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Liu Y, Zhang Q, Huang X. Effect of metformin on incidence, recurrence, and mortality in prostate cancer patients: integrating evidence from real-world studies. Prostate Cancer Prostatic Dis 2025; 28:210-219. [PMID: 39014063 DOI: 10.1038/s41391-024-00871-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2024] [Revised: 06/14/2024] [Accepted: 07/08/2024] [Indexed: 07/18/2024]
Abstract
PURPOSE Metformin has been suggested to reduce the risk of cancer. However, previous studies have been inconsistent regarding the relationship between metformin use and the risk of occurrence of prostate cancer (PCa). The purpose of this study was to assess the effect of metformin on clinical outcomes in patients with PCa in a meta-analysis and to explore the possible dose-response relationship. METHODS A systematic literature search was conducted in 10 electronic databases and 4 registries. The combined relative risks (RRs) were calculated using a random-effects model with 95% confidence interval (CIs) to assess the effect of metformin on the risk of PCa. Relevant subgroup analyses and sensitivity analyses were performed. RESULTS The across studies results show that metformin use associated with lower incidence of PCa (RR: 0.82, 95% CI: 0.74-0.91). Metformin use was also found to reduce PCa recurrence, but the results were not statistically significant (RR: 0.97, 95% CI: 0.81-1.15). Metformin use was not associated with PCa mortality (RR: 0.94, 95% CI: 0.81-1.09). The results of subgroup analyses indicated that the type of study was a cohort study and the population came from both Asia and Europe showed that taking metformin reduced the incidence of PCa. A linear correlation was found between the duration of metformin use and its protective effect. CONCLUSIONS This meta-analysis revealed an independent correlation between metformin use and reduced incidence of PCa. Metformin use was not associated with either PCa recurrence rate or mortality. Furthermore, the effect of metformin on PCa incidence was found to be related to duration.
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Affiliation(s)
- Yuchen Liu
- Nanchang University Queen Mary School, Nanchang, Jiangxi, PR China
| | - Qingfang Zhang
- Nanchang University Queen Mary School, Nanchang, Jiangxi, PR China
| | - Xuan Huang
- Institute of Translational Medicine, Nanchang University, Nanchang, Jiangxi, PR China.
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Papachristodoulou A, Heidegger I, Virk RK, Di Bernardo M, Kim JY, Laplaca C, Picech F, Schäfer G, De Castro GJ, Hibshoosh H, Loda M, Klocker H, Rubin MA, Zheng T, Benson MC, McKiernan JM, Dutta A, Abate-Shen C. Metformin Overcomes the Consequences of NKX3.1 Loss to Suppress Prostate Cancer Progression. Eur Urol 2024; 85:361-372. [PMID: 37659962 PMCID: PMC10902192 DOI: 10.1016/j.eururo.2023.07.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 06/30/2023] [Accepted: 07/26/2023] [Indexed: 09/04/2023]
Abstract
BACKGROUND The antidiabetic drug metformin has known anticancer effects related to its antioxidant activity; however, its clinical benefit for prostate cancer (PCa) has thus far been inconclusive. Here, we investigate whether the efficacy of metformin in PCa is related to the expression status of NKX3.1, a prostate-specific homeobox gene that functions in mitochondria to protect the prostate from aberrant oxidative stress. OBJECTIVE To investigate the relationship of NKX3.1 expression and metformin efficacy in PCa. DESIGN, SETTING, AND PARTICIPANTS Functional studies were performed in vivo and in vitro in genetically engineered mouse models and human LNCaP cells, and organotypic cultures having normal or reduced/absent levels of NKX3.1. Correlative studies were performed using two independent retrospective tissue microarray cohorts of radical prostatectomies and a retrospective cohort of prostate biopsies from patients on active surveillance. INTERVENTION Metformin was administered before or after the induction of oxidative stress by treatment with paraquat. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Functional endpoints included analyses of histopathology, tumorigenicity, and mitochondrial function. Correlative endpoints include Kaplan-Meier curves and Cox proportional hazard regression models. RESULTS AND LIMITATIONS Metformin reversed the adverse consequences of NKX3.1 deficiency following oxidative stress in vivo and in vitro, as evident by reduced tumorigenicity and restored mitochondrial function. Patients with low NKX3.1 expression showed a significant clinical benefit from taking metformin. CONCLUSIONS Metformin can overcome the adverse consequences of NKX3.1 loss for PCa progression by protecting against oxidative stress and promoting normal mitochondrial function. These functional activities and clinical correlates were observed only with low NKX3.1 expression. Thus, the clinical benefit of metformin in PCa may depend on the status of NKX3.1 expression. PATIENT SUMMARY Prostate cancer patients with low NKX3.1 are likely to benefit most from metformin treatment to delay disease progression in a precision interception paradigm.
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Affiliation(s)
- Alexandros Papachristodoulou
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Isabel Heidegger
- Department of Urology, Medical University Innsbruck, Innsbruck, AT, Austria
| | - Renu K Virk
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Matteo Di Bernardo
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Jaime Y Kim
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Caroline Laplaca
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Florencia Picech
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Georg Schäfer
- Department of Pathology, Medical University Innsbruck, Innsbruck, AT, Austria
| | - Guarionex Joel De Castro
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Hanina Hibshoosh
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Massimo Loda
- Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY, USA
| | - Helmut Klocker
- Department of Urology, Medical University Innsbruck, Innsbruck, AT, Austria
| | - Mark A Rubin
- Department of Biomedical Research, University of Bern, Bern, Switzerland
| | - Tian Zheng
- Department of Statistics, Columbia University, New York, NY, USA
| | - Mitchell C Benson
- Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - James M McKiernan
- Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA
| | - Aditya Dutta
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
| | - Cory Abate-Shen
- Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Urology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Systems Biology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA; Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, USA.
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Khan S, Chang SH, Seyerle AA, Wang M, Hicks V, Drake BF. Post-diagnostic metformin and statin use and risk of biochemical recurrence in Veterans diagnosed with prostate cancer. Prostate 2023; 83:1150-1157. [PMID: 37191401 DOI: 10.1002/pros.24557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/03/2023] [Accepted: 05/01/2023] [Indexed: 05/17/2023]
Abstract
OBJECTIVE To evaluate the impact of post-diagnostic metformin or statin use and duration on risk of biochemical recurrence in a racially-diverse cohort of Veterans. METHODS The population consisted of men diagnosed with prostate cancer in the Veterans Health Administration and treated with either radical prostatectomy or radiation (Full cohort n = 65,759, Black men n = 18,817, White men n = 46,631, Other = 311). The association between post-diagnostic (1) metformin and (2) statin use with biochemical recurrence was assessed using multivariable, time-varying Cox Proportional Hazard Models for the overall cohort and by race. In a secondary analysis, metformin and statin duration were evaluated. RESULTS Post-diagnostic metformin use was not associated with biochemical recurrence (multivariable-adjusted hazard ratio [aHR]: 1.01; 95% confidence interval [CI]: 0.94, 1.09), with similar results observed for both Black and White men. However, duration of metformin use was associated with a reduced risk of biochemical recurrence in the cohort overall (HR: 0.94; 95% CI: 0.92, 0.95) as well as both Black and White men. By contrast, statin use was associated with a reduced risk of biochemical recurrence (HR: 0.83; 95% CI: 0.79, 0.88) in the overall cohort as well as both White and Black men. Duration of statin use was also inversely associated with biochemical recurrence in all groups. CONCLUSION Post-diagnostic metformin and statin use have the potential to prevent biochemical recurrence in men diagnosed with prostate cancer.
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Affiliation(s)
- Saira Khan
- Research Service, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri, USA
- Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
- Epidemiology Program, College of Heath Sciences, University of Delaware, Newark, Delaware, USA
| | - Su-Hsin Chang
- Research Service, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri, USA
- Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Amanda A Seyerle
- Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, Chapel Hill, North Carolina, USA
| | - Mei Wang
- Research Service, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri, USA
- Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Veronica Hicks
- Research Service, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri, USA
- Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Bettina F Drake
- Research Service, St. Louis Veterans Affairs Medical Center, St. Louis, Missouri, USA
- Department of Surgery, Division of Public Health Sciences, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA
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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: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [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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Liu Z, Zhu X, He J, Lu J. Metabolic syndrome and its components predict the biochemical recurrence and adverse pathological features of patients following radical prostatectomy: a propensity score matching study. BMC Cancer 2023; 23:50. [PMID: 36641426 PMCID: PMC9840841 DOI: 10.1186/s12885-023-10507-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 01/02/2023] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND To investigate the predictive value of metabolic syndrome (MetS) and its components in biochemical recurrence (BCR) and adverse pathological features of patients with prostate cancer (PCa) after radical prostatectomy (RP). METHODS A total of 525 PCa patients who underwent RP between 2010 and 2019 at Peking University Third Hospital were analyzed retrospectively. The Kaplan-Meier method was performed to assess BCR-free survival (BCRFS). Univariate and multivariate Cox regression models and multivariate logistic regression models were conducted to identify the predictive factors of BCRFS and adverse pathological features respectively before and after propensity score matching (PSM). RESULTS Enrolled patients were allocated into MetS group (n = 136) and non-MetS group (n = 389) according to the presence or absence of MetS, and 127 new matched pairs were identified to balance the baseline characteristics after 1:1 PSM. In propensity matched patients, the Kaplan-Meier analysis revealed that MetS (P = 0.020), hyperglycemia (P = 0.015) and hypertriglyceridemia (P = 0.001) were significantly associated with worse BCRFS; the results of multivariate Cox analyses showed that hyperglycemia (P = 0.040), hypertriglyceridemia (P = 0.017), percentage of positive biopsy cores (P = 0.041) and prostate specific antigen (P = 0.019) were identified as independent prognostic factors for BCRFS. In addition, hypertriglyceridemia was independently associated with non-organ confined disease (NOCD) (P = 0.010), extra-capsular extension (ECE) (P = 0.010) and upgrading (P = 0.017) in the multivariate logistic analyses. CONCLUSIONS Hyperglycemia and hypertriglyceridemia are the two effective MetS components both identified as independent risk factors for worse BCRFS after RP, while hypertriglyceridemia was independently associated with NOCD, ECE and upgrading as well.
