1434 ROLE OF METFORMIN IN PROSTATE CANCER PROGRESSION: MECHANISTIC STUDIES IN A XENOGRAFT MODEL (2010)

You have accessJournal of UrologyProstate Cancer: Basic Research VIII1 Apr 20101434 ROLE OF METFORMIN IN PROSTATE CANCER PROGRESSION: MECHANISTIC STUDIES IN A XENOGRAFT MODEL Min Hou, Natalie Venier, Linda Sugar, Mireia Musquera, Michael Pollak, Neil Fleshner, Laurence Klotz, and Vasundara Venkateswaran Min HouMin Hou Toronto, Canada More articles by this author , Natalie VenierNatalie Venier Toronto, Canada More articles by this author , Linda SugarLinda Sugar Toronto, Canada More articles by this author , Mireia MusqueraMireia Musquera Toronto, Canada More articles by this author , Michael PollakMichael Pollak Montreal, Canada More articles by this author , Neil FleshnerNeil Fleshner Toronto, Canada More articles by this author , Laurence KlotzLaurence Klotz Toronto, Canada More articles by this author , and Vasundara VenkateswaranVasundara Venkateswaran Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1127AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We previously reported an association of a high carbohydrate-high fat (HC-HF) diet-induced hyperinsulinemia with accelerated PCa growth. We hypothesize that metformin, an antidiabetic drug, may have a protective effect against the progression of PCa in animals placed on a HC-HF diet. Two studies were carried out. The initial study on CD1 animals was to assess the dose of metformin. The second study utilized a xenograft model to observe the potential benefit of metformin on PCa progression and to determine the mechanism of action. METHODS CD1 mice on a HC-HF diet were subjected to metformin in drinking water {50-250mg/kg body weight (bw)}. Based on the results of this study, athymic mice were inoculated with LNCaP cells and randomized to the following groups: HC-HF diet; HC-HF diet with metformin at a dose of 50 and 250mg/kg bw respectively. RESULTS The study on CD1 mice revealed that metformin at a dose of 250mg/kg bw caused a significant decrease (>2 folds, p<0.0001) in food intake and a significant reduction (2 folds, p<0.05) in overall gain in body weight relative to the controls. At such a dosage, metformin significantly reduced serum insulin (control:2.307 ng/ml vs metformin:1.076 ng/ml;p<0.05) and inhibition of gluconeogenesis (blood glucose-control:10.2 mmol/L vs metformin:6.6 mmol/L;p<0.05). In addition, it conferred normal to very mild fatty changes in liver histology. The expression of insulin receptor in prostates was down regulated in the metformin group compared to the control group. The xenograft study showed a steady increase and plateaued towards the end of the study in the group receiving 50mg/kg bw metformin, whereas it was almost linear for the control animals and animals on a dose of 250mg/kg bw metformin. Tumor volume at necropsy was 728.1 mm3 with 50mg/kg bw metformin compared to 1267.5 mm3 in the controls (p<0.05). In vitro mitogenicity assay on LNCaP cells treated with serum from xenografts demonstrated that a dose of 50 mg/kg bw metformin was significantly less mitogenic (7%; p<0.01). We are presently delineating the mechanisms of metformin's action on the progression of PCa during a hyperinsulinemic state. CONCLUSIONS We were able to demonstrate that metformin causes a significant reduction in body weight and tumor volume, partially by reduction in food consumption. A decrease in the levels of insulin by the use of metformin may have direct implications in PCa growth particularly in a metabolic. These results will eventually contribute to the rationale for evaluation of the anti-neoplastic activity of metformin in hyperinsulinemic prostate cancer patients. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e552-e553 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Min Hou Toronto, Canada More articles by this author Natalie Venier Toronto, Canada More articles by this author Linda Sugar Toronto, Canada More articles by this author Mireia Musquera Toronto, Canada More articles by this author Michael Pollak Montreal, Canada More articles by this author Neil Fleshner Toronto, Canada More articles by this author Laurence Klotz Toronto, Canada More articles by this author Vasundara Venkateswaran Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...