Abstract B16: Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells

Abstract

Abstract Globally prostate cancer is the sixth leading cause of cancer-related death in men, and it is now the first in the United Kingdom and second in the United States. At the early stage, prostate cancer growth and progression depend on androgen receptor (AR) signaling. Therefore, androgen-deprivation therapy (ADT) is effective to patient with prostate cancer by inhibition of androgen synthesis. With time, however, most patients with prostate cancer eventually lose sensitivity to androgen withdrawal and progress to the development of castration-resistant prostate cancer (CRPC). Though docetaxel is a standard of care therapy in CRPC, most of patients develop resistance to this therapy. