Abstract 1796: Novel triazole nucleoside inhibits heat shock factor 1 and androgen receptor to fight against prostate cancer

Abstract

Abstract Prostate cancer is one of the most commonly diagnosed cancers and leading cause of cancer-related mortality in men in developed countries. While most patients initially respond to first-line androgen deprivation therapy (ADT), many become refractory to hormonal and other conventional therapies and eventually develop castration-resistant prostate cancer (CRPC) with time. CRPC is often characterized by the reactivation of androgen receptor (AR) and constitutes the most important therapeutic target in CRPC. It is known that AR is bound to heat shock protein (HSPs) complex to maintain its stable and mature conformation with high affinity to androgen. Targeting HSPs are therefore to result in perturbation of AR. Using a lead optimization process, we have recently identified a novel triazole nucleoside VM-1 which can down-regulate heat shock transcription factor 1 (HSF1), the dominant upstream transcriptional regulator for HSPs. The down-regulation of HSF1 by VM-1 leads to the simultaneous suppression of multiple HSPs and results in growth inhibition of various prostate cancer cells. Interestingly, VM-1 displays more potent antiproliferation activity in AR-positive LNCaP, C4-2 and 22RV-1 cells than AR-negative PC-3 cells. Our further studies have showed that VM-1 reduces the expression of AR and a panel of AR targeted genes as well as inhibits AR transactivation, which consequently leads to effective caspase-dependent apoptosis in LNCaP, C4-2 and 22RV-1 cells. Moreover, VM-1 arrests cell cycle of prostate cancer cells in AR-governed phase suggesting the potential functionality of this compound involved in the crosstalk between AR and cell cycle pathways. Taken together, the above data suggest the role of HSF1 in regulation of AR, and the inhibition on both HSF1 and AR contribute to the activity of VM-1 in prostate cancer cells. Therefore, VM-1 may serve as a novel structural motif in the search of anticancer candidates to fight against prostate cancer via inhibiting HSF1 and AR. Citation Format: Yi Xia, Eliana Beraldi, Amina Zoubeidi, Ling Peng, Martin Gleave. Novel triazole nucleoside inhibits heat shock factor 1 and androgen receptor to fight against prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1796. doi:10.1158/1538-7445.AM2014-1796