973 A NEW STRATEGY FOR CASTRATION RESISTANT PROSTATE CANCER WITH TARGETING TO FEEDBACK MECHANISM OF PI3K/AKT/MTOR PATHWAY

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research (V)1 Apr 2013973 A NEW STRATEGY FOR CASTRATION RESISTANT PROSTATE CANCER WITH TARGETING TO FEEDBACK MECHANISM OF PI3K/AKT/MTOR PATHWAY Yota Yasumizu, Akira Miyajima, Takeo Kosaka, Yasumasa Miyazaki, Suguru Shirotake, Eiji Kikuchi, and Mototsugu Oya Yota YasumizuYota Yasumizu Tokyo, Japan More articles by this author , Akira MiyajimaAkira Miyajima Tokyo, Japan More articles by this author , Takeo KosakaTakeo Kosaka Tokyo, Japan More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki Tokyo, Japan More articles by this author , Suguru ShirotakeSuguru Shirotake Saitama, Japan More articles by this author , Eiji KikuchiEiji Kikuchi Tokyo, Japan More articles by this author , and Mototsugu OyaMototsugu Oya Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.555AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The clinical trials of mTORC1 inhibiton in CRPC have failed to demonstarate anti-tumor effect despite the deficit of PTEN observed in about 70% of castration resistant prostate cancer (CRPC) with metastasis. The up-regulation of phosphorylated Akt (pAkt) through mTORC2 is reported as one factor of mTORC1 inhibitor resistance. In this study we aimed to establish a new strategy for docetaxel resistant CRPC, with a focus on regulatory system in PI3K/Akt/mTOR signaling pathway. METHODS The efficacy of PI3K/Akt/mTOR signaling pathway inhibition by the mTORC1 inhibitor: RAD001 and the PI3K and mTORC1/2 dual inhibitor: NVP-BEZ235 was examined in C4-2AT6 cells in vivo and in vitro. C4-2AT6 cells are a new CRPC cell line established by our laboratory under androgen ablation conditions and shows docetaxel resistance. RESULTS To examine the inhibitory effect of NVP-BEZ235 or RAD001, we performed the western blotting using C4-2AT6 cells. The expression of pAkt and phosphorylated S6 ribosomal protein (pS6) were significantly inhibited by 50nM NVP-BEZ235. On the other hand, the expression of pAKT was not inhibited by the treatment with RAD001, although the expression of pS6 was inhibited by 10nM RAD001. Next we tested the effect of NVP-BEZ235 or RAD001 to C4-2AT6 cells by WST assay. The mean cell viability at 24 h of treatment with 50nM NVP-BEZ235 and 10nM RAD001 was 59.2&undefined;} 6.4% and 61.2&undefined;} 7.2%, respectively. There was no significant difference between the two cell viability. The cell viability with 50nM NVP-BEZ235 and 5nM docetaxel was 41.2&undefined;} 5.2% and the cell viability with 10nM RAD001 and 5nM docetaxel was 50.1&undefined;} 4.8%. The combination of NVP-BEZ235 and docetaxel showed significantly higher anti-tumor effect than the combination of RAD001 and docetaxel (p<0.05). In vivo, we assigned castrated male nude mice to 4 groups; control, NVP-BEZ235 (12.5mg/kg/day), docetaxel (2mg/kg), and NVP-BEZ235 combined with docetaxel. We examined the time course changes in C4-2AT6 tumor growth with NVP-BEZ235 and docetaxel. The tumor volume of NVP-BEZ235 at day15 was 89.8&undefined;} 9.8%, and the tumor volume of docetaxel was 81.2&undefined;} 6.4%, compared to the control group. While the tumor volume of combined treatment was 6.1&undefined;} 5.5% of control. The combination therapy exhibited marked suppression of tumor growth compared to control, NVP-BEZ235 monotherapy, or docetaxel monotherapy (p<0.05). CONCLUSIONS The combination of NVP-BEZ235 and docetaxel showed significant anti-tumor effects in CRPC, suggesting the efficacy of PI3K/mTORC1/2 dual inhibitor for regulation of PI3K/Akt/mTOR pathway in CRPC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e400 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yota Yasumizu Tokyo, Japan More articles by this author Akira Miyajima Tokyo, Japan More articles by this author Takeo Kosaka Tokyo, Japan More articles by this author Yasumasa Miyazaki Tokyo, Japan More articles by this author Suguru Shirotake Saitama, Japan More articles by this author Eiji Kikuchi Tokyo, Japan More articles by this author Mototsugu Oya Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...