MP64-08 A NOVEL BIGUANIDE DERIVATIVE DRUG, IM176, INHIBITS PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2018MP64-08 A NOVEL BIGUANIDE DERIVATIVE DRUG, IM176, INHIBITS PROSTATE CANCER Choung-Soo KIM, Wonseok Choi, YOONRIM KIM, and Bong-Min Kim Choung-Soo KIMChoung-Soo KIM More articles by this author , Wonseok ChoiWonseok Choi More articles by this author , YOONRIM KIMYOONRIM KIM More articles by this author , and Bong-Min KimBong-Min Kim More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2018.02.2053AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Biguanides were originally developed for the treatment of hyperglycemia and type 2 diabetes mellitus. Recently, the biguanides metformin and phenformin have been shown to exert potential anticancer effects in prostate cancer. We evaluated the anti-cancer efficacy and mechanism of IM176, a novel biguanide derivate drug on prostate cancer using prostate cancer cell lines and patient-derived castration-resistant prostate cancer cell lines. METHODS Cell viability assay, annexin V-FITC apoptosis detection, microscopy with immunofluorescence staining, real-time quantitative reverse transcription-polymerase chain reaction, and western blotting were conducted. Efficacy of IM176 was also evaluated using 2 cell lines derived from castration-resistant prostate cancer patient. RESULTS IM176 dose-dependently inhibited cell viability in all prostate cancer cell lines at lowest IC50 concentrations (LNCaP: 18.5μM, 22Rv1: 36.8 μM) compared to those of metformin, and phenformin. IM176-mediated AMPK activation caused mTOR inhibition, and a decrement in the phosphorylation of p70S6K1 and S6. IM176 inhibited the expression of AR, AR-splice variant 7 (AR-V7) and prostate-specific antigen in LNCaP and 22Rv1. IM176 induced apoptosis with increased levels of cleavage of caspase-3, and annexin V-positive / PI-positive, respectively. Moreover, IM176 inhibited cell viability at lowest IC50 concentrations in 2 cell lines derived from castration-resistant prostate cancer patient. We evaluate the relationship between AMPK-mTOR pathway and AR signaling pathway by blocking each pathway separately. After AR knockdown, phosphorylation of AMPK was significantly increased. However, AR and AR-V7 were not increased after treating AMPK inhibitor, Compound C. CONCLUSIONS IM176 showed comparable anti-tumor effects via AMPK-mTOR pathway and AR signaling pathway with the lowest IC50 compared to other biguanide derivative drugs in prostate cancer cell lines, including patient-derived castration resistant prostate cancer cell line and may be a novel anti-cancer drug for the treatment of prostate cancer. © 2018FiguresReferencesRelatedDetails Volume 199Issue 4SApril 2018Page: e853 Advertisement Copyright & Permissions© 2018MetricsAuthor Information Choung-Soo KIM More articles by this author Wonseok Choi More articles by this author YOONRIM KIM More articles by this author Bong-Min Kim More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...