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Affiliation(s)
- Zenan Liu
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Xuehua Zhu
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Jide He
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Jian Lu
- Department of Urology, Peking University Third Hospital, Beijing, China.
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Ben Hadj Alouane H, Raboudi M, Maatougui J, Dridi M, Ghozzi S. Are Diabetic Patients at Increased Risk for Biochemical Recurrence After Radical Prostatectomy? Cureus 2022; 14:e24717. [PMID: 35663714 PMCID: PMC9164171 DOI: 10.7759/cureus.24717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2022] [Indexed: 11/05/2022] Open
Abstract
Introduction Diabetic patients are at a lower risk for prostate cancer. However, the relationship between diabetes mellitus (DM) and biochemical recurrence (BCR) after radical prostatectomy (RP) is less clear. The goal of our study was to determine diabetes's value as a biochemical recurrence predictor. Materials and methods We conducted a retrospective analysis of 117 patients who had undergone open radical prostatectomy between 1999 and 2021 at our institution. Univariate and multivariate statistical analyses were used to identify factors associated with biochemical recurrence. Results On univariate analysis, factors associated with biochemical recurrence were diabetes (p=0.002), preoperative prostate-specific antigen (PSA) levels (p=0.022), positive digital rectal exam (p=0.035), number of positive biopsy cores (p<0.001), unfavorable intermediate risk group (p=0.014), peri-neural invasion (PNI) on RP specimen (p=0.043), tumor volume (p=0.011), and positive surgical margins (p<0.001). Multivariate analysis showed that factors independently associated with biochemical recurrence were diabetes (p=0.039; OR=2.788), number of positive cores (p=0.016; OR=4.124), and positive surgical margins (p=0.008; OR=3.876). Conclusion A history of diabetes mellitus should be taken into consideration when assessing patients' risk of biochemical recurrence after radical prostatectomy. More research on a larger scale is needed to determine diabetes' value as a biochemical predictor.
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Affiliation(s)
| | - Mehdi Raboudi
- Department of Urology, Military Hospital of Tunis, Tunisia, TUN
| | | | - Mohamed Dridi
- Department of Urology, Military Hospital of Tunis, Tunisia, TUN
| | - Samir Ghozzi
- Department of Urology, Military Hospital of Tunis, Tunisia, TUN
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Papachristodoulou A, Abate-Shen C. Precision intervention for prostate cancer: Re-evaluating who is at risk. Cancer Lett 2022; 538:215709. [DOI: 10.1016/j.canlet.2022.215709] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/30/2022] [Accepted: 04/25/2022] [Indexed: 02/08/2023]
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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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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: 7] [Impact Index Per Article: 1.4] [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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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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Aminsharifi A, Howard LE, Amling CL, Aronson WJ, Cooperberg MR, Kane CJ, Terris MK, Polascik TJ, Freedland SJ. Statins are Associated With Increased Biochemical Recurrence After Radical Prostatectomy in Diabetic Men but no Association was Seen in Men also Taking Metformin: Results From the SEARCH Database. Clin Genitourin Cancer 2019; 17:e140-e149. [DOI: 10.1016/j.clgc.2018.09.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 12/19/2022]
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Yan M, Qi H, Xia T, Zhao X, Wang W, Wang Z, Lu C, Ning Z, Chen H, Li T, Tekcham DS, Liu X, Liu J, Chen D, Liu X, Xu G, Piao HL. Metabolomics profiling of metformin-mediated metabolic reprogramming bypassing AMPKα. Metabolism 2019; 91:18-29. [PMID: 30468782 DOI: 10.1016/j.metabol.2018.11.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 11/12/2018] [Accepted: 11/15/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Metformin is a first-line drug for treating type 2 diabetes and has gained considerable interest as a potential anticancer agent. Increasing evidence suggests that metformin antagonizes diabetes and tumors through disrupting metabolic homeostasis and altering energy state. However, whether AMP activated protein kinase (AMPK) contributes to such effects of metformin remains controversial. METHODS We performed integrative metabolomics analyses to systematically examine the effects of metformin on metabolic pathways in Prkaa1 wild type (WT) and knock-out (KO) mouse embryonic fibroblast (MEF) cells as well as human cells based on gas chromatography-mass spectrometry and capillary electrophoresis-mass spectrometry (CE-MS). RESULTS Metformin treatment induced metabolic reprogramming and reduced the energy state of both Prkaa1 WT and KO MEF cells, as evidenced by suppressed tricarboxylic acid (TCA) cycle, elevated lactate production as well as decreased NAD+/NADH ratio. Additionally, metabolic flux analysis also showed that metformin Ampkα-independently increased metabolic flux from glucose to lactate and decreased metabolic flux from acetyl-CoA to TCA cycle as well as from pyruvate to malate. Moreover, metformin Ampkα-dependently upregulated P-Acc but Ampkα-independently inhibited the levels of P-mTor, P-S6, Lc3, Atgl and P-Erk in MEF cells. Similarly, we demonstrated that a commonly used AMPK agonist 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR) and fetal bovine serum (FBS) starvation, as a common model for energy stress, both led to Ampkα-independent metabolism alterations in MEF cells. Furthermore, these effects of metformin were also confirmed in human hepatocellular carcinoma (HCC) cells as well as in MCF10A shControl and shPRKAA1 cells. Importantly, we found that metformin could obviously inhibit colony conformation of HCC cells in an Ampkα-independent manner. CONCLUSIONS Our data highlight a comprehensive view of metabolic reprogramming mediated by metformin as well as AICAR. These observations suggest that metformin could affect cellular metabolism largely bypassing Ampkα, and may provide a new insight for its clinical usage.
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Affiliation(s)
- Min Yan
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Huan Qi
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Tian Xia
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Xinjie Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Wen Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhichao Wang
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Chang Lu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, China
| | - Zhen Ning
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, China
| | - Huan Chen
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tongming Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Dinesh Singh Tekcham
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Xiumei Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Jing Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Di Chen
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Xiaolong Liu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
| | - Hai-Long Piao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Scientific Research Center for Translational Medicine, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Lin C, Salzillo TC, Bader DA, Wilkenfeld SR, Awad D, Pulliam TL, Dutta P, Pudakalakatti S, Titus M, McGuire SE, Bhattacharya PK, Frigo DE. Prostate Cancer Energetics and Biosynthesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1210:185-237. [PMID: 31900911 PMCID: PMC8096614 DOI: 10.1007/978-3-030-32656-2_10] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Cancers must alter their metabolism to satisfy the increased demand for energy and to produce building blocks that are required to create a rapidly growing tumor. Further, for cancer cells to thrive, they must also adapt to an often changing tumor microenvironment, which can present new metabolic challenges (ex. hypoxia) that are unfavorable for most other cells. As such, altered metabolism is now considered an emerging hallmark of cancer. Like many other malignancies, the metabolism of prostate cancer is considerably different compared to matched benign tissue. However, prostate cancers exhibit distinct metabolic characteristics that set them apart from many other tumor types. In this chapter, we will describe the known alterations in prostate cancer metabolism that occur during initial tumorigenesis and throughout disease progression. In addition, we will highlight upstream regulators that control these metabolic changes. Finally, we will discuss how this new knowledge is being leveraged to improve patient care through the development of novel biomarkers and metabolically targeted therapies.
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Affiliation(s)
- Chenchu Lin
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Travis C Salzillo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - David A Bader
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
| | - Sandi R Wilkenfeld
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Dominik Awad
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Thomas L Pulliam
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA
| | - Prasanta Dutta
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shivanand Pudakalakatti
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Mark Titus
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sean E McGuire
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Pratip K Bhattacharya
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Daniel E Frigo
- Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, USA.
- Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Molecular Medicine Program, The Houston Methodist Research Institute, Houston, TX, USA.
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Pircher A, Zieher M, Eigentler A, Pichler R, Schäfer G, Fritz J, Puhr M, Steiner E, Horninger W, Klocker H, Heidegger I. Antidiabetic drugs influence molecular mechanisms in prostate cancer. Cancer Biol Ther 2018; 19:1153-1161. [PMID: 30067448 PMCID: PMC6301819 DOI: 10.1080/15384047.2018.1491490] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Background: We investigated the role of diabetes mellitus (DM) and the molecular mechanisms of antidiabetic drugs in prostate cancer (PCa). Patients and Methods: 167 patients with both DM and PCa underwent radical prostatectomy (RPE). We divided our patient collective into “metformin” users, “insulin” users, “other antidiabetic drug” users and those with “no antidiabetic drug/diet only” (control group) and analyzed differences in PCa aggressiveness and laboratory parameters among treatment groups. In addition, we generated a tissue-micro-array (TMA) from RPE specimens for the analysis of candidate target pathways of antidiabetic drugs by immunohistochemistry (IHC). Results: Gleason score of both biopsy and RPE, biopsy undergrading, tumor stage as well as positive resection margins did not significantly change among groups. Preoperative body mass-index, PSA, fPSA and prostate volume/weight did not change among the treatment groups. As well, CRP, GOT, GPT, yGT, LDH, amylase, hemoglobin, TSH, FT3 and FT4 did not differ. Metformin or insulin use was not associated with changes in biochemical tumor recurrence or PCa specific mortality rates. However, tissue TMA analyses by IHC showed decreased mTOR activation, as indicated by phospho-mTOR in cancer tissue of patients with metformin and also with insulin use compared to the control group. In addition, we were able to show that the androgen receptor and the epithelial-cell contact marker E-cadherin decreased upon metformin use compared to the control group. Conclusion: We did not find a connection between antidiabetic drugs and PCa aggressiveness or progression. However, tumor biology seems to be different among patients with and without antidiabetic drugs.
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Affiliation(s)
- Andreas Pircher
- a Department of Internal Medicine V, Hematology and Oncology , Medical University Innsbruck , Austria
| | - Martin Zieher
- b Department of Urology , Medical University Innsbruck , Austria
| | - Andrea Eigentler
- b Department of Urology , Medical University Innsbruck , Austria
| | - Renate Pichler
- b Department of Urology , Medical University Innsbruck , Austria
| | - Georg Schäfer
- c Department of Pathology , Medical University Innsbruck , Austria
| | - Josef Fritz
- d Department of Medical Statistics, Informatics and Health Economics , Medical University , Innsbruck , Austria
| | - Martin Puhr
- b Department of Urology , Medical University Innsbruck , Austria
| | - Eberhard Steiner
- b Department of Urology , Medical University Innsbruck , Austria
| | | | - Helmut Klocker
- b Department of Urology , Medical University Innsbruck , Austria
| | - Isabel Heidegger
- b Department of Urology , Medical University Innsbruck , Austria
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15
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Dell'Atti L, Galosi AB. The impact of metformin use on the risk of prostate cancer after prostate biopsy in patients with high grade intraepithelial neoplasia. Int Braz J Urol 2018; 44:69-74. [PMID: 29211393 PMCID: PMC5815534 DOI: 10.1590/s1677-5538.ibju.2017.0046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 07/08/2017] [Indexed: 01/24/2023] Open
Abstract
Purpose We report our experience on metformin use in diabetic patients and its impact on prostate cancer (PCa) after a high-grade prostatic intraepithelial neoplasia (HGPIN) diagnosis. Materials and Methods We retrospectively analyzed 551 patients with a diagnosis of HGPIN without PCa in a first prostate biopsy. The cohort of the study consisted of 456 nondiabetic subjects, and 95 diabetic patients. Among the patients with diabetes 44 were treated with metformin, and 51 with other antidiabetic drugs. A transrectal ultrasound prostate biopsy scheme with 22 cores was carried out 4-6 months after the first diagnosis of HGPIN. Results Among 195 (35.4%) patients with cancer, there were statistically significant differences in terms of PCa detection (p<0.001), Gleason score distribution (p<0.001), and number of positive biopsy cores (p<0.002) between metformin users and non-users. Metformin use was associated with a decreased risk of PCa compared with neveruse (p<0.001). Moreover, increasing duration of metformin assumption (≥2 years) was associated with decreasing incidence of PCa and higher Gleason score ≥7 compared with assumption <2 years. Conclusions This preliminary experience suggests that metformin use may have some beneficial effects in patients with diabetes and HGPIN; metformin should not be overlooked in these patients because it is neither new nor expensive.
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Affiliation(s)
- Lucio Dell'Atti
- Department of Urology, University Hospital "St. Anna", Ferrara, Italy
| | - Andrea B Galosi
- Department of Urology, Marche Polytechnic University, Ancona, Italy
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16
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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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17
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Khan S, Cai J, Nielsen ME, Troester MA, Mohler JL, Fontham ETH, Hendrix LH, Farnan L, Olshan AF, Bensen JT. The Association of Diabetes and Obesity With Prostate Cancer Progression: HCaP-NC. Prostate 2017; 77:878-887. [PMID: 28261834 PMCID: PMC5695861 DOI: 10.1002/pros.23342] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 02/13/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND The role of race in modifying the association among diabetes, obesity, and prostate cancer (CaP) progression is not well studied. We evaluated diabetes and obesity in association with time to CaP progression in White Americans (Whites) and Black Americans (Blacks). METHODS Our study sample consisted of 363 White and 284 Black research participants from the Health Care Access and CaP Treatment in North Carolina (HCaP-NC) cohort. The association between self-reported diabetes or obesity and CaP progression (mean follow-up time approximately 5 years) was assessed using Cox proportional hazards modeling, with adjustment for potential confounders. Stratum-specific hazard ratio (HR) estimates for Whites and Blacks were evaluated. RESULTS Self-reported diabetes was not associated with CaP progression in the cohort as a whole (HR: 0.86, 95%CI: 0.54, 1.35), or among racially defined groups (Whites, HR: 1.03, 95%CI: 0.50, 2.13 or Blacks, HR: 0.77, 95%CI: 0.43, 1.39). Obesity was positively associated with CaP progression among Whites, in models including (HR: 1.79, 95%CI: 1.08, 2.97), and excluding (HR: 1.80, 95%CI: 1.09, 2.96) diabetes as a covariate. No association was observed between obesity and CaP progression in Blacks or the cohort as whole. CONCLUSIONS Self-reported diabetes was not associated with CaP progression In HCaP-NC. Obesity was associated with CaP progression only among White research participants. Prostate 77:878-887, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Saira Khan
- Division of Public Health Sciences, Department of Surgery, Washington University in St. Louis School of Medicine, St. Louis, Missouri
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Jianwen Cai
- Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Matthew E. Nielsen
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Department of Urology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Melissa A. Troester
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - James L. Mohler
- Department of Urology, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Department of Urology, Roswell Park Cancer Institute, Buffalo, New York
- Department of Urology, University of Buffalo School of Medicine and Biotechnology, Buffalo, New York
| | - Elizabeth T. H. Fontham
- School of Public Health, Louisiana State University Health Science Center, New Orleans, Louisiana
| | - Laura H. Hendrix
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Laura Farnan
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Andrew F. Olshan
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
| | - Jeannette T. Bensen
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, North Carolina
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18
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Khan AS, Frigo DE. A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer. Nat Rev Urol 2017; 14:164-180. [PMID: 28169991 PMCID: PMC5672799 DOI: 10.1038/nrurol.2016.272] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The 5'-AMP-activated protein kinase (AMPK) is a master regulator of cellular homeostasis. Despite AMPK's known function in physiology, its role in pathological processes such as prostate cancer is enigmatic. However, emerging evidence is now beginning to decode the paradoxical role of AMPK in cancer and, therefore, inform clinicians if - and how - AMPK could be therapeutically targeted. Spatiotemporal regulation of AMPK complexes could be one of the mechanisms that governs this kinase's role in cancer. We hypothesize that different upstream stimuli will activate select subcellular AMPK complexes. This hypothesis is supported by the distinct subcellular locations of the various AMPK subunits. Each of these unique AMPK complexes regulates discrete downstream processes that can be tumour suppressive or oncogenic. AMPK's final biological output is then determined by the weighted net function of these downstream signalling events, influenced by additional prostate-specific signalling.
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Affiliation(s)
- Ayesha S. Khan
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX USA
| | - Daniel E. Frigo
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX USA
- Genomic Medicine Program, The Houston Methodist Research Institute, Houston, TX USA
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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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20
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Hua Q, Zhu Y, Liu H, Ye X. Diabetes and the risk of biochemical recurrence in patients with treated localized prostate cancer: a meta-analysis. Int Urol Nephrol 2016; 48:1437-43. [DOI: 10.1007/s11255-016-1316-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 05/05/2016] [Indexed: 10/21/2022]
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21
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Heidari F, Abbas Zade S, Mir Hosseini SH, Ghadian A. Metformin for the Prevention of Bladder Cancer Recurrence: Is it Effective? Nephrourol Mon 2016; 8:e30261. [PMID: 27570750 PMCID: PMC4983155 DOI: 10.5812/numonthly.30261] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 12/27/2015] [Accepted: 02/24/2016] [Indexed: 12/30/2022] Open
Abstract
Background Many methods have been used for preventing and reducing recurrences of bladder cancers. In recent years, some investigators have examined the use of metformin for this purpose. First lines of evidence have shown that metformin inhibits cancer cell growth and prevents cancer occurrence in patients with type 2 diabetes. Objectives This study is designed to assess metformin usage in the prevention of bladder cancer recurrence after the trans-urethral resection of a bladder tumor (TUR-T). Patients and Methods In the present study, metformin was administered in the treatment of 32 patients with a history of bladder cancer, and their results were compared with those of 33 patients with bladder cancer recurrence (placebo group). Patients in the metformin group received 1000 mg metformin (2 tablets 500 mg) for 1 year. Frequency of tumor recurrence was calculated and compared with the placebo group. Results There was no statistical difference between the 2 groups with respect to the recurrence rate (P > 0.05). Although the recurrence interval was longer for the metformin group, this increase was not statistical significant (P > 0.05). Furthermore, tumor recurrence had no correlation with sex or the grade of the tumors. Conclusions According to our findings, it seems that metformin has no considerable inhibitory effect on the recurrence rate of bladder cancer, but that it can delay tumor recurrence.
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Affiliation(s)
- Fatemeh Heidari
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Shahin Abbas Zade
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Seyed Hassan Mir Hosseini
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
| | - Alireza Ghadian
- Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
- Corresponding author: Alireza Ghadian, Nephrology and Urology Research Center, Baqiyatallah University of Medical Sciences, Tehran, IR Iran. Tel: +98-2181262073, E-mail:
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Chong RW, Vasudevan V, Zuber J, Solomon SS. Metformin Has a Positive Therapeutic Effect on Prostate Cancer in Patients With Type 2 Diabetes Mellitus. Am J Med Sci 2016; 351:416-9. [PMID: 27079349 DOI: 10.1016/j.amjms.2016.01.013] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 11/17/2015] [Indexed: 10/22/2022]
Abstract
OBJECTIVE Prostate cancer and type 2 diabetes mellitus (DM2) are both common diseases found in the elderly male population. The diabetic drug, metformin, has been shown to have antineoplastic properties and demonstrated better treatment outcomes when used as adjuvant therapy in patients with breast cancer. The hormonally-sensitive cancer analogous to breast cancer in men is prostate cancer. We investigated improved survival, lower risks of recurrences, and lower, more stable levels of prostate-specific antigen (PSA) in patients with DM2 along with prostate cancer on metformin. METHODS Patients with prostate cancer along with DM2 who remained on metformin were compared with controls who were not on metformin matched by age, weight, race and Gleason score cancer staging. The endpoints of our study included final PSA values, number of recurrences, metastases and number living for each group. RESULTS There were significantly fewer deaths (23% versus 10%), fewer recurrences (15% versus 8%), fewer metastases (5% versus 0%) and fewer secondary cancers (17% versus 6%) in the metformin group (P < 0.004). The final PSA value was lower in the metformin-treated group with a result approaching significance (P = 0.067). The primary treatments for prostate cancer (ie, surgery, radiation and androgen depletion) were found to be comparable in both the groups. CONCLUSIONS Our retrospective study shows that adjuvant metformin therapy leads to a better prognosis in prostate cancer. Not only are PSA levels controlled for several years but also there are significantly fewer cancer recurrences in metformin-treated patients. Overall, these results are promising and should be followed up with a prospective study to assess long-term survival.
