduced oxygen consumption in these cells and increased the activation of AMP-activated protein kinase (AMPK), a major regulator of energy homeostasis. In addition, the reaction products of SBP1, H2 O2 , and H2 S also activated AMPK. CONCLUSIONS Based on the obtained data, it is hypothesized that SBP1 negatively regulates oxidative phosphorylation (OXPHOS) in the healthy prostate cells by the production of H2 O2 and H2 S and consequential activation of AMPK. The reduction of SBP1 levels in prostate cancer can occur due to increased binding of HNF4α, acting as a transcriptional inhibitor to the SBP1 promoter. Consequently, there is a reduction in H2 O2 and H2 S-mediated signaling, inhibition of AMPK, and stimulation of OXPHOS and building blocks of biomolecules needed for tumor growth and progression. Other effects of SBP1 loss in tumor cells remain to be discovered.
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Affiliation(s)
- Mostafa Elhodaky
- Department of Pathology, College of MedicineUniversity of Illinois at ChicagoChicagoIllinois
| | - Lenny K. Hong
- Department of Pathology, College of MedicineUniversity of Illinois at ChicagoChicagoIllinois
| | - Shrinidhi Kadkol
- Department of Pathology, College of MedicineUniversity of Illinois at ChicagoChicagoIllinois
| | - Alan M. Diamond
- Department of Pathology, College of MedicineUniversity of Illinois at ChicagoChicagoIllinois
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Linkeviciute-Ulinskiene D, Patasius A, Kincius M, Zabuliene L, Smailyte G. Preexisting diabetes, metformin use and long-term survival in patients with prostate cancer. Scand J Urol 2020; 54:401-407. [PMID: 32748714 DOI: 10.1080/21681805.2020.1798502] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
OBJECTIVE To assess prostate cancer-specific and overall survival in prostate cancer patients with or without preexisting type 2 diabetes mellitus (T2DM) with regards to metformin use. METHODS Patients diagnosed with prostate cancer in the Lithuanian population between 2001 and 2005 were identified through the Lithuanian Cancer Registry and followed until 2016, date of death, loss to follow-up or whichever came first. Information regarding the diagnosis of T2DM and antihyperglycemic medications were obtained from the National Health Insurance Fund database. Prostate cancer-specific and overall survival outcomes were analysed using univariate and multivariate Cox proportional hazard models. RESULTS Out of 6689 men included, 254 (3.8%) had preexisting T2DM. There were 4807 deaths during follow-up, including 2084 from prostate cancer. No differences were found in prostate cancer-specific survival between men with or without T2DM. The risk of overall mortality was higher (HR = 1.24, 95% CI = 1.07-1.43) in diabetic men. Univariate analysis showed cancer stage at diagnosis and age to be significant predictors of survival. After adjustment for age and stage at diagnosis, there was no difference in prostate-specific survival between non-diabetic patients compared to metformin users or metformin non-users. However, overall survival was lower in T2DM patients, with a higher mortality risk for metformin non-users (HR = 1.63, 95% CI = 1.27-2.10). Prostate cancer-specific mortality risk was insignificantly lower in diabetic men on metformin (HR = 0.74, 95% CI = 0.54-1.02). CONCLUSION There was no difference in long-term prostate cancer-specific survival in patients with or without T2DM. Overall survival was lower in T2DM patients not treated with metformin.
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Affiliation(s)
- Donata Linkeviciute-Ulinskiene
- Department of Pathology, Forensic Medicine and Pharmacology, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Ausvydas Patasius
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania.,Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Marius Kincius
- Department of Oncourology, National Cancer Institute, Vilnius, Lithuania
| | - Lina Zabuliene
- Clinic of Rheumatology, Orthopaedics, Traumatology and Reconstructive Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
| | - Giedre Smailyte
- Laboratory of Cancer Epidemiology, National Cancer Institute, Vilnius, Lithuania.,Department of Public Health, Institute of Health Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania
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Improving Dissolution and Cytotoxicity by Forming Multidrug Crystals. Molecules 2020; 25:molecules25061343. [PMID: 32188020 PMCID: PMC7144552 DOI: 10.3390/molecules25061343] [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] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 12/13/2022] Open
Abstract
Both rosiglitazone and metformin have effects on blood glucose regulation and the proliferation of liver cancer cells. Combination therapy with these two drugs is common and effective for the treatment of diabetes in the clinic, however, the application of these two drugs is influenced by the poor dissolution of rosiglitazone and the gastrointestinal side-effect of metformin resulting from a high solubility. The formation of a multidrug crystal form (Rsg-Met) by a solvent evaporation method can solve the solubility issue. Crystal structure data and intramolecular hydrogen bonds were detected by X-ray diffraction and infrared spectroscopy. Surprisingly, Rsg-Met shortens the time spent in solubility equilibrium and multiplies the dissolution rate of Rsg. Finally, we found that a low concentration of Rsg-Met enhanced the proliferation inhibition effect on liver cancer cells (HepG2, SK-hep1) compared with rosiglitazone, without affecting the human normal cell line LO2.
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Hayashi T, Fujita K, Matsushita M, Nonomura N. Main Inflammatory Cells and Potentials of Anti-Inflammatory Agents in Prostate Cancer. Cancers (Basel) 2019; 11:cancers11081153. [PMID: 31408948 PMCID: PMC6721573 DOI: 10.3390/cancers11081153] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 08/08/2019] [Accepted: 08/09/2019] [Indexed: 02/07/2023] Open
Abstract
Prostate cancer is the most common type of cancer and the leading cause of cancer deaths among men in many countries. Preventing progression is a major concern for prostate cancer patients on active surveillance, patients with recurrence after radical therapies, and patients who acquired resistance to systemic therapies. Inflammation, which is induced by various factors such as infection, microbiome, obesity, and a high-fat diet, is the major etiology in the development of prostate cancer. Inflammatory cells play important roles in tumor progression. Various immune cells including tumor-associated neutrophils, tumor-infiltrating macrophages, myeloid-derived suppressor cells, and mast cells promote prostate cancer via various intercellular signaling. Further basic studies examining the relationship between the inflammatory process and prostate cancer progression are warranted. Interventions by medications and diets to control systemic and/or local inflammation might be effective therapies for prostate cancer progression. Epidemiological investigations and basic research using human immune cells or mouse models have revealed that non-steroidal anti-inflammatory drugs, metformin, statins, soy isoflavones, and other diets are potential interventions for preventing progression of prostate cancer by suppressing inflammation. It is essential to evaluate appropriate indications and doses of each drug and diet.
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Affiliation(s)
- Takuji Hayashi
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Kazutoshi Fujita
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
| | - Makoto Matsushita
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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27
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Hu X, Hu C, Zhang C, Zhang M, Long S, Cao Z. Role of Adiponectin in prostate cancer. Int Braz J Urol 2019; 45:220-228. [PMID: 30648824 PMCID: PMC6541146 DOI: 10.1590/s1677-5538.ibju.2018.0261] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 09/13/2018] [Indexed: 02/07/2023] Open
Abstract
Obesity is defined as a chronic and excessive growth of adipose tissue. It has been associated with a high risk for development and progression of obesity-associated malignancies, while adipokines may mediate this association. Adiponectin is an adipose tissue-derived adipokines, with significant anti-diabetic, anti-inflammatory, anti-atherosclerotic and anti-proliferative properties. Plasma adiponectin levels are decreased in obese individuals, and this feature is closely correlated with development of several metabolic, immunological and neoplastic diseases. Recent studies have shown that prostate cancer patients have lower serum adiponectin levels and decreased expression of adiponectin receptors in tumor tissues, which suggests plasma adiponectin level is a risk factor for prostate cancer. Furthermore, exogenous adiponectin has exhibited therapeutic potential in animal models. In this review, we focus on the potential role of adiponectin and the underlying mechanism of adiponectin in the development and progression of prostate cancer. Exploring the signaling pathways linking adiponectin with tumorigenesis might provide a potential target for therapy.
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Affiliation(s)
- Xiaobo Hu
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China.,Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
| | - Cong Hu
- Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
| | - Caiping Zhang
- Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
| | - Min Zhang
- Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
| | - Shiyin Long
- Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
| | - Zhaohui Cao
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, China.,Department of Biotechnology, School of Pharmacy and Biosciences, University of South China, Hengyang, China
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Ranasinghe WK, Williams S, Ischia J, Wetherell D, Baldwin G, Shulkes A, Sengupta S, Bolton D, Patel O. Metformin may offer no protective effect in men undergoing external beam radiation therapy for prostate cancer. BJU Int 2019; 123 Suppl 5:36-42. [DOI: 10.1111/bju.14709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Weranja K.B. Ranasinghe
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Scott Williams
- Peter MacCallum Cancer Institute; Parkville Vic. Australia
| | - Joseph Ischia
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - David Wetherell
- Department of Urology; Austin Health; Heidelberg Vic. Australia
| | - Graham Baldwin
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Arthur Shulkes
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Shomik Sengupta
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
- Department of Urology; Eastern Health; Box Hill Vic Australia
- Eastern Health Clinical School; Monash University; Box Hill Vic Australia
| | - Damien Bolton
- Department of Urology; Austin Health; Heidelberg Vic. Australia
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
| | - Oneel Patel
- Department of Surgery; University of Melbourne; Heidelberg Vic. Australia
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Association of prostate cancer SLCO gene expression with Gleason grade and alterations following androgen deprivation therapy. Prostate Cancer Prostatic Dis 2019; 22:560-568. [PMID: 30890759 PMCID: PMC6752995 DOI: 10.1038/s41391-019-0141-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/03/2019] [Accepted: 01/23/2019] [Indexed: 02/06/2023]
Abstract
Background. SLCO-encoded transporters have been associated with progression to castration resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence. Methods. We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone. Results. Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (p<0.05 for all). Conclusions. We observed clear differences in SLCO expression in PCa vs NP samples, in Gleason 4 vs Gleason 3 tumors, and in ADT-treated vs untreated tissues. These findings are hypothesis generating due to small sample size, but suggest that baseline and ADT-induced changes in PCa OATP expression may influence steroid uptake and response to ADT, as well as uptake and response to drugs such as abiraterone and docetaxel which are also subject to OATP-mediated transport and are now being routinely combined with ADT in the metastatic castration sensitive setting.
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30
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Wang G, Yu Y, Wang YZ, Wang JJ, Guan R, Sun Y, Shi F, Gao J, Fu XL. Role of SCFAs in gut microbiome and glycolysis for colorectal cancer therapy. J Cell Physiol 2019; 234:17023-17049. [PMID: 30888065 DOI: 10.1002/jcp.28436] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 02/02/2019] [Accepted: 02/14/2019] [Indexed: 12/19/2022]
Abstract
Increased risk of colorectal cancer (CRC) is associated with altered intestinal microbiota as well as short-chain fatty acids (SCFAs) reduction of output The energy source of colon cells relies mainly on three SCFAs, namely butyrate (BT), propionate, and acetate, while CRC transformed cells rely mainly on aerobic glycolysis to provide energy. This review summarizes recent research results for dysregulated glucose metabolism of SCFAs, which could be initiated by gut microbiome of CRC. Moreover, the relationship between SCFA transporters and glycolysis, which may correlate with the initiation and progression of CRC, are also discussed. Additionally, this review explores the linkage of BT to transport of SCFAs expressions between normal and cancerous colonocyte cell growth for tumorigenesis inhibition in CRC. Furthermore, the link between gut microbiota and SCFAs in the metabolism of CRC, in addition, the proteins and genes related to SCFAs-mediated signaling pathways, coupled with their correlation with the initiation and progression of CRC are also discussed. Therefore, targeting the SCFA transporters to regulate lactate generation and export of BT, as well as applying SCFAs or gut microbiota and natural compounds for chemoprevention may be clinically useful for CRCs treatment. Future research should focus on the combination these therapeutic agents with metabolic inhibitors to effectively target the tumor SCFAs and regulate the bacterial ecology for activation of potent anticancer effect, which may provide more effective application prospect for CRC therapy.
