Abstract 3922: 20(S)-protopanaxadiol-aglycone inhibition of the development and growth of castration-resistant prostate cancer

Abstract

Abstract Recurrence with lethal castration-resistant prostate cancer after androgen deprivation therapy remains the major challenge in treatment of advanced prostate cancer. The main mechanism for the development of castration resistance is continuous androgen receptor signaling via promiscuous or hypersensitive androgen receptor, ligand-independent androgen receptor activation, expression of androgen receptor splice variants lacking the ligand-binding domain but remaining constitutively active, and/or de novo androgen synthesis in the prostate. Several new drugs targeting androgen receptor reactivation, such as abiraterone acetate, are showing benefit in prolonging survival in patients with castration-resistant prostate cancer. However, even this potent inhibitor of androgen synthesis has a relatively short time to disease progression. One potential mechanism is the prevalent upregulation of constitutively active, ligand-binding-domain-truncated androgen receptor splice variants in castration-resistant prostate cancer. Therefore, therapeutic approaches that can diminish the availability of both the full-length and the splice variants of androgen receptor should offer considerable benefit in preventing and inhibiting prostate cancer recurrence after androgen deprivation therapy. In the present study, we show that ginsenoside 20(S)-protopanaxadiol-aglycone (PPD), a steroidal saponin from ginseng, effectively downregulates the abundance and activity of both the full-length and the splice variants of androgen receptor. The effect is manifested by an immediate drop in androgen receptor proteins, followed by a reduction in androgen receptor mRNAs. The initial decrease in androgen receptor proteins could be attributed to PPD induction of proteasome-mediated degradation, possibly as a result of disrupted androgen receptor N-C interaction. Our xenograft studies show that PPD inhibits not only the development of castration-resistant prostate cancer after androgen deprivation but also the growth of prostate tumors that are already castration resistant. The inhibition is accompanied by a pronounced decrease of tumor androgen receptor and serum prostate-specific antigen levels. Our findings therefore provide strong justification and lay the groundwork for an effective treatment modality to improve the therapeutic outcome of androgen deprivation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3922. doi:1538-7445.AM2012-3922