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Affiliation(s)
- R William Chong
- Division of Endocrinology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Vijaya Vasudevan
- Division of Endocrinology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Medicine (Endocrinology) and Research Service, Veterans Affairs Medical Center, Memphis, Tennessee
| | - Jeffrey Zuber
- Department of Preventive Medicine, College of Medicine, Veterans Affairs Medical Center, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Solomon S Solomon
- Division of Endocrinology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Pharmacology, College of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee; Department of Medicine (Endocrinology) and Research Service, Veterans Affairs Medical Center, Memphis, Tennessee.
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Hwang IC, Park SM, Shin D, Ahn HY, Rieken M, Shariat SF. Metformin association with lower prostate cancer recurrence in type 2 diabetes: a systematic review and meta-analysis. Asian Pac J Cancer Prev 2015; 16:595-600. [PMID: 25684493 DOI: 10.7314/apjcp.2015.16.2.595] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Accumulating evidence suggests that metformin possesses anticarcinogenic properties, and its use is associated with favorable outcomes in several cancers. However, it remains unclear whether metformin influences prognosis in prostate cancer (PCa) with concurrent type 2 diabetes (T2D). MATERIALS AND METHODS We searched PubMed, EMBASE, and the Cochrane Library from database inception to April 16, 2014 without language restrictions to identify studies investigating the effect of metformin treatment on outcomes of PCa with concurrent T2D. We conducted a meta-analysis to quantify the risk of recurrence, progression, cancer-specific mortality, and all-cause mortality. Summary relative risks (RRs) with corresponding 95% confidence intervals (CIs) were calculated. Publication bias was assessed by Begg's rank correlation test. RESULTS A total of eight studies fulfilled the eligibility criteria. We found that diabetic PCa patients who did not use metformin were at increased risk of cancer recurrence (RR, 1.20; 95%CI, 1.00-1.44), compared with those who used metformin. A similar trend was observed for other outcomes, but their relationships did not reach statistical significance. Funnel plot asymmetry was not observed among studies reporting recurrence (p=0.086). CONCLUSIONS Our results suggest that metformin may improve outcomes in PCa patients with concurrent T2D. Well-designed large studies and collaborative basic research are warranted.
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Affiliation(s)
- In Cheol Hwang
- Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Korea E-mail :
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Allott EH, Hursting SD. Obesity and cancer: mechanistic insights from transdisciplinary studies. Endocr Relat Cancer 2015; 22:R365-86. [PMID: 26373570 PMCID: PMC4631382 DOI: 10.1530/erc-15-0400] [Citation(s) in RCA: 114] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/15/2015] [Indexed: 12/11/2022]
Abstract
Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link.
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Affiliation(s)
- Emma H Allott
- Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA
| | - Stephen D Hursting
- Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA Department of EpidemiologyCB 7435, University of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USALineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USADepartment of NutritionUniversity of North Carolina at Chapel Hill, 135 Dauer Drive, Chapel Hill, North Carolina 27599, USA
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Metformin and prostate cancer mortality: a meta-analysis. Cancer Causes Control 2015; 27:105-13. [DOI: 10.1007/s10552-015-0687-0] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Accepted: 10/20/2015] [Indexed: 12/21/2022]
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Winters B, Plymate S, Zeliadt SB, Holt S, Zhang X, Hu E, Lin DW, Morrissey C, Wooldridge B, Gore JL, Porter MP, Wright JL. Metformin effects on biochemical recurrence and metabolic signaling in the prostate. Prostate 2015. [PMID: 26201966 PMCID: PMC4578998 DOI: 10.1002/pros.23049] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB). METHODS Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK. RESULTS One thousand seven hundred and thirty four men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). "Ever" metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR = 0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (P-values all <0.006). When stratified by metformin use, IGF-1R remained significantly elevated (P = 0.01) in men with PCa detected whereas p-AMPK (P = 0.05) was elevated only in those without PCa. CONCLUSION Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p-AMPK elevation in negative PNBs suggests altered metabolic pathway activation precipitated by metformin use.
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Affiliation(s)
- Brian Winters
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Stephen Plymate
- Department of Medicine, University of Washington School of Medicine, Seattle, WA
- Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, WA
| | - Steven B Zeliadt
- Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, WA
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Sarah Holt
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Xiaotun Zhang
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Elaine Hu
- Health Services Research & Development and GRECC, VA Puget Sound Health Care System, Seattle, WA
| | - Daniel W. Lin
- Department of Urology, University of Washington School of Medicine, Seattle, WA
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Colm Morrissey
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Bryan Wooldridge
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - John L Gore
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Michael P Porter
- Department of Urology, University of Washington School of Medicine, Seattle, WA
| | - Jonathan L Wright
- Department of Urology, University of Washington School of Medicine, Seattle, WA
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA
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Jia Y, Ma Z, Liu X, Zhou W, He S, Xu X, Ren G, Xu G, Tian K. Metformin prevents DMH-induced colorectal cancer in diabetic rats by reversing the warburg effect. Cancer Med 2015; 4:1730-41. [PMID: 26376762 PMCID: PMC4674000 DOI: 10.1002/cam4.521] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 08/06/2015] [Accepted: 08/09/2015] [Indexed: 12/17/2022] Open
Abstract
Epidemiologic studies have shown that the treatment of diabetics with metformin reduced the risk of cancer-related mortality. Here, we investigated the chemopreventive effects of metformin on dimethylhydrazine (DMH)-induced colorectal carcinogenesis in diabetic SD rats following metformin treatment and the effect on Warburg effect involved in this process. Diabetic rat models were induced with high-fat feeding in combination with a low dose of Streptozotocin (STZ) and then induce colorectal cancer with a low dose of DMH. The formation of colorectal Aberrant crypt foci (ACF) and the incidence, number and size of the tumor were measured. The proliferation indices of colonic tissues were determined through Proliferating cell nuclear antigen (PCNA) immunostaining. Then detect the expression of PK and IDH in colonic tissues using immunohistochemistry and Western blot. The enzyme activities of HK and PDH in colonic tissues were measured. The growth and expression of PK and IDH and activity of HK and PDH in cell lines LoVo and HT-29 were measured after metformin treatment. The results showed that metformin treatment significantly inhibited the formation of ACF and tumors. The proliferation index of colonic tissues was significantly decreased following metformin treatment. In addition, metformin inhibited cell growth and decreased the imbalance in the expression of the enzymes involved in glycolysis and the TCA cycle. These findings suggested that metformin might produce a synergistic colon cancer-preventative effect in diabetic patients through the regulation of the enzymes expression involved in glucose metabolism.
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Affiliation(s)
- Yanglei Jia
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Zengyi Ma
- Department of Gastroenterology, 456 Hospital of PLAJinan, Shandong, China
| | - Xiaofei Liu
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Wenjing Zhou
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Shan He
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Xia Xu
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Guijie Ren
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
| | - Gang Xu
- Department of Gastroenterology, 456 Hospital of PLAJinan, Shandong, China
| | - Keli Tian
- Department of Biochemistry and Molecular Biology, Shandong University School of MedicineJinan, Shandong, China
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Van De Voorde L, Janssen L, Larue R, Houben R, Buijsen J, Sosef M, Vanneste B, Schraepen MC, Berbée M, Lambin P. Can metformin improve ‘the tomorrow’ of patients treated for oesophageal cancer? Eur J Surg Oncol 2015; 41:1333-9. [DOI: 10.1016/j.ejso.2015.05.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Revised: 04/24/2015] [Accepted: 05/15/2015] [Indexed: 02/07/2023] Open
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Deng D, Yang Y, Tang X, Skrip L, Qiu J, Wang Y, Zhang F. Association between metformin therapy and incidence, recurrence and mortality of prostate cancer: evidence from a meta-analysis. Diabetes Metab Res Rev 2015; 31:595-602. [PMID: 25708557 DOI: 10.1002/dmrr.2645] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Revised: 11/26/2014] [Accepted: 12/21/2014] [Indexed: 12/22/2022]
Abstract
OBJECTIVE Previous studies suggested that metformin is associated with decreased risk of cancer; however, results specifically addressing the potential association with prostate cancer were limited and contradictory. This study considers the association between metformin and the incidence, mortality and recurrence of prostate cancer by performing a meta-analysis of observational studies. METHODS Literatures published before January 2014 were searched by using databases of PubMed and Embase. Pooled relative risks (RRs) were determined using a random effects model to evaluate the strength of association between metformin therapy and risk of prostate cancer. RESULTS Thirteen studies involving a total of 334 532 participants were included in this meta-analysis. Compared with the control group, metformin therapy was associated with significantly decreased incidence of prostate cancer [RR = 0.88, 95% confidence interval (CI) [0.78, 0.99], p = 0.03, I(2) = 74.7%]. However, metformin therapy was not associated with decreased all-cause mortality (RR = 1.07, 95% CI [0.86, 1.32], p = 0.55, I(2) = 58.2%) or decreased recurrence of prostate cancer (RR = 0.90, 95% CI [0.75, 1.09], p = 0.27, I(2) = 0.0%). No publication bias was detected (pBegg = 0.55, pEgger = 0.46). CONCLUSIONS The present study suggested that metformin therapy may decrease the incidence of prostate cancer but that there was no association between the treatment and all-cause mortality or recurrence. It is recommended that this finding should be considered carefully and confirmed with further studies.
