969 PI3K/AKT DUAL INHIBITOR RESTORES DOCETAXEL SENSITIVITY IN CASTRATION RESISTANT PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research V1 Apr 2012969 PI3K/AKT DUAL INHIBITOR RESTORES DOCETAXEL SENSITIVITY IN CASTRATION RESISTANT PROSTATE CANCER Yota Yasumizu, Akira Miyajima, Takeo Kosaka, 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 , Suguru ShirotakeSuguru Shirotake Tokyo, 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.2012.02.1068AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The specific aim of this study was to establish a new treatment strategy for docetaxel resistant CRPC, with a special focus on dual regulation of the phosphoinositide3-kinase (PI3K) and Akt signaling pathways. METHODS The efficacy of PI3K/Akt signaling pathway inhibition by the PI3K/Akt dual inhibitor BEZ235 in combination with docetaxel was examined in C4-2 and 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 lasting for 6 months. RESULTS We compared the cytotoxic effect of docetaxel on C4-2 and C4-2AT6 cells. The cytotoxic response was measured by WST assay. In C4-2 cells and C4-2AT6 cells, the mean cell viability at 24 h of treatment with 2nM docetaxel was 43.0% ± 5.2 % and 69.8% ± 6.3 %, respectively. These results indicated that C4-2AT6 cells showed significantly higher resistance to docetaxel than C4-2 cells. We investigated the expression of phosphorylation of Akt (pAkt) in C4-2 and C4-2AT6 cells by Western blotting and immunohistochemistry. C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, suggesting the possibility of a treatment strategy targeting PI3K/Akt. In C4-2AT6 cells WST assay showed that cell viability was 44.8 ± 4.2 % with 10nM BEZ235 and 20.9 ± 3.9 % with combined 2nM docetaxel and 10nM BEZ235. Combine administration of BEZ235 and docetaxel showed significantly higher cytotoxicity in C4-2AT6 than monotherapy with either BEZ235 or docetaxel alone (p<0.01). Combination index was 0.31, suggesting the synergic effect of this combination therapy. Western blotting showed 50nM BEZ235 inhibited the expression of pAKT in a time-dependent manner. In vivo, we assigned castrated male nude mice to 4 groups; control, BEZ235 monotherapy (40mg/kg/day), docetaxel monotherapy (4mg/kg), and BEZ235 combined with docetaxel. We examined the time course changes in C4-2AT6 tumor growth with BEZ235 and docetaxel. In the control group tumor size grew up to 298% on day 15, compared with day 1. In contrast, the ratio of tumor size on day 15 to day 0 was 103% and 140% in the BEZ235 and docetaxel monotherapy groups, respectively. In the combination group, tumor volume was significantly decreased to 43.9% (p<0.01). These results indicate that the combination of BEZ235 and docetaxel has a significant antitumor effect in C4-2AT6 in vivo, as well as in vitro. CONCLUSIONS The combination of BEZ235 and docetaxel showed significant anti-tumor effects in CRPC, suggesting that PI3K/Akt dual inhibitor may be a promising modality for docetaxel resistant CRPC. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e394-e395 Advertisement Copyright & Permissions© 2012 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 Suguru Shirotake Tokyo, 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 ...