PD32-02 NOVEL PI3K/P110BETA-SPECIFIC INHIBITORS ELIMINATE ENZALUTAMIDE RESISTANCE IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) III1 Apr 2016PD32-02 NOVEL PI3K/P110BETA-SPECIFIC INHIBITORS ELIMINATE ENZALUTAMIDE RESISTANCE IN PROSTATE CANCER Marcus Austenfeld, Chenchen He, Yifen Wang, Qingting Hu, Brantley Thrasher, and Benyi Li Marcus AustenfeldMarcus Austenfeld More articles by this author , Chenchen HeChenchen He More articles by this author , Yifen WangYifen Wang More articles by this author , Qingting HuQingting Hu More articles by this author , Brantley ThrasherBrantley Thrasher More articles by this author , and Benyi LiBenyi Li More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2016.02.678AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We and others have demonstrated that the class IA PI3K isoform p110beta is critical in prostate cancer development and progression, indicating p110beta as a bona fide target for prostate cancer therapy. Our recent work consistently shows that prostate cancer cell-specific delivery of nano-micellar TGX221 completely blocked prostate cancer growth in vivo, suggesting that TGX221-based therapy is feasible for further development. Unfortunately, the small chemical TGX221 is not soluble in water, hampering its clinical development. To solve this problem, we recently synthesized a panel of TGX221 analogs with increased water solubility. In this study, we tested these novel inhibitors (TGX221 analogs) in multiple enzalutamide-resistant prostate cancer cell lines for their activity in androgen receptor (AR) signaling and cancer cell growth. METHODS Prostate cancer cell lines 22RV1, VCaP and C4-2 were utilized. AR transactivation was evaluated with the ARE-LUC luciferase reporter assay and PSA mRNA level was assessed with real-time RT-PCR. Cancer cell growth was assessed with NCI-approved Sulforhodamine B-based assay. PI3K activation, AR protein levels and cell apoptosis were evaluated in Western blot assays. RESULTS Our novel TGX221 analogs, shown in Figure 1 with water solubility, are much more water soluble (47-99 mM in water) than TGX221, which can only be dissolved in organic solution. Most importantly, these analogs retained a similar inhibitory effect as TGX221 on cell proliferation, AR transactivation and PI3K/AKT activation in prostate cancer cells. Addition of our TGX221 analogs significantly enhanced the enzalutamide-induced anti-cancer effect in LNCaP and LAPC4 cells already sensitive to enzalutamide treatment, as evaluated by cell proliferation and AR transactivation assays. Moreover, these novel TGX221 analogs also sensitized resistant 22RV1 cells to enzalutamide treatment with increased apoptotic cell death. CONCLUSIONS These data strongly suggest that our novel TGX221 analogs possess great potential to be developed as feasible anti-cancer agents for castration-resistant prostate cancers. © 2016FiguresReferencesRelatedDetails Volume 195Issue 4SApril 2016Page: e761 Advertisement Copyright & Permissions© 2016MetricsAuthor Information Marcus Austenfeld More articles by this author Chenchen He More articles by this author Yifen Wang More articles by this author Qingting Hu More articles by this author Brantley Thrasher More articles by this author Benyi Li More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...