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Affiliation(s)
- Dan Deng
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yuan Yang
- Department of Cardiovascular Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaojun Tang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Laura Skrip
- Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA
| | - Jingfu Qiu
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Yang Wang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
| | - Fan Zhang
- School of Public Health and Management, Chongqing Medical University, Chongqing, China
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Ahmed I, Ferro A, Cohler A, Langenfeld J, Surakanti SG, Aisner J, Zou W, Haffty BG, Jabbour SK. Impact of metformin use on survival in locally-advanced, inoperable non-small cell lung cancer treated with definitive chemoradiation. J Thorac Dis 2015; 7:346-55. [PMID: 25922712 DOI: 10.3978/j.issn.2072-1439.2014.12.32] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 06/24/2014] [Indexed: 12/28/2022]
Abstract
BACKGROUND We investigated survival outcomes in diabetic patients with non-small cell lung cancer (NSCLC) treated with concurrent metformin and definitive chemoradiation. METHODS This single-institution, retrospective cohort study included 166 patients with NSCLC who were treated definitively with chemoradiation between 1999 and 2013. Of 40 patients who had type II diabetes, 20 (50%) were on metformin, and 20 (50%) were not on metformin. The primary outcome was overall survival (OS), and secondary outcomes included progression-free survival (PFS), locoregional recurrence-free survival (LRRFS) and distant metastasis-free survival (DMFS). Kaplan Meier method and log-rank test were performed in survival analysis. Cox regression was utilized in univariate analysis of potential confounders. RESULTS Median follow-up was 17.0 months. Compared with non-diabetic patients, diabetic patients on metformin demonstrated similar OS (16.3 vs. 14.3 mo, P=0.23), PFS (11.6 vs. 9.7 mo, P=0.26), LRRFS (14.1 vs. 11.9 mo, P=0.78), and DMFS (13.4 vs. 10.0 mo, P=0.69). Compared with diabetic patients not on metformin, diabetic patients on metformin also exhibited similar OS (14.3 vs. 19.2 mo, P=0.18), PFS (19.7 vs. 10.1 mo, P=0.38), LRRFS (11.9 vs. 15.5 mo, P=0.69), and DMFS (10.0 vs. 17.4 mo, P=0.12). Identified negative prognostic factors on included squamous cell histology, lower performance status, higher T stage, and non-caucasian ethnicity. CONCLUSIONS No statistically significant differences in survival or patterns of failure were found among the three cohorts in this small set of patients. No statistically significant differences in survival or patterns of failure were found between the three cohorts in this small set of patients. Though it is possible that metformin use may in fact have no effect on survival in NSCLC patients treated with definitive RT, larger-scale retrospective and prospective studies are implicated for clarification.
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Affiliation(s)
- Inaya Ahmed
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Adam Ferro
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Alan Cohler
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - John Langenfeld
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Sujani G Surakanti
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Joseph Aisner
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Wei Zou
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Bruce G Haffty
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Salma K Jabbour
- 1 Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA ; 2 Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA ; 3 Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
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Lee H, Kuk H, Byun SS, Lee SE, Hong SK. Preoperative glycemic control status as a significant predictor of biochemical recurrence in prostate cancer patients after radical prostatectomy. PLoS One 2015; 10:e0124761. [PMID: 25897669 PMCID: PMC4405577 DOI: 10.1371/journal.pone.0124761] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 03/07/2015] [Indexed: 11/18/2022] Open
Abstract
Background The effect of diabetes mellitus (DM) on prostate cancer (PCa) outcome remains controversial. Thus, we investigated the association of DM history, glycemic control, and metformin use with oncologic outcomes after radical prostatectomy (RP). Methods We reviewed the records of 746 contemporary patients who had hemoglobin A1c (HbA1c) measured within the 6 months preceding RP. The associations between clinical variables and risk of adverse pathological features and biochemical recurrence (BCR) were tested using a multivariate logistic regression and multiple Cox-proportional hazards model, respectively. BCR was defined as prostatic specific antigen (PSA) > 0.2 ng/mL in 2 consecutive tests. Results There were no significant differences in the rates of adverse pathologic features and BCR-free survival between patients with (n = 209) and without (n = 537) a history of DM diagnosis (all p > 0.05). In multivariate analyses, high HbA1c level (≥ 6.5%) was significantly related with high pathologic Gleason score (≥ 4+3; odds ratio [OR] 1.704, p = 0.019) and BCR-free survival (OR 1.853, p = 0.007). Metformin use was not associated with BCR-free survival (OR 0.662, p = 0.125). Conclusions Poor glycemic control was significantly associated with BCR after RP. Meanwhile, metformin use was not associated with biochemical outcome after RP. Further investigation would be needed to identify exact mechanism underlying the impact of glycemic control on PCa treatment outcome.
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Affiliation(s)
- Hakmin Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Harim Kuk
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Seok-Soo Byun
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sang Eun Lee
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Sung Kyu Hong
- Department of Urology, Seoul National University Bundang Hospital, Seongnam, Korea
- * E-mail:
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Yokoyama NN, Denmon A, Uchio EM, Jordan M, Mercola D, Zi X. When Anti-Aging Studies Meet Cancer Chemoprevention: Can Anti-Aging Agent Kill Two Birds with One Blow? ACTA ACUST UNITED AC 2015; 1:420-433. [PMID: 26756023 DOI: 10.1007/s40495-015-0039-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Recent evidence has strongly supported that the rate of aging is controlled, at least to some extent, by evolutionarily conserved nutrient sensing pathways (e.g. the insulin/IGF-1-signaling, mTOR, AMPK, and sirtuins) from worms to humans. These pathways are also commonly involved in carcinogenesis and cancer metabolism. Agents (e.g. metformin, resveratrol, and Rhodiola) that target these nutrient sensing pathways often have both anti-aging and anti-cancer efficacy. These agents not only reprogram energy metabolism of malignant cells, but also target normal postmitotic cells by suppressing their conversion into senescent cells, which confers systematic metabolism benefits. These agents are fundamentally different from chemotherapy (e.g. paclitaxel and doxorubicin) or radiation therapy that causes molecular damage (e.g. DNA and protein damages) and thereby no selection resistance may be expected. By reviewing molecular mechanisms of action, epidemiological evidence, experimental data in tumor models, and early clinical study results, this review provides information supporting the promising use of agents with both anti-aging and anti-cancer efficacy for cancer chemoprevention.
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Affiliation(s)
- Noriko N Yokoyama
- Department of Urology, University of California, Irvine, Orange, CA 92868, USA
| | - Andria Denmon
- Department of Urology, University of California, Irvine, Orange, CA 92868, USA
| | - Edward M Uchio
- Department of Urology, University of California, Irvine, Orange, CA 92868, USA
| | - Mark Jordan
- Department of Urology, University of California, Irvine, Orange, CA 92868, USA
| | - Dan Mercola
- Department of Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA 92868, USA
| | - Xiaolin Zi
- Department of Urology, University of California, Irvine, Orange, CA 92868, USA; Department of Pharmacology, University of California, Irvine, Orange, CA 92868, USA; Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 92868, USA
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Raval AD, Thakker D, Vyas A, Salkini M, Madhavan S, Sambamoorthi U. Impact of metformin on clinical outcomes among men with prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2015; 18:110-21. [PMID: 25667109 DOI: 10.1038/pcan.2014.52] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/18/2014] [Accepted: 11/19/2014] [Indexed: 01/08/2023]
Abstract
BACKGROUND Conflicting evidence exists regarding the beneficial effects of metformin in prostate cancer. To determine the association between metformin and clinical outcomes in prostate cancer using systematic review and meta-analysis. METHODS Original articles published in English until third week of July, 2014 were searched in electronic databases (Medline-Ovid, Scopus, The Cochrane Library, Web of Science, ProQuest) for studies on metformin use in prostate cancer. The clinical outcomes assessed were: development of biochemical recurrence, metastases or castration-resistant metastatic cancer, all-cause and prostate cancer-specific mortality. Meta-analysis was performed to calculate the pooled hazard ratio (pHR) and their 95% confidence interval (95% CI). Heterogeneity between the studies was examined using I2 statistics. Sensitivity analysis was conducted to assess the robustness of findings and publication bias was assessed by the Egger's regression asymmetry test and contour plot. RESULTS Out of 230 retrieved citations, eight retrospective cohort studies and one nested-case-control study met the inclusion criteria. Metformin use was marginally associated with reduction in the risk of biochemical recurrence (pHR: 0.82, 95% CI: 0.67, 1.01, P-value=0.06, I2=25%, five studies). Metformin use was not significantly associated with metastases (pHR: 0.59, 95% 0.30-1.18, P-value=0.14, I2=74%, three studies), all-cause mortality (pHR: 0.86; 95% CI, 0.67, 1.10, P-value=0.23, I2: 73%, six studies) and prostate cancer-specific mortality (pHR: 0.76, 95% CI: 0.43, 1.33, P-value = 0.33, I2=60%, four studies). Pooled estimates for all outcomes varied in sensitivity analysis by diabetes status and primary treatment of prostate cancer. Systematic review revealed mixed findings on metformin use and the risk of CRPC. CONCLUSIONS Metformin may reduce the risk of biochemical recurrence in prostate cancer. Given the potential of selection bias in the observational studies, randomized trials should be designed to assess the efficacy of metformin use in prostate cancer.
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Affiliation(s)
- A D Raval
- Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - D Thakker
- Shrimati Kaumudiniben Health Outcomes Research Group (SKHORG), Dhrangadhra, Gujarat, India
| | - A Vyas
- Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - M Salkini
- Department of Surgery/Urology, School of Medicine, West Virginia University, Morgantown, WV, USA
| | - S Madhavan
- Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA
| | - U Sambamoorthi
- Department of Pharmaceutical Systems and Policy, School of Pharmacy, West Virginia University, Morgantown, WV, USA
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Tung JC, Barnes JM, Desai SR, Sistrunk C, Conklin MW, Schedin P, Eliceiri KW, Keely PJ, Seewaldt VL, Weaver VM. Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 2015; 79:269-80. [PMID: 25532934 PMCID: PMC4339308 DOI: 10.1016/j.freeradbiomed.2014.11.020] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2014] [Revised: 11/01/2014] [Accepted: 11/25/2014] [Indexed: 12/14/2022]
Abstract
Desmosplasia is a characteristic of most solid tumors and leads to fibrosis through abnormal extracellular matrix (ECM) deposition, remodeling, and posttranslational modifications. The resulting stiff tumor stroma not only compromises vascular integrity to induce hypoxia and impede drug delivery, but also promotes aggressiveness by potentiating the activity of key growth, invasion, and survival pathways. Intriguingly, many of the protumorigenic signaling pathways that are mechanically activated by ECM stiffness also promote glucose uptake and aerobic glycolysis, and an altered metabolism is a recognized hallmark of cancer. Indeed, emerging evidence suggests that metabolic alterations and an abnormal ECM may cooperatively drive cancer cell aggression and treatment resistance. Accordingly, improved methods to monitor tissue mechanics and metabolism promise to improve diagnostics and treatments to ameliorate ECM stiffening and elevated mechanosignaling may improve patient outcome. Here we discuss the interplay between ECM mechanics and metabolism in tumor biology and suggest that monitoring these processes and targeting their regulatory pathways may improve diagnostics, therapy, and the prevention of malignant transformation.