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Affiliation(s)
- Gang Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Yang Yu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Yu-Zhu Wang
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jun-Jie Wang
- Department of Pharmaceutics, Shanghai Eighth People's Hospital, Jiangsu University, Shanghai, China
| | - Rui Guan
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Yan Sun
- Information Resources Department, Hubei University of Medicine, Shiyan, Hubei, China
| | - Feng Shi
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jing Gao
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xing-Li Fu
- Department of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China
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Lee JS, Sul JY, Park JB, Lee MS, Cha EY, Ko YB. Honokiol induces apoptosis and suppresses migration and invasion of ovarian carcinoma cells via AMPK/mTOR signaling pathway. Int J Mol Med 2019; 43:1969-1978. [PMID: 30864681 PMCID: PMC6443331 DOI: 10.3892/ijmm.2019.4122] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 02/18/2019] [Indexed: 01/08/2023] Open
Abstract
Honokiol, a natural biphenolic compound, exerts anticancer effects through a variety of mechanisms on multiple types of cancer with relatively low toxicity. Adenosine 5'‑phosphate‑activated protein kinase (AMPK), an essential regulator of cellular homeostasis, may control cancer progression. The present study aimed to investigate whether the anticancer activities of honokiol in ovarian cancer cells were mediated through the activation of AMPK. Honokiol decreased cell viability of 2 ovarian cancer cell lines, with an half‑maximal inhibitory concentration value of 48.71±11.31 µM for SKOV3 cells and 46.42±5.37 µM for Caov‑3 cells. Honokiol induced apoptosis via activation of caspase‑3, caspase‑7 and caspase‑9, and cleavage of poly‑(adenosine 5'‑diphosphate‑ribose) polymerase. Apoptosis induced by honokiol was weakened by compound C, an AMPK inhibitor, suggesting that honokiol‑induced apoptosis was dependent on the AMPK/mechanistic target of rapamycin signaling pathway. Additionally, honokiol inhibited the migration and invasion of ovarian cancer cells. The combined treatment of honokiol with compound C reversed the activities of honokiol in wound healing and Matrigel invasion assays. These results indicated that honokiol may have therapeutic potential in ovarian cancer by targeting AMPK activation.
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Affiliation(s)
- Jin Sun Lee
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Ji Young Sul
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jun Beom Park
- Department of Surgery, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Myung Sun Lee
- Surgical Oncology Research Laboratory, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Eun Young Cha
- Surgical Oncology Research Laboratory, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
| | - Young Bok Ko
- Research Institute for Medicinal Sciences, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
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32
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The anticancer potential of metformin on prostate cancer. Prostate Cancer Prostatic Dis 2019; 22:351-361. [PMID: 30651580 DOI: 10.1038/s41391-018-0085-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 06/29/2018] [Accepted: 07/05/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Prostate cancer (PCa) is characterized as the most frequent type of cancer in males. Recent research has suggested patients who have diabetes mellitus taking metformin (MF) have a lower risk of PCa. MF has antineoplastic effects such as adenosine monophosphate-activated protein kinase (AMPK)-dependent and independent mechanisms, suppression of androgen signaling pathway, and alterations of insulin-like growth factor-1 (IGF-1) signaling pathways that cause the growth and proliferation of PCa. Based on epidemiological factors, patients with diabetes mellitus may have a protective effect on PCa. METHODS A literature search on MEDLINE® was conducted using a combined query of "prostate cancer" and "metformin" to yield publications unveiling the mechanisms of action, biological effects, epidemiological evidence, and research advances of MF with respect to PCa. RESULTS Evidence has shown that MF has multiple antineoplastic effects through AMPK-dependent and independent mechanisms, the alteration of IGF-1 signaling pathways, suppression of the androgen receptor pathway, inhibition of the mTOR pathway, and lipogenesis. Conduction of meta-analysis suggests mortality benefit to patients who exhibit PCa when taking MF. Clinical trials have shown evidence, demonstrating MF to improving significantly. CONCLUSIONS Herewith we review the literature regarding the numerous mechanisms of action of MF on PCa in order to decrease or repress the growth, proliferation, and differentiation of PCa cells. We analyze the molecular impacts of MF as well as adjunct therapies such as androgen deprivation therapy, aspirin, statin, or chemotherapy, proposing that MF may have a future role in the treatment protocol of PCa whether as a monotherapy or in combination with other drugs.
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Liu Y, Hu X, Shan X, Chen K, Tang H. Rosiglitazone metformin adduct inhibits hepatocellular carcinoma proliferation via activation of AMPK/p21 pathway. Cancer Cell Int 2019; 19:13. [PMID: 30651718 PMCID: PMC6330460 DOI: 10.1186/s12935-019-0732-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 01/08/2019] [Indexed: 12/25/2022] Open
Abstract
Background Rosiglitazone metformin adduct (RZM) is a novel compound, synthesized from rosiglitazone (Ros) and metformin (Met) combined at a molar mass ratio of 1:1. Met and Ros are widely used together for treating type 2 diabetes to improve drug effectiveness and reduce adverse drug reactions. Recent studies reported that both Met and Ros may possess antineoplastic properties in several cancers, including hepatocellular carcinoma (HCC). However, the effects of RZM in HCC and its underlying mechanisms remain unknown. Methods RZM was synthesized from Ros and Met at an equal molar ratio and identified by infrared spectroscopy. MTS and colony formation assays were performed to detect proliferative repression of RZM, the mixture, Met and Ros, respectively. Tumorigenesis assay in vivo was used to confirm the anti-tumorigenesis potential of RZM and Met. Moreover, cellular apoptosis caused by RZM was analyzed by hoechst staining assay and flow cytometry. RT-qPCR and western blotting were performed to reveal mechanisms for the function of RZM. Results Both in vitro and in vivo data showed that low doses of RZM enhanced inhibitory effect on HCC cells growth compared with Met. Flow cytometry analysis confirmed that treatment with RZM at 1 mM for 48 h triggered HCC cells apoptosis. RT-qPCR and western blotting analyses showed that p21 was upregulated in response to 1 mM RZM treatment. Furthermore, RZM could increase AMPK activation compared with Met. The increased p21 expression induced by RZM treatment was attenuated by an AMPK inhibitor compound C. Conclusions All these observations demonstrate that RZM increases the antiproliferative effect of Met in HCC via upregulating p21 expression in an AMPK-dependent manner. Our results suggest that RZM has the potential to be an adjuvant for HCC therapy.
