737 UTILIZING METFORMIN AS A RADIOSENSITIZING AGENT IN THE TREATMENT OF PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research1 Apr 2011737 UTILIZING METFORMIN AS A RADIOSENSITIZING AGENT IN THE TREATMENT OF PROSTATE CANCER Alexandra Colquhoun, Natalie Venier, Avi Vandersluis, Neil Fleshner, Michael Pollak, Laurence Klotz, and Vasundara Venkateswaran Alexandra ColquhounAlexandra Colquhoun Toronto, Canada More articles by this author , Natalie VenierNatalie Venier Toronto, Canada More articles by this author , Avi VandersluisAvi Vandersluis Toronto, Canada More articles by this author , Neil FleshnerNeil Fleshner Toronto, Canada More articles by this author , Michael PollakMichael Pollak Montreal, 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.2011.02.1706AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES External beam radiation therapy (EBRT) is a well recognised curative treatment modality for prostate cancer (PCa) which utilizes ionizing radiation (IR). In addition to mediating DNA damage IR upregulates several intracellular pro-survival pathways, designed to minimize the insult of radiation. Such pathways, which include the insulin-like growth factor (IGR) signaling network, are felt to contribute to the intrinsic radioresistance exhibited by certain tumors. Diabetic patients with PCa experience poorer outcomes following EBRT than their non-diabetic counterparts. Some attribute this to diabetes-induced chronic hyperinsulinemia, causing upregulation of pro-survival insulin/IGF signaling. Indeed previous work by our group showed diet-induced hyperinsulinemia to enhance PCa tumour growth in vivo. Metformin, a treatment for diabetes, alleviates hyperinsulinemia, and has recently been shown to exhibit anti-neoplastic properties. We postulate that pre-treating PCa cells with metformin may protect them from radiation-mediated pro-survival insulin/IGF signaling. Thus we assessed the radiosensitizing potential of metformin using both in vitro and in vivo PCa models. METHODS Using clonogenic assays we assessed the effect of IR and/or metformin on colony formation rates in LNCaP, PC3, DU145 and PC3AR2 PCa cell lines. The combination treatment regimen was also assessed in vivo using a LNCaP murine xenograft model. Western blot and cell cycle analyses are ongoing to try and elucidate a mechanism of potential interaction between metformin and IR in both androgen receptor (AR) positive (LNCaP) and AR negative (PC3) PCa cells. RESULTS Monotherapy with IR (1–8 Gy) or metformin (0.01–10.0 mM) caused significant dose-dependent reduction in colony formation rates (p<0.001). Combination treatment further significantly reduced colony formation rates (p<0.03). This effect was more marked in AR positive cell lines. Preliminary results from our in vivo study show significantly diminished tumor growth in response to the combination treatment regimen (p<0.0001). CONCLUSIONS Our in vitro findings confirm combining metformin with IR significantly reduces PCa cell colony formation rates further than either monotherapy. If further statistical analyses fully recapitulate these results in vivo justification will exist to translate this work into a phase II clinical trial of metformin as a radiosensitizing agent. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e296 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexandra Colquhoun Toronto, Canada More articles by this author Natalie Venier Toronto, Canada More articles by this author Avi Vandersluis Toronto, Canada More articles by this author Neil Fleshner Toronto, Canada More articles by this author Michael Pollak Montreal, 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 ...