MP73-08 METFORMIN DRIVES SYNERGISTIC EFFECT AND OVERCOMES THE TREATMENT RESISTANCE OF MOLECULAR TARGETED DRUGS FOR RENAL CELL CARCINOMA

Field: Medicine (Health Sciences)

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2017MP73-08 METFORMIN DRIVES SYNERGISTIC EFFECT AND OVERCOMES THE TREATMENT RESISTANCE OF MOLECULAR TARGETED DRUGS FOR RENAL CELL CARCINOMA Hiroaki Matsumoto, Juiichi Mori, Kosuke Shimizu, Nakanori Fujii, Yoshihisa Kawai, Ryo Inoue, Yoshiaki Yamamoto, Hiroshi Hirata, Tomoaki Shimabukuro, and Hideyasu Matsuyama Hiroaki MatsumotoHiroaki Matsumoto More articles by this author , Juiichi MoriJuiichi Mori More articles by this author , Kosuke ShimizuKosuke Shimizu More articles by this author , Nakanori FujiiNakanori Fujii More articles by this author , Yoshihisa KawaiYoshihisa Kawai More articles by this author , Ryo InoueRyo Inoue More articles by this author , Yoshiaki YamamotoYoshiaki Yamamoto More articles by this author , Hiroshi HirataHiroshi Hirata More articles by this author , Tomoaki ShimabukuroTomoaki Shimabukuro More articles by this author , and Hideyasu MatsuyamaHideyasu Matsuyama More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3353AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Molecular targeted drugs have shown clinical benefit and improvement of their QOL for patients with advanced renal cell carcinoma. However, conquest of primary or acquired drug resistance is urgent problem in clinical practice. The previous reports have shown that Metformin is promising treatment approach for several cancers by regulating AMPK-mTOR pathway. In this study, we assessed whether combination of Metformin synergized molecular targeted drugs and repressed the progression of renal cancer model. METHODS We tested synergy effect of Metformin combined with molecular targeted drugs, Everolimus and Axitinib. We assessed cell proliferation and apoptosis by WST-1 assay or a crystal violet assay and flow cytometry. We examined the gene expression profile of parental and molecular targeted drug resistant cells by microarray analysis. And protein expression of the AMPK-mTOR pathway by Western blot. The effects of combination treatment on A498 tumor growth was assessed in orthotropic renal cell carcinoma model. RESULTS Combination of Metformin + Axitinib showed synergistic effect and more potently suppressed A498 cell growth rates in a dose and time dependent manner compared to Metformin or Axitinib monotherapy. Apoptosis detected by flow cytometry with Annexin V was most enhanced with combination treatment. We compared gene expression profile between parental and Axitinib resistant cell line, several pathways enhanced to survive from cellar stress. Metformin induced AMPK expression and suppressed Akt and mTOR expression in Axitinib treatment. In vivo, combination of Metformin + Axitinib therapy significantly repressed tumor growth compared with their mono therapy. In addition, micro vessel density and VEGF immunostaining were significantly reduced in tumor tissue of combination treatment. CONCLUSIONS Metformin showed synergistic effect for renal cell carcinoma growth combined with Axitinib in vitro and in vivo. Combination treatment of Metformin + Axitinib is providing pre-clinical proof-of-principle as a promising approach against drug resistance for renal cell carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e966 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hiroaki Matsumoto More articles by this author Juiichi Mori More articles by this author Kosuke Shimizu More articles by this author Nakanori Fujii More articles by this author Yoshihisa Kawai More articles by this author Ryo Inoue More articles by this author Yoshiaki Yamamoto More articles by this author Hiroshi Hirata More articles by this author Tomoaki Shimabukuro More articles by this author Hideyasu Matsuyama More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...