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Affiliation(s)
- Yuyang Liu
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
| | - Xiangnan Hu
- 2Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing Medical University, Chongqing, China
| | - Xuefeng Shan
- 3Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ke Chen
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
| | - Hua Tang
- 1Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016 China
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Bojková B, Kubatka P, Qaradakhi T, Zulli A, Kajo K. Melatonin May Increase Anticancer Potential of Pleiotropic Drugs. Int J Mol Sci 2018; 19:E3910. [PMID: 30563247 PMCID: PMC6320927 DOI: 10.3390/ijms19123910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 12/03/2018] [Indexed: 12/14/2022] Open
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research.
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Affiliation(s)
- Bianka Bojková
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárová 2, 041 54 Košice, Slovak Republic.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4, 036 01 Martin, Slovak Republic.
- Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4C, 036 01 Martin, Slovak Republic.
| | - Tawar Qaradakhi
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC 3011, Australia.
| | - Anthony Zulli
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC 3011, Australia.
| | - Karol Kajo
- St. Elisabeth Oncology Institute, Heydukova 10, 811 08 Bratislava, Slovak Republic.
- Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05 Bratislava, Slovak Republic.
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35
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Kao LT, Xirasagar S, Lin HC, Huang CY. Association Between Pioglitazone Use and Prostate Cancer: A Population-Based Case-Control Study in the Han Population. J Clin Pharmacol 2018; 59:344-349. [DOI: 10.1002/jcph.1326] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 09/20/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Li-Ting Kao
- Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.,Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,Sleep Research Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Sudha Xirasagar
- Department of Health Services Policy and Management, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA
| | - Herng-Ching Lin
- Sleep Research Center, Taipei Medical University Hospital, Taipei, Taiwan.,School of Health Care Administration, Taipei Medical University, Taipei, Taiwan
| | - Chao-Yuan Huang
- Department of Urology, National Taiwan University Hospital, Yun-Lin Branch, Douliu, Taiwan.,Department of Urology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taiwan.,School of Public Health, Taipei Medical University, Taipei, Taiwan
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36
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The association of metformin use with prostate cancer aggressiveness among Black Americans and White Americans in a population-based study. Cancer Causes Control 2018; 29:1143-1150. [PMID: 30267174 DOI: 10.1007/s10552-018-1087-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 09/25/2018] [Indexed: 12/13/2022]
Abstract
PURPOSE Metformin has been associated with a reduced incidence of prostate cancer and improved prostate cancer outcomes. However, whether race modifies the association between metformin use and prostate cancer aggressiveness remains uncertain. The association between metformin use and prostate cancer aggressiveness was examined separately in Black Americans (Blacks) and White Americans (Whites). METHODS The study population consisted of 305 Black and 195 White research participants with incident prostate cancer and self-reported diabetes from the North Carolina-Louisiana Prostate Cancer Project. High-aggressive prostate cancer was defined using a composite measure of Gleason sum, prostate-specific antigen, and clinical stage. Multivariable logistic regression was used to assess the association between metformin use and high-aggressive prostate cancer at diagnosis, separately among Whites and Blacks, with adjustment for age, screening history, site, education, insurance, and body mass index. RESULTS Metformin use was associated positively with high-aggressive prostate cancer in Blacks (OR 2.01; 95% CI 1.05, 3.83). By contrast, a weak inverse association between metformin use and high-aggressive prostate cancer was found in Whites (OR 0.80, 95% CI 0.34, 1.85). CONCLUSIONS The association between metformin use and prostate cancer aggressiveness may be modified by race.
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Ni J, Zhou LL, Ding L, Zhang XQ, Zhao X, Li H, Cao H, Liu S, Wang Z, Ma R, Wu J, Feng J. Efatutazone and T0901317 exert synergistically therapeutic effects in acquired gefitinib-resistant lung adenocarcinoma cells. Cancer Med 2018; 7:1955-1966. [PMID: 29573196 PMCID: PMC5943475 DOI: 10.1002/cam4.1440] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2017] [Revised: 02/16/2018] [Accepted: 02/17/2018] [Indexed: 12/17/2022] Open
Abstract
The development of acquired EGFR‐TKI therapeutic resistance is still a serious clinical problem in the management of lung adenocarcinoma. Peroxisome proliferator activated receptor gamma (PPARγ) agonists may exhibit anti‐tumor activity by transactivating genes which are closely associated with cell proliferation, apoptosis, and differentiation. However, it remains not clear whether efatutazone has similar roles in lung adenocarcinoma cells of gefitinib resistant such as HCC827‐GR and PC9‐GR. It has been demonstrated by us that efatutazone prominently increased the mRNA and protein expression of PPARγ, liver X receptor alpha (LXRα),as well as ATP binding cassette subfamily A member 1 (ABCA1). In the presence of GW9662 (a specific antagonist of PPARγ) or GGPP (a specific antagonist of LXRα), efatutazone (40 μmol/L) restored the proliferation of both HCC827‐GR and PC9‐GR cells and obviously inhibited the increased protein and mRNA expression of PPAR‐gamma, LXR‐alpha, and ABCA1 induced by efatutazone. LXRα knockdown by siRNA (si‐LXRα) significantly promoted the HCC827‐GR and PC9‐GR cells proliferation, whereas incubation efatutazone with si‐LXRα restored the proliferation ability compared with the control group. In addition, combination of efatutazone and LXRα agonist T0901317 showed a synergistic therapeutic effect on lung adenocarcinoma cell proliferation and PPAR gamma, LXR A and ABCA1 protein expression. These results indicate that efatutazone could inhibit the cells proliferation of HCC827‐GR and PC9‐GR through PPARγ/LXRα/ABCA1 pathway, and synergistic therapeutic effect is achieved when combined with T0901317.
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Affiliation(s)
- Jie Ni
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Lei-Lei Zhou
- Department of Oncology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Li Ding
- The Jiangsu Province Research Institute for Clinical Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 210029, China
| | | | - Xia Zhao
- Department of Oncology, First People's Hospital of Yancheng, Fourth Affiliated Hospital of Nantong University, Yancheng, 224001, China
| | - Huizi Li
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Haixia Cao
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Siwen Liu
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Zhuo Wang
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Rong Ma
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Jianzhong Wu
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
| | - Jifeng Feng
- Nanjing Medical University Affiliated Cancer Hospital, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu, 210000, China
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Prognostic value of metformin for non-small cell lung cancer patients with diabetes. World J Surg Oncol 2018; 16:60. [PMID: 29558957 PMCID: PMC5859437 DOI: 10.1186/s12957-018-1362-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Accepted: 03/09/2018] [Indexed: 12/16/2022] Open
Abstract
Background The anti-cancer role of metformin has been reported in many different kinds of solid tumors, but how it affects non-small cell lung cancer (NSCLC) is currently elusive. The aim of this study was to investigate the influence of metformin treatment on diabetic NSCLC. Methods Two hundred fifty-five patients of diabetic NSCLC receiving therapy in our hospital from 2014 to 2016 were enrolled in our study. The information on clinical diagnosis, pathology, and prognosis as well as the influence of metformin in diabetic NSCLC were collected and assessed. Univariate and multivariate analytical techniques were applied to explore how metformin affect the survival of NSCLC. Results One hundred fifty of the 255 diabetic NSCLC patients took metformin. The median overall survival time (OST) and disease-free survival time (DFST) were significantly prolonged with metformin treatment compared to without metformin treatment (OST 25.0 vs 11.5 months, p = 0.005; DFST 15.6 vs 8.5 months, p = 0.010). Multivariate analysis indicated that metformin treatment could be used to predict the long-term outcome of diabetic NSCLC independently (HR = 0.588, 95% CI 0.466–0.895, p = 0.035). Conclusion Our study revealed that the metformin could help in improving the final outcome of NSCLC patients with diabetes in the long term and thus could be applied to treat NSCLC.
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Effects of metformin on prostatic tissue of rats with metabolic syndrome and benign prostatic hyperplasia. Int Urol Nephrol 2018; 50:611-617. [PMID: 29460133 DOI: 10.1007/s11255-018-1826-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 02/13/2018] [Indexed: 01/20/2023]
Abstract
OBJECTIVES To investigate the efficacy of insulin sensitizer on prostatic tissue in animal model with benign prostatic hyperplasia (BPH) secondary to metabolic syndrome (MetS). METHODS Models were established by providing Sprague-Dawley rats with high fat diet (HFD) combined with metformin or not. All objects were killed 40 days later with prostatic tissue being removed, weighed before stained, as well as the expression level of insulin-like growth factor I (IGF-1) and receptor (IGF-1R) being measured, and the level of insulin resistance (IR) has also been evaluated. RESULTS Model has been successfully established. Level of prostatic hyperplasia and IR as well as IGF-1 and IGF-1R expressions in the blank and saline control subunits of HFD group was higher than that of normal diet group (P < 0.05). In the subunit of metformin, along with the suppression of IR, the level of prostatic hyperplasia and the expression of IGF-1 pathway have both decreased (P < 0.05). CONCLUSION MetS can promote the growth of prostate during the formation of central obesity and IR. IGF-1 pathway may have an important role in the induction of BPH following IR. The application of metformin can suppress the expression of IGF-1 and IGF-1R, thus preventing the promotive effect of IR on prostate tissue in animal model of MetS.
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Zou S, Fang L, Lee MH. Dysbiosis of gut microbiota in promoting the development of colorectal cancer. Gastroenterol Rep (Oxf) 2018; 6:1-12. [PMID: 29479437 PMCID: PMC5806407 DOI: 10.1093/gastro/gox031] [Citation(s) in RCA: 183] [Impact Index Per Article: 26.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 07/21/2017] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal microbiome, containing at least 100 trillion bacteria, resides in the mucosal surface of human intestine. Recent studies show that perturbations in the microbiota may influence physiology and link to a number of diseases, including colon tumorigenesis. Colorectal cancer (CRC), the third most common cancer, is the disease resulting from multi-genes and multi-factors, but the mechanistic details between gut microenvironment and CRC remain poorly characterized. Thanks to new technologies such as metagenome sequencing, progress in large-scale analysis of the genetic and metabolic profile of gut microbial has been possible, which has facilitated studies about microbiota composition, taxonomic alterations and host interactions. Different bacterial species and their metabolites play critical roles in the development of CRC. Also, microbiota is important in the inflammatory response and immune processes deregulation during the development and progression of CRC. This review summarizes current studies regarding the association between gastrointestinal microbiota and the development of CRC, which provides insights into the therapeutic strategy of CRC.