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Affiliation(s)
- Jason C Tung
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California at San Francisco, San Francisco, CA 94143, USA
| | - J Matthew Barnes
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California at San Francisco, San Francisco, CA 94143, USA
| | | | | | - Matthew W Conklin
- Department of Biomedical Engineering, University of Wisconsin Carbone Comprehensive Cancer Center, Wisconsin Institute for Medical Research, University of Wisconsin at Madison, Madison, WI 53706, USA
| | - Pepper Schedin
- Department of Cell, Developmental, and Cancer Biology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Kevin W Eliceiri
- Laboratory for Optical and Computational Instrumentation, Laboratory for Cell and Molecular Biology, University of Wisconsin at Madison, Madison, WI 53706, USA
| | - Patricia J Keely
- Department of Biomedical Engineering, University of Wisconsin Carbone Comprehensive Cancer Center, Wisconsin Institute for Medical Research, University of Wisconsin at Madison, Madison, WI 53706, USA
| | | | - Valerie M Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California at San Francisco, San Francisco, CA 94143, USA; Department of Anatomy, University of California at San Francisco, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, University of California at San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California at San Francisco, San Francisco, CA 94143, USA; Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94143, USA.
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Soffer D, Shi J, Chung J, Schottinger JE, Wallner LP, Chlebowski RT, Lentz SE, Haque R. Metformin and breast and gynecological cancer risk among women with diabetes. BMJ Open Diabetes Res Care 2015; 3:e000049. [PMID: 25664181 PMCID: PMC4316195 DOI: 10.1136/bmjdrc-2014-000049] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Revised: 11/19/2014] [Accepted: 11/25/2014] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications. RESEARCH DESIGN AND METHODS We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ(2) analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status. RESULTS Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users. CONCLUSIONS Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.
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Affiliation(s)
- Diana Soffer
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
| | - Jiaxiao Shi
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
| | - Joanie Chung
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
| | - Joanne E Schottinger
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
| | - Lauren P Wallner
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
| | - Rowan T Chlebowski
- Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center, Torrance, California, USA
| | - Scott E Lentz
- Department of Gynecologic Oncology, Kaiser Permanente Southern California, Los Angeles, California, USA
| | - Reina Haque
- Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena, California, USA
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Yu H, Yin L, Jiang X, Sun X, Wu J, Tian H, Gao X, He X. Effect of metformin on cancer risk and treatment outcome of prostate cancer: a meta-analysis of epidemiological observational studies. PLoS One 2014; 9:e116327. [PMID: 25545701 PMCID: PMC4278883 DOI: 10.1371/journal.pone.0116327] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 12/04/2014] [Indexed: 11/30/2022] Open
Abstract
Background Laboratory studies have shown the anti-tumor effect of metformin on prostate cancer. However, recent epidemiological studies have yielded inconclusive results. Methods We searched PubMed database from the inception to May 30 2014 for studies which assessed the effect of metformin use on cancer risk of prostate cancer, biochemical recurrence (BCR) and all-cause mortality of patients with prostate cancer. The pooled results and 95% confidence intervals (CIs) were estimated by random-effect model. Results Twenty-one studies were eligible according to the inclusion criteria. Based on the pooled results of available observational studies, metformin use was significantly associated with a decreased cancer risk (14 datasets, 963991 male subjects, odds ratio: 0.91, 95% CI: 0.85–0.97) and BCR (6 datasets, 2953 patients, hazard ratio: 0.81, 95% CI: 0.68–0.98) of prostate cancer. However, the association of metformin use with all-cause mortality of patients with prostate cancer was not significant (5 datasets, 9241 patients, hazard ratio: 0.86, 95% CI: 0.64–1.14). Conclusion Results suggest that metformin use appears to be associated with a significant reduction in the cancer risk and BCR of prostate cancer, but not in all-cause mortality of patients with prostate cancer.
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Affiliation(s)
- Hongliang Yu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Li Yin
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Xuesong Jiang
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Xiujin Sun
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Jing Wu
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Hao Tian
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
| | - Xianshu Gao
- Department of Radiation Oncology, Peking University First Hospital, Peking University, Beijing, P. R. China
| | - Xia He
- Department of Radiation Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, the Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, P. R. China
- * E-mail:
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Strine AC, Rice KR, Masterson TA. Metabolic syndrome in the development and progression of prostate cancer. World J Clin Urol 2014; 3:168-183. [DOI: 10.5410/wjcu.v3.i3.168] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Revised: 06/12/2014] [Accepted: 07/14/2014] [Indexed: 02/06/2023] Open
Abstract
Prostate cancer (PCa) is the most common noncutaneous malignancy and second leading cause of cancer-specific mortality for men in the United States. There is a wide spectrum of aggressiveness ranging from biologically significant to indolent disease, which has led to an interest in the identification of risk factors for its development and progression. Emerging evidence has suggested an association between metabolic syndrome (MetS) and PCa. MetS represents a cluster of metabolic derangements that confer an increased risk of cardiovascular disease and type 2 diabetes mellitus. Its individual components include obesity, dyslipidemias, high blood pressure, and high fasting glucose levels. MetS has become pervasive and is currently associated with a high socioeconomic cost in both industrialized and developing countries throughout the world. The relationship between MetS and PCa is complex and yet to be fully defined. A better understanding of this relationship will facilitate the development of novel therapeutic targets for the prevention of PCa and improvement of outcomes among diagnosed men in the future. In this review, we evaluate the current evidence on the role of MetS in the development and progression of PCa. We also discuss the clinical implications on the management of PCa and consider the future direction of this subject.
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Metformin is not associated with improved biochemical free survival or cause-specific survival in men with prostate cancer treated with permanent interstitial brachytherapy. J Contemp Brachytherapy 2014; 6:254-61. [PMID: 25337126 PMCID: PMC4200187 DOI: 10.5114/jcb.2014.45757] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/04/2014] [Accepted: 09/30/2014] [Indexed: 12/12/2022] Open
Abstract
Purpose Several recent studies have suggested improved clinical outcomes in diabetic men with prostate cancer who also use metformin. We explore whether metformin use is associated with improved outcomes specifically in men undergoing prostate brachytherapy. Material and methods 2,298 consecutive patients underwent permanent interstitial brachytherapy by a single brachytherapist (GSM). The cohort included 2028 non-diabetic men, 144 men with diabetes who were not taking metformin, and 126 men with diabetes who were taking metformin. Median follow up was 8.3 years. Differences in biochemical free survival, cause specific survival, and overall survival between men taking metformin and those not taking metformin were compared using Kaplan-Meier curves and log rank tests. Results Fifteen year biochemical failure rate, cause specific mortality and overall mortality for non-diabetic men was 4.6%, 1.5%, 47.0%, respectively; for diabetic men taking metformin 4.8%, 2.0%, 37.2%; and for diabetic men not taking metformin was 2.8%, 0%, 72.7%, respectively. Metformin use was not predictive in multivariate analysis of biochemical failure or prostate cancer specific mortality. However, diabetic men not taking metformin had higher overall mortality than non-diabetic men. Conclusions Metformin use was not associated with improved biochemical survival or cancer specific survival in this cohort of men treated with prostate brachytherapy.
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Szablewski L. Diabetes mellitus: influences on cancer risk. Diabetes Metab Res Rev 2014; 30:543-53. [PMID: 25044584 DOI: 10.1002/dmrr.2573] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Revised: 03/11/2013] [Accepted: 03/19/2013] [Indexed: 12/20/2022]
Abstract
Diabetes mellitus and cancer are common conditions, and their co-diagnosis in the same individual is not infrequent. The relative risks associated with type 2 diabetes are greater than twofold for hepatic, pancreatic, and endometrial cancers. The relative risk is somewhat lower, at 1.2-1.5-fold for colorectal, breast, and bladder cancers. In comparison, the relative risk of lung cancer is less than 1. The evidence for other malignancies (e.g. kidney, non-Hodgkin lymphoma) is inconclusive, whereas prostatic cancer occurs less frequently in male patients with diabetes. The potential biologic links between the two diseases are incompletely understood. Evidence from observational studies suggests that some medications used to treat hyperglycemia are associated with either increased or reduced risk of cancer. Whereas anti-diabetic drugs have a minor influence on cancer risk, drugs used to treat cancer may either cause diabetes or worsen pre-existing diabetes. If hyperinsulinemia acts as a critical link between the observed increased cancer risk and type 2 diabetes, one would predict that patients with type 1 diabetes would have a different cancer risk pattern than patients with type 2 diabetes because the former patients are exposed to lower levels of exogenous administered insulin. Obtained results showed that patients with type 1 diabetes had elevated risks of cancers of the stomach, cervix, and endometrium. Type 1 diabetes is associated with a modest excess cancer risk overall and risks of specific cancers that differ from those associated with type 2 diabetes.
