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MP55-13 TRIPTOLIDE INHIBIT CASTRATE RESISTANT AND ENZALUTAMIDE RESISTANT PROSTATE CANCER GROWTH BY DECREASING ANDROGEN RECEPTOR FULL LENGTH AND SPLICE VARIANTS EXPRESSION
Abstract   Peer reviewed

MP55-13 TRIPTOLIDE INHIBIT CASTRATE RESISTANT AND ENZALUTAMIDE RESISTANT PROSTATE CANCER GROWTH BY DECREASING ANDROGEN RECEPTOR FULL LENGTH AND SPLICE VARIANTS EXPRESSION

Sumit Isharwal, Shrey Modi, Usman Barlass, Rohit Chugh, Sulagna Banerjee, Vikas Dudeja, Ashok Saluja and Badrinath Konety
The Journal of urology, Vol.193(4S), pp.e677-e678
04/2015
DOI: 10.1016/j.juro.2015.02.2056

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Abstract

INTRODUCTION AND OBJECTIVES Recent studies have linked androgen receptor splice variant (AR-V7), which is encoded by contiguous splicing of AR exons 1/2/3/CE3, to the development of enzalutamide resistance. Therefore developing novel chemotherapeutic agents for enzalutamide resistant and castrate resistant prostate cancer (CRPC) treatment is critical to improve survival in men with CRPC. Hence, we assessed therapeutic potential of a novel chemotherapeutic agent “Triptolide” on androgen dependent, CRPC and enzalutamide resistant CRPC in vitro and in vivo. Further, we explored the mechanism by which triptolide induces prostate cancer cell death. METHODS Androgen dependent (LNCaP), CRPC (C4-2) and enzalutamide resistant CRPC (22RV1) tumor cells were treated with triptolide with subsequent viability measured using colorimetric assays. Active Caspase-3 and cleaved PARP (Aso 214) positive cells were measured by flow cytometry. Real time polymerase chain reaction (qPCR) and Western blots were used to determine expression of AR full length and AR splice variants at mRNA and protein levels respectively. In vivo models were generated by subcutaneously injecting enzalutamide resistant CRPC (22RV1) cells into mice. The animals received daily intraperitoneal injection of Minnelide™ (a Triptolide prodrug) and tumor volume was measured weekly until tumor size reached 2cm3. RESULTS Triptolide treatment resulted in dose- and time-dependent cell death via apoptosis (assessed by caspase-3 activation and PARP cleavage) in androgen dependent, CRPC and enzalutamide resistant CRPC tumor cells. Triptolide treatment decreased AR full length, AR splice variants and its downstream targets (PSA, NKX3.1) expression at the mRNA and protein levels. Mice receiving daily injection of Minnelide (Triptolide prodrug) had significantly smaller tumors than controls as early as two week of treatment (p=0.008). CONCLUSIONS Triptolide therapy inhibited enzalutamide resistant CRPC growth both in vitro and in vivo. Further, our studies for the first time showed that triptolide induces prostate tumor cell death by reducing AR full length and AR splice variants expression.

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