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Affiliation(s)
- Shaomin Zou
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
| | - Lekun Fang
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
| | - Mong-Hong Lee
- Research Institute of Gastroenterology, Sun Yat-sen University, Guangzhou 510020, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510020, China
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Chuang MC, Yang YH, Tsai YH, Hsieh MJ, Lin YC, Lin CK, Chen PC, Yang TM. Survival benefit associated with metformin use in inoperable non-small cell lung cancer patients with diabetes: A population-based retrospective cohort study. PLoS One 2018; 13:e0191129. [PMID: 29329345 PMCID: PMC5766148 DOI: 10.1371/journal.pone.0191129] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 12/28/2017] [Indexed: 12/15/2022] Open
Abstract
Objective To evaluate the effects of metformin use on the survival of inoperable non-small cell lung cancer (NSCLC) patients with diabetes using the Taiwanese National Health Insurance Research Database. Research design and methods In total, 7,620 patients were eligible in this study, among them, 3,578 patients were metformin users and 4,042 were non-users. Propensity score matching was used to reduce possible confounding factors. In total, 4,182 patients (2,091 matched pairs) were included in the matched cohort. Cox proportional hazard model with time-dependent covariate were also applied to evaluate the association between metformin use and overall survival (OS). Results A total of 3,578 patients were metformin users at the time of diagnosis of NSCLC. Cox proportional hazard model with time-dependent covariate revealed that metformin use was associated with a significantly longer OS (HR: 0.85, 95.0% CI: 0.80–0.90). The survival benefit of metformin use was maintained after propensity score matching at a ratio of 1:1 (HR: 0.90, 95.0% CI: 0.84–0.97). Conclusions Metformin use is associated with longer OS in inoperable NSCLC patients with diabetes, suggesting a potential anti-tumorigenic effect for metformin. Further research is needed to investigate the actual role of metformin in the treatment of NSCLC patients with diabetes.
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Affiliation(s)
- Min-Chun Chuang
- Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan City, Taiwan
| | - Yao-Hsu Yang
- Department of Traditional Chinese Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
- Health Information and Epidemiology Laboratory of Chang Gung Memorial Hospital, Chiayi, Taiwan
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ying-Huang Tsai
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan
| | - Meng-Jer Hsieh
- Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Yu-Ching Lin
- Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Chin-Kuo Lin
- Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
| | - Pau-Chung Chen
- Institute of Occupational Medicine and Industrial Hygiene, National Taiwan University College of Public Health, Taipei, Taiwan
- Department of Environmental and Occupational Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Tsung-Ming Yang
- Department of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Chiayi, Taiwan
- * E-mail:
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Andrzejewski S, Siegel PM, St-Pierre J. Metabolic Profiles Associated With Metformin Efficacy in Cancer. Front Endocrinol (Lausanne) 2018; 9:372. [PMID: 30186229 PMCID: PMC6110930 DOI: 10.3389/fendo.2018.00372] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 06/21/2018] [Indexed: 12/18/2022] Open
Abstract
Metformin is one of the most commonly prescribed medications for the treatment of type 2 diabetes. Numerous reports have suggested potential anti-cancerous and cancer preventive properties of metformin, although these findings vary depending on the intrinsic properties of the tumor, as well as the systemic physiology of patients. These intriguing studies have led to a renewed interest in metformin use in the oncology setting, and fueled research to unveil its elusive mode of action. It is now appreciated that metformin inhibits complex I of the electron transport chain in mitochondria, causing bioenergetic stress in cancer cells, and rendering them dependent on glycolysis for ATP production. Understanding the mode of action of metformin and the consequences of its use on cancer cell bioenergetics permits the identification of cancer types most susceptible to metformin action. Such knowledge may also shed light on the varying results to metformin usage that have been observed in clinical trials. In this review, we discuss metabolic profiles of cancer cells that are associated with metformin sensitivity, and rationalize combinatorial treatment options. We use the concept of bioenergetic flexibility, which has recently emerged in the field of cancer cell metabolism, to further understand metabolic rearrangements that occur upon metformin treatment. Finally, we advance the notion that metabolic fitness of cancer cells increases during progression to metastatic disease and the emergence of therapeutic resistance. As a result, sophisticated combinatorial approaches that prevent metabolic compensatory mechanisms will be required to effectively manage metastatic disease.
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Affiliation(s)
- Sylvia Andrzejewski
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Peter M. Siegel
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Julie St-Pierre
- Department of Biochemistry, Microbiology and Immunology, and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- *Correspondence: Julie St-Pierre
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Zi F, Zi H, Li Y, He J, Shi Q, Cai Z. Metformin and cancer: An existing drug for cancer prevention and therapy. Oncol Lett 2018; 15:683-690. [PMID: 29422962 PMCID: PMC5772929 DOI: 10.3892/ol.2017.7412] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2016] [Accepted: 09/22/2017] [Indexed: 12/17/2022] Open
Abstract
Metformin is a standard clinical drug used to treat type 2 diabetes mellitus (T2DM) and polycystic ovary syndrome. Recently, epidemiological studies and meta-analyses have revealed that patients with T2DM have a lower incidence of tumor development than healthy controls and that patients diagnosed with cancer have a lower risk of mortality when treated with metformin, demonstrating an association between metformin and tumorigenesis. In vivo and in vitro studies have revealed that metformin has a direct antitumor effect, which may depress tumor proliferation and induce the apoptosis, autophagy and cell cycle arrest of tumor cells. The mechanism underpinning the antitumor effect of metformin has not been well established. Studies have demonstrated that reducing insulin and insulin-like growth factor levels in the peripheral blood circulation may lead to the inhibition of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin (mTOR) signaling or activation of AMP-activated protein kinase, which inhibits mTOR signaling, a process that may be associated with the antitumor effect of metformin. The present review primarily focuses on the recent progress in understanding the function of metformin in tumor development.
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Affiliation(s)
- Fuming Zi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Huapu Zi
- Department of Oncology, Rizhao Traditional Chinese Medicine Hospital of Shandong Traditional Chinese Medicine University, Rizhao, Shandong 276800, P.R. China
| | - Yi Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jingsong He
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Qingzhi Shi
- Department of Hematology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330008, P.R. China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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Xiao Y, Zheng L, Mei Z, Xu C, Liu C, Chu X, Hao B. The impact of metformin use on survival in prostate cancer: a systematic review and meta-analysis. Oncotarget 2017; 8:100449-100458. [PMID: 29245991 PMCID: PMC5725033 DOI: 10.18632/oncotarget.22117] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 10/13/2017] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Metformin has been implicated to reduce the risk of prostate cancer (PCa) beyond its glucose-lowering effect. However, the influence of metformin on prognosis of PCa is often controversial. RESULTS A total of 13 cohort studies encompassing 177,490 individuals were included in the meta-analysis. Data on overall survival (OS) and cancer-specific survival (CSS) was extracted from 8 and six studies, respectively. Comparing metformin users with non-metformin users, the pooled hazard ratios (HRs) for OS and CSS were 0.79 (95% confidence interval [CI] 0.63-0.98) and 0.76 (95% CI 0.57-1.02), respectively. Subgroup analyses stratified by baseline charcteristics indicated significant CSS benefits were noted in studies conducted in USA/Canada with prospective, large sample size, multiple-centered study design. Five studies reported the PCa prognosis for recurrence-free survival (RFS) and metformin use was significantly associated with patient RFS (HR 0.74, 95% CI, 0.58-0.95). METHODS Relevant studies were searched and identified using PubMed, Embase and Cochrane databases from inception through January 2017, which investigated associations between the use of metformin and PCa prognosis. Combined HRs with 95% CI were pooled using a random-effects model. The primary outcomes of interest were OS and CSS. CONCLUSIONS Our findings provide indication that metformin therapy has a trend to improve survival for patients with PCa. Further prospective, multi-centered, large sample size cohort studies are warranted to determine the true relationship.
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Affiliation(s)
- Yao Xiao
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Lei Zheng
- Department of Endocrinology, The First Affiliated Hospital of Chinese PLA General Hospital, Beijing, China
| | - Zubing Mei
- Department of Anorectal Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Changbao Xu
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Changwei Liu
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xiaohan Chu
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Bin Hao
- Department of Urology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
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Cao X, Wu Y, Wang J, Liu K, Wang X. The Effect of Metformin on Mortality Among Diabetic Cancer Patients: A Systematic Review and Meta-analysis. JNCI Cancer Spectr 2017; 1:pkx007. [PMID: 31360833 PMCID: PMC6649807 DOI: 10.1093/jncics/pkx007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Revised: 09/16/2017] [Accepted: 09/26/2017] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Most data suggest that cancer patients with diabetes have worse outcomes, which may be reversed with metformin. Metformin might modulate the clinical outcomes of diabetic cancer patients. We performed a systematic review and meta-analysis based on published studies over the past five years to summarize the effects of metformin on diabetic cancer patients. METHODS We systematically searched for studies that were published over the past five years. Then, we evaluated these studies for inclusion and extracted the relevant data. The summary risk estimates for the association between metformin treatment and all-cause mortality (ACM) and cancer-specific mortality (CSM) were analyzed using random or fixed-effects models. Stratified analyses by cancer site and country were also conducted. RESULTS Based on the 42 studies included in our analysis (37 015 diabetic cancer patients), we found a significant benefit associated with metformin treatment on survival corresponding to 27% and 26% reductions in ACM (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.68 to 0.79, P < .001) and CSM (HR = 0.74, 95% CI = 0.64 to 0.86, P < .001), respectively. The ACM rates for colorectal cancer, endometrial cancer, breast cancer, prostate cancer, and ovarian cancer showed significant benefits associated with metformin treatment in our stratified analyses by cancer site. Stratified analyses by cancer site also showed a significant reduction in CSM for breast cancer. This association between metformin treatment and reduced CSM for diabetic breast cancer patients was also observed in our country subgroup analyses. CONCLUSIONS We found an association between metformin exposure and reduced ACM and CSM in diabetic patients with cancer. Our findings suggest that metformin treatment could be an effective treatment option for diabetic cancer patients.
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Affiliation(s)
- Xun Cao
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Yaopan Wu
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Jing Wang
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Kuiyuan Liu
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
| | - Xin Wang
- Affiliations of authors: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, Guangdong, China (XC, YPW, JW, KYL, XW); Department of Thoracic Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China (KYL, XW)
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Abstract
Cancer is a major health issue worldwide, and the global burden of cancer is expected to increase in the coming years. Whereas the limited success with current therapies has driven huge investments into drug development, the average number of FDA approvals per year has declined since the 1990s. This unmet need for more effective anti-cancer drugs has sparked a growing interest for drug repurposing, i.e. using drugs already approved for other indications to treat cancer. As such, data both from pre-clinical experiments, clinical trials and observational studies have demonstrated anti-tumor efficacy for compounds within a wide range of drug classes other than cancer. Whereas some of them induce cancer cell death or suppress various aspects of cancer cell behavior in established tumors, others may prevent cancer development. Here, we provide an overview of promising candidates for drug repurposing in cancer, as well as studies describing the biological mechanisms underlying their anti-neoplastic effects.
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Affiliation(s)
- Linda Sleire
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway
| | - Hilde Elise Førde
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway
| | - Inger Anne Netland
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway
| | - Lina Leiss
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway
| | - Bente Sandvei Skeie
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway; Department of Neurosurgery, Haukeland University Hospital, Jonas Lies vei, 71, 5021 Bergen, Norway
| | - Per Øyvind Enger
- Oncomatrix Research Group, Department of Biomedicine, University of Bergen, Jonas Lies vei 91 5009 Bergen, Norway; Department of Neurosurgery, Haukeland University Hospital, Jonas Lies vei, 71, 5021 Bergen, Norway.
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Abstract
Purpose of Review Since epidemiological studies first demonstrated a potential positive effect of metformin in reducing cancer incidence and mortality, there has been an increased interest in not only better understanding metformin’s mechanisms of action but also in exploring its potential anti-cancer effects. In this review, we aim to summarise the current evidence exploring a role for metformin in prostate cancer therapy. Recent Findings Preclinical studies have demonstrated a number of antineoplastic biological effects via a range of molecular mechanisms. Data from retrospective epidemiological studies in prostate cancer has been mixed; however, there are several clinical trials currently underway evaluating metformin’s role as an anti-cancer agent. Early studies have shown benefits of metformin to inhibit cancer cell proliferation and improve metabolic syndrome in prostate cancer patients receiving androgen deprivation therapy (ADT). Summary While the body of evidence to support a role for metformin in prostate cancer therapy is rapidly growing, there is still insufficient data from randomised trials, which are currently still ongoing. However, evidence so far suggests metformin could be a useful adjuvant agent, particularly in patients on ADT.
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Affiliation(s)
- Jessica Whitburn
- Nuffield Department of Surgical Sciences, University of Oxford, Botnar Research Centre Old Road, Oxford, OX3 7LD, UK.
| | - Claire M Edwards
- Nuffield Department of Surgical Sciences, University of Oxford, Botnar Research Centre Old Road, Oxford, OX3 7LD, UK
| | - Prasanna Sooriakumaran
- Nuffield Department of Surgical Sciences, University of Oxford, Botnar Research Centre Old Road, Oxford, OX3 7LD, UK.,Department of Urology, University College London Hospitals NHS Foundation Trust, London, UK
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Gonnissen A, Isebaert S, McKee CM, Muschel RJ, Haustermans K. The Effect of Metformin and GANT61 Combinations on the Radiosensitivity of Prostate Cancer Cells. Int J Mol Sci 2017; 18:E399. [PMID: 28208838 PMCID: PMC5343511 DOI: 10.3390/ijms18020399] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/07/2017] [Indexed: 01/02/2023] Open
Abstract
The anti-diabetes drug metformin has been shown to have anti-neoplastic effects in several tumor models through its effects on energy metabolism and protein synthesis. Recent studies show that metformin also targets Hedgehog (Hh) signaling, a developmental pathway re-activated in several tumor types, including prostate cancer (PCa). Furthermore, we and others have shown that Hh signaling is an important target for radiosensitization. Here, we evaluated the combination of metformin and the Hh inhibitor GANT61 (GLI-ANTagonist 61) with or without ionizing radiation in three PCa cell lines (PC3, DU145, 22Rv1). The effect on proliferation, radiosensitivity, apoptosis, cell cycle distribution, reactive oxygen species production, DNA repair, gene and protein expression was investigated. Furthermore, this treatment combination was also assessed in vivo. Metformin was shown to interact with Hh signaling by inhibiting the effector protein glioma-associated oncogene homolog 1 (GLI1) in PCa cells both in vitro and in vivo. The combination of metformin and GANT61 significantly inhibited PCa cell growth in vitro and enhanced the radiation response of 22Rv1 cells compared to either single agent. Nevertheless, neither the growth inhibitory effect nor the radiosensitization effect of the combination treatment observed in vitro was seen in vivo. Although the interaction between metformin and Hh signaling seems to be promising from a therapeutic point of view in vitro, more research is needed when implementing this combination strategy in vivo.
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Affiliation(s)
- Annelies Gonnissen
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
- Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium.
| | - Sofie Isebaert
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
- Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium.
| | - Chad M McKee
- Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
| | - Ruth J Muschel
- Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
| | - Karin Haustermans
- Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven-University of Leuven, 3000 Leuven, Belgium.
- Department of Radiation Oncology, University Hospitals Leuven, 3000 Leuven, Belgium.
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Biernacka KM, Persad RA, Bahl A, Gillatt D, Holly JMP, Perks CM. Hyperglycaemia-induced resistance to Docetaxel is negated by metformin: a role for IGFBP-2. Endocr Relat Cancer 2017; 24:17-30. [PMID: 27754854 PMCID: PMC5118949 DOI: 10.1530/erc-16-0095] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 10/17/2016] [Indexed: 12/13/2022]
Abstract
The incidence of many common cancers varies between different populations and appears to be affected by a Western lifestyle. Highly proliferative malignant cells require sufficient levels of nutrients for their anabolic activity. Therefore, targeting genes and pathways involved in metabolic pathways could yield future therapeutics. A common pathway implicated in energetic and nutritional requirements of a cell is the LKB1/AMPK pathway. Metformin is a widely studied anti-diabetic drug, which improves glycaemia in patients with type 2 diabetes by targeting this pathway. We investigated the effect of metformin on prostate cancer cell lines and evaluated its mechanism of action using DU145, LNCaP, PC3 and VCaP prostate cancer cell lines. Trypan blue dye-exclusion assay was used to assess levels of cell death. Western immunoblotting was used to determine the abundance of proteins. Insulin-like growth factor-binding protein-2 (IGFBP-2) and AMPK genes were silenced using siRNA. Effects on cell morphology were visualised using microscopy. IGFBP-2 gene expression was assessed using real-time RT-PCR. With DU145 and LNCaP cells metformin alone induced cell death, but this was reduced in hyperglycaemic conditions. Hyperglycaemia also reduced the sensitivity to Docetaxel, but this was countered by co-treatment with metformin. LKB1 was required for the activation of AMPK but was not essential to mediate the induction of cell death. An alternative pathway by which metformin exerted its action was through downregulation of IGFBP-2 in DU145 and LNCaP cells, independently of AMPK. This finding could have important implications in relation to therapeutic strategies in prostate cancer patients presenting with diabetes.
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Affiliation(s)
- K M Biernacka
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - R A Persad
- Department of UrologySouthmead Hospital, Bristol, UK
| | - A Bahl
- Department of Clinical OncologyBristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, UK
| | - D Gillatt
- Department of UrologySouthmead Hospital, Bristol, UK
| | - J M P Holly
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
| | - C M Perks
- IGFs & Metabolic Endocrinology GroupSchool of Clinical Sciences, Learning & Research Building, Southmead Hospital, Bristol, UK
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