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Affiliation(s)
- Leszek Szablewski
- Chair of General Biology and Parasitology, Center of Biostructure Research, Medical University of Warsaw, Warsaw, Poland
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Bensimon L, Yin H, Suissa S, Pollak MN, Azoulay L. The use of metformin in patients with prostate cancer and the risk of death. Cancer Epidemiol Biomarkers Prev 2014; 23:2111-8. [PMID: 25017246 DOI: 10.1158/1055-9965.epi-14-0056] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Given the conflicting results from observational studies, we assessed whether the use of metformin after a prostate cancer diagnosis is associated with a decreased risk of cancer-specific and all-cause mortality. METHODS This study was conducted linking four databases from the United Kingdom. A cohort of men newly diagnosed with nonmetastatic prostate cancer with a history of treated type II diabetes, between April 1, 1998 and December 31, 2009, was followed until October 1, 2012. Nested case-control analyses were performed for cancer-specific mortality and all-cause mortality, in which exposure was defined as use of metformin during the time to risk-set. Conditional logistic regression was used to estimate adjusted rate ratios (RR) of each outcome with 95% confidence intervals (CI). RESULTS The cohort consisted of 935 men with prostate cancer and a history of type II diabetes. After a mean follow-up of 3.7 years, 258 deaths occurred, including 112 from prostate cancer. Overall, the post-diagnostic use of metformin was not associated with a decreased risk of cancer-specific mortality (RR, 1.09; 95% CI, 0.51-2.33). In a secondary analysis, a cumulative duration ≥938 days was associated with an increased risk (RR, 3.20; 95% CI, 1.00-10.24). The post-diagnostic use of metformin was not associated with all-cause mortality (RR, 0.79; 95% CI, 0.50-1.23). CONCLUSION The use of metformin after a prostate cancer diagnosis was not associated with an overall decreased risk of cancer-specific and all-cause mortality. IMPACT The results of this study do not support a role for metformin in the prevention of prostate cancer outcomes.
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Affiliation(s)
- Leah Bensimon
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Hui Yin
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada
| | - Samy Suissa
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
| | - Michael N Pollak
- Experimental Medicine, McGill University, Montreal, Quebec, Canada. Department of Oncology, McGill University, Montreal, Canada
| | - Laurent Azoulay
- Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Canada. Department of Oncology, McGill University, Montreal, Canada.
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Wu JW, Boudreau DM, Park Y, Simonds NI, Freedman AN. Commonly used diabetes and cardiovascular medications and cancer recurrence and cancer-specific mortality: a review of the literature. Expert Opin Drug Saf 2014; 13:1071-99. [PMID: 24999107 DOI: 10.1517/14740338.2014.926887] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Cancer most commonly arises in the elderly who are often burdened with comorbidities. Medications used for treating these comorbidities may alter cancer prognosis. Understanding the impact of these medications on cancer is important in order to make effective evidence-based decisions about managing comorbidities while improving cancer outcomes. AREAS COVERED The evidence on diabetes, statins, antihypertensive and anti-inflammatory medications and their association with cancer recurrence and cancer-specific mortality are reviewed. The strengths and limitations of the existing literature, the current state of the field and future directions are discussed. EXPERT OPINION Metformin and aspirin were associated with a reduced risk of cancer recurrence and cancer-specific mortality. The evidence for statins and antihypertensive medications on cancer survival was inconsistent. There were few studies to suggest that any of the medication classes of interest were associated with negative effects on cancer survival. Methodological shortcomings within observational studies, such as confounding, distinguishing between use of medications pre-cancer versus post-cancer diagnosis/treatment, misclassification of exposures/outcomes, informative censoring and competing risks, must be considered. New observational studies addressing these limitations are essential. Some clinical trials are underway to further investigate the beneficial effects of these drugs and completed trials have confirmed results demonstrated in observational studies.
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Affiliation(s)
- Jennifer W Wu
- McGill University, Epidemiology, Biostatistics, and Occupational Health , 1020 Pine Avenue, Montreal, Quebec, H3A 1A2 , Canada
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Nenu I, Popescu T, Aldea MD, Craciun L, Olteanu D, Tatomir C, Bolfa P, Ion RM, Muresan A, Filip AG. Metformin associated with photodynamic therapy--a novel oncological direction. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2014; 138:80-91. [PMID: 24911275 DOI: 10.1016/j.jphotobiol.2014.04.027] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2014] [Revised: 04/15/2014] [Accepted: 04/28/2014] [Indexed: 12/31/2022]
Abstract
The aim of our study was to assess the effect of the combined treatment of Metformin (Metf) and 5, 10, 15, 20-tetra-sulfophenyl-porphyrin (TSPP)-mediated photodynamic therapy (PDT) on an in vivo tumour model. Wistar male rats were divided in 6 groups: group 1, treated with TSPP; groups 2 and 4 treated with TSPP and Metf, respectively, and irradiated 24h thereafter; group 3 was treated with Metf and the last two groups received the combined treatment, Metf administered prior (group 5) or after (group 6) irradiation. 72 h from the start of the treatment, tumour tissue was sampled for the investigation of oxidative and nitrosative stress. The apoptotic rate, inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 expressions and matrix metalloproteinases activities were also quantified. Malondialdehyde and glutathione levels were significantly elevated in the groups treated with combined therapy (p<0.05). Metf associated with TSPP-PDT reduced iNOS and COX-2 expressions and enhanced nitrotyrosine levels in both therapeutic regimens. Peroxynitrate formation and its cytotoxic effect on tumour cells were related to an elevated index of apoptosis and necrosis. Moreover, MMP-2 activity reached a minimum in the groups which received combined therapy. Our results confirmed that the association of Metf with PDT might prove a new and promising oncological approach.
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Affiliation(s)
- Iuliana Nenu
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Tiberiu Popescu
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Mihaela D Aldea
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Lucian Craciun
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Diana Olteanu
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Corina Tatomir
- Departments of Radiobiology and Tumor Biology, Oncology Institute "Prof. I. Chiricuta", 34-36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Pompei Bolfa
- Department of Pathology, Cluj-Napoca, University of Agricultural Sciences and Veterinary Medicine, 3-5 Calea Manastur, 400372 Cluj-Napoca, Romania; Department of Biomedical Sciences, Ross University School of Veterinary Medicine Basseterre, PO Box 334, Saint Kitts and Nevis
| | - Rodica M Ion
- National Research & Development Institute for Chemistry and Petrochemistry ICECHIM 202 Splaiul Independentei, 060021 Bucharest, Romania
| | - Adriana Muresan
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania
| | - Adriana G Filip
- Department of Physiology, "Iuliu Hatieganu" University of Medicine and Pharmacy, 1 Clinicilor Street, 400006 Cluj-Napoca, Romania.
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Ishak-Howard MB, Okoth LA, Cooney KA. Statin use and the risk of recurrence after radical prostatectomy in a cohort of men with inherited and/or early-onset forms of prostate cancer. Urology 2014; 83:1356-61. [PMID: 24745796 DOI: 10.1016/j.urology.2014.02.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Revised: 01/23/2014] [Accepted: 02/13/2014] [Indexed: 10/25/2022]
Abstract
OBJECTIVE To investigate whether the use of statin medications is associated with a reduced risk of biochemical recurrence (BCR) in men with inherited and/or early-onset prostate cancer who have been treated with radical retropubic prostatectomy (RRP). METHODS Study patients are men with inherited and/or early-onset prostate cancer enrolled in the University of Michigan Prostate Cancer Genetics Project. Men enrolled in Prostate Cancer Genetics Project were surveyed to determine statin medication use history from 1999 to 2009. Diagnosis and treatment data were taken from medical records. BCR was defined as a single increase in prostate-specific antigen level to ≥0.4 ng/mL after treatment with RRP. Statin use was modeled as a time-dependent variable, and BCR after RRP was both examined using crude Cox proportional hazards models and adjusted for known clinical prognostic factors. RESULTS A total of 539 men treated with RRP were included in this study. Of these, 47.9% of men used statin medications, and 115 (21%) men experienced a recurrence. Ever-statin use was not associated with risk of recurrence in crude models (hazards ratio=1.04, 95% confidence interval=0.72-1.49, P value=.86) or in models adjusted for clinical characteristics (hazards ratio=1.06, 95% confidence interval=0.68-1.64, P value=.81). Furthermore, no association was observed when comparing men with high-Gleason grade cancers with those with low-Gleason grade cancers. CONCLUSION Statin use was not associated with a reduced risk of BCR after RRP in this study; however, these men at increased risk for prostate cancer represent a subgroup of men who may benefit from further study of statin medication use to slow or prevent BCR.
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Affiliation(s)
- Miriam B Ishak-Howard
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI.
| | - Linda A Okoth
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI
| | - Kathleen A Cooney
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI; Department of Urology, University of Michigan Medical School, Ann Arbor, MI
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Type 2 diabetes and the risk of mortality among patients with prostate cancer. Cancer Causes Control 2014; 25:329-38. [DOI: 10.1007/s10552-013-0334-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 12/24/2013] [Indexed: 02/06/2023]
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Keizman D, Gottfried M, Ish-Shalom M, Maimon N, Peer A, Neumann A, Hammers H, Eisenberger MA, Sinibaldi V, Pili R, Hayat H, Kovel S, Sella A, Boursi B, Weitzen R, Mermershtain W, Rouvinov K, Berger R, Carducci MA. Active smoking may negatively affect response rate, progression-free survival, and overall survival of patients with metastatic renal cell carcinoma treated with sunitinib. Oncologist 2013; 19:51-60. [PMID: 24309979 DOI: 10.1634/theoncologist.2012-0335] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Obesity, smoking, hypertension, and diabetes are risk factors for renal cell carcinoma development. Their presence has been associated with a worse outcome in various cancers. We sought to determine their association with outcome of sunitinib treatment in metastatic renal cell carcinoma (mRCC). METHODS An international multicenter retrospective study of sunitinib-treated mRCC patients was performed. Multivariate analyses were performed to determine the association between outcome and the pretreatment status of smoking, body mass index, hypertension, diabetes, and other known prognostic factors. RESULTS Between 2004 and 2013, 278 mRCC patients were treated with sunitinib: 59 were active smokers, 67 were obese, 73 were diabetic, and 165 had pretreatment hypertension. Median progression-free survival (PFS) was 9 months, and overall survival (OS) was 22 months. Factors associated with PFS were smoking status (past and active smokers: hazard ratio [HR]: 1.17, p = .39; never smokers: HR: 2.94, p < .0001), non-clear cell histology (HR: 1.62, p = .011), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 3.51, p < .0001), use of angiotensin system inhibitors (HR: 0.63, p = .01), sunitinib dose reduction or treatment interruption (HR: 0.72, p = .045), and Heng risk (good and intermediate risk: HR: 1.07, p = .77; poor risk: HR: 1.87, p = .046). Factors associated with OS were smoking status (past and active smokers: HR: 1.25, p = .29; never smokers: HR: 2.7, p < .0001), pretreatment neutrophil-to-lymphocyte ratio >3 (HR: 2.95, p < .0001), and sunitinib-induced hypertension (HR: 0.57, p = .002). CONCLUSION Active smoking may negatively affect the PFS and OS of sunitinib-treated mRCC. Clinicians should consider advising patients to quit smoking at initiation of sunitinib treatment for mRCC.
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Affiliation(s)
- Daniel Keizman
- Genitourinary Oncology Service, Institute of Oncology, Meir Medical Center and the Sackler School of Medicine, Tel Aviv University, Kfar-Saba, Israel; Department of Oncology, Rambam Medical Center, Haifa, Israel; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA; Roswell Park Cancer Institute, Buffalo, New York, USA; Department of Oncology, Wolfson Medical Center, Holon, Israel; Department of Oncology, Asaf Harofe Medical Center, Zerifin, Israel; Department of Oncology, Sheba Medical Center, Tel Hashomer, Israel; Department of Oncology, Soroka University Medical Center, Beer-sheva, Israel
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Yin M, Zhou J, Gorak EJ, Quddus F. Metformin is associated with survival benefit in cancer patients with concurrent type 2 diabetes: a systematic review and meta-analysis. Oncologist 2013; 18:1248-55. [PMID: 24258613 DOI: 10.1634/theoncologist.2013-0111] [Citation(s) in RCA: 117] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
UNLABELLED Patients with type 2 diabetes have increased cancer risk and cancer-related mortality, which can be reduced by metformin treatment. However, it is unclear whether metformin can also modulate clinical outcomes in patients with cancer and concurrent type 2 diabetes. PATIENTS AND METHODS A meta-analysis of 20 publications that included 13,008 subjects was performed to investigate the association between metformin and overall survival (OS) as well as cancer-specific survival (CSS) in patients with cancer and concurrent type 2 diabetes. RESULTS We found that there was a relative survival benefit associated with metformin treatment compared with treatment with other glucose-lowering medications in both OS and CSS (hazard ratio [HR] = 0.66; 95% confidence interval [CI]: 0.55-0.79 and HR = 0.62; 95% CI: 0.46-0.84, respectively). These associations were also observed in subgroups by cancer type and country. CONCLUSION These results suggest that metformin is the drug of choice in the treatment of patients with cancer and concurrent type 2 diabetes.
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Chevalier S, Farsijani S. Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment. Appl Physiol Nutr Metab 2013; 39:643-53. [PMID: 24869969 DOI: 10.1139/apnm-2013-0369] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cancer cachexia is a metabolic syndrome featuring many alterations typical of type 2 diabetes (T2D). While muscle wasting is a hallmark of cachexia, epidemiological evidence also supports an accelerated age-related muscle loss in T2D. Insulin resistance manifests in both conditions and impairs glucose disposal and protein anabolism by tissues. A greater contribution of gluconeogenesis to glucose production may limit amino acid availability for muscle protein synthesis, further aggravating muscle loss. In the context of inter-dependence between glucose and protein metabolism, the present review summarizes the current state of knowledge on alterations that may lead to muscle wasting in human cancer. By highlighting the similarities with T2D, a disease that has been more extensively studied, the objective of this review is to provide a better understanding of the pathophysiology of cancer cachexia and to consider potential treatments usually targeted for T2D. Nutritional approaches aimed at stimulating protein anabolism might include specially formulated food with optimal protein and amino acid composition. Because the gradual muscle loss in T2D may be attenuated by diabetes treatment, anti-diabetic drugs might be considered in cachexia treatment. Metformin emerges as a choice candidate as it acts both on reducing gluconeogenesis and improving insulin sensitivity, and has demonstrated tumour suppressor properties in multiple cancer types. Such a multimodal approach to slow or reverse muscle wasting in cachexia warrants further investigation.
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Affiliation(s)
- Stéphanie Chevalier
- a Department of Medicine and School of Dietetics and Human Nutrition, Crabtree Nutrition Laboratories, McGill University Health Centre-Royal Victoria Hospital, 687 ave des Pins Ouest, room H6.61, Montreal, QC H3A 1A1, Canada
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Allott EH, Abern MR, Gerber L, Keto CJ, Aronson WJ, Terris MK, Kane CJ, Amling CL, Cooperberg MR, Moorman PG, Freedland SJ. Metformin does not affect risk of biochemical recurrence following radical prostatectomy: results from the SEARCH database. Prostate Cancer Prostatic Dis 2013; 16:391-7. [PMID: 24100644 PMCID: PMC3830588 DOI: 10.1038/pcan.2013.48] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Revised: 09/05/2013] [Accepted: 09/09/2013] [Indexed: 02/08/2023]
Abstract
Background While epidemiologic studies suggest that metformin use among diabetics may decrease prostate cancer (PC) incidence, the effect of metformin use on PC outcome is unclear. We investigated the association between pre-operative metformin use, dose and duration of use and biochemical recurrence (BCR) in PC patients with diabetes who underwent radical prostatectomy (RP). Methods We conducted a retrospective cohort analysis within the Shared Equal Access Regional Cancer Hospital (SEARCH) database of 371 PC patients with diabetes who underwent RP. Time to BCR between metformin users and non-users, and by metformin dose and duration of use was assessed using multivariable Cox proportional analysis adjusted for demographic, clinical and/or pathologic features. Time to castrate-resistant PC (CPRC), metastases and PC-specific mortality were explored as secondary outcomes using unadjusted analyses. Results Of 371 diabetic men, 156 (42%) were using metformin prior to RP. Metformin use was associated with more recent year of surgery (p<0.0001) but no clinical or pathologic characteristics. After adjustment for year of surgery, clinical and pathologic features, there were no associations between metformin use (HR 0.93; 95%CI 0.61–1.41), high metformin dose (HR 0.96; 95%CI 0.57–1.61) or duration of use (HR 1.00; 95%CI 0.99–1.02) and time to BCR. A total of 14 patients (3.8%) developed CRPC, 10 (2.7%) distant metastases and 8 (2.2%) died from PC. Unadjusted analysis suggested high metformin dose versus non-use was associated with increased risk of CRPC (HR 5.1; 95%CI 1.6–16.5), metastases (HR 4.8; 95%CI 1.2–18.5) and PC-specific mortality (HR 5.0; 95%CI 1.1–22.5). Conclusions Metformin use, dose or duration of use was not associated with BCR in this cohort of diabetic PC patients treated with RP. The suggestion that higher metformin dose was associated with increased risk of CPRC, metastases and PC-specific mortality merits testing in large prospective studies with longer follow-up.
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Affiliation(s)
- E H Allott
- 1] Division of Urology, Department of Surgery, Duke University School of Medicine, Durham, NC, USA [2] Cancer Prevention, Detection and Control Program, Duke Cancer Institute, Durham, NC, USA [3] Section of Urology, Veterans Affairs Medical Center, Durham, NC, USA
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Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer. World J Urol 2013; 32:999-1005. [PMID: 24062093 DOI: 10.1007/s00345-013-1171-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2013] [Accepted: 09/12/2013] [Indexed: 10/26/2022] Open
Abstract
PURPOSE The impact of diabetes mellitus (DM) and metformin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS We retrospectively evaluated 6,863 patients who underwent RP for clinically localized PC between 2000 and 2011. Univariable and multivariable Cox regression models addressed the association of DM and metformin use with BCR. RESULTS Overall, 664 patients had a diagnosis of DM from which 287 (43 %) were on metformin and 377 (57 %) were on anti-diabetics other than metformin. DM and metformin were not associated with any clinicopathologic features (p values >0.05). Within a median follow-up of 25 months (interquartile range 35 months), 774 (11.3 %) patients experienced BCR. Actuarial 5-year biochemical-free survival was 83 % for non-diabetic, 79 % for diabetic patients without metformin use, and 85 % for diabetic patients with metformin use (log rank p = 0.17). In uni- and multivariable Cox regression analyses with the non-diabetic group as referent, DM without metformin use (HR = 0.99; 95 % CI 0.75-1.30, p = 0.65) and DM with metformin use (HR = 0.84, 95 % CI 0.58-1.22, p = 0.36) were not associated with BCR after RP. A subgroup analysis stratified by nodal status, surgical margins, tumor stage, and Gleason sum did not reveal any significant association between DM, use of metformin and risk of BCR. CONCLUSIONS We found no association between DM or metformin use and cancer-specific features or BCR in patients treated with RP. The effect of DM and metformin on complications, wound healing and overall survival needs to be assessed in similar cohorts.
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Risk of cancer in diabetes: the effect of metformin. ISRN ENDOCRINOLOGY 2013; 2013:636927. [PMID: 24224094 PMCID: PMC3800579 DOI: 10.1155/2013/636927] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Accepted: 08/16/2013] [Indexed: 12/20/2022]
Abstract
Cancer is the second cause of death. Association of diabetes as a growing and costly disease with cancer is a major health concern. Meanwhile, preexisting diabetes is associated with an increased risk of all-cause and cancer-specific mortalities. Presence of diabetes related comorbidities, poorer response to cancer treatment, and excess mortality related to diabetes are among the most important explanations. Although diabetes appear to be a risk factor for cancer and is associated with the mortality risk in cancer patients, several factors such as diabetes duration, multiple drug therapy, and the presence of diabetes comorbidities make the assessment of the effect of diabetes treatment on cancer risk and mortality difficult. Metformin is the drug of choice for the treatment of type 2 diabetes. The available evidence from basic science, clinical, and population-based research supports the anticancer effect of metformin. However, randomized controlled clinical trials do not provide enough evidence for a strong protective effect of metformin on cancer incidence or mortality. One of the most important limitations of these trials is the short duration of the followup. Further long-term randomized controlled clinical trials specifically designed to determine metformin effect on cancer risk are needed to provide the best answer to this challenge.
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