Abstract 5660: Galbanic acid downregulates androgen receptor and induces G1 arrest and apoptosis in LNCaP cells

Abstract

Abstract Studies have demonstrated that androgen receptor (AR) is crucial for the genesis and progression of human prostate cancer (PCa). Targeting AR signaling is an important approach for the prevention of PCa. Identification of novel herbal phytochemicals that target AR signaling from Oriental medicinal herbs holds the promise to deal with this malignant disease at the root. Ferula asafetida is used as a food spice and as a traditional herbal medicine for many illnesses in Asia, where the incidence of PCa is lower than that in USA. We report here, for the first time, that one of the main components of ferula asafetida, galbanic acid (GA) down-regulates AR and suppresses the growth of LNCaP cells via an induction of G1 arrest and apoptosis. After exposure to GA for 24h and 48h, GA dose-dependently decreased cellular AR level via posttranscriptional and posttranslational regulation in LNCaP cells. Consequently, GA dose-dependently reduced PSA protein expression and inhibited its AR-dependent promoter transactivation. Flow cytometric analysis showed that GA does-dependently induced G1 arrest accompanied by a decrease of CDK4, dephosphorylation of RB and inhibition of E2F1-dependent target gene products, but independent of p21 and p27. In addition, GA induced moderate apoptosis characterized by increased cleaved PARP, DNA fragmentation and annexinV staining as early as 6h after treatment. The induction of apoptosis was attenuated by a general caspase inhibitor (zVADfmk), supporting caspase-dependency. Furthermore, colony formation assay showed that GA suppressed the growth of LNCaP cells with an IC50 of approximate 7 microM. In contrast, GA did not affect the cell cycle distribution or apoptosis or growth of AR-independent DU 145 or PC-3 cells at the same doses of exposure. Taken together, these data suggests that GA exerts growth inhibitory effect against AR-dependent PCa with down-regulation of AR signaling and the induction of G1 arrest and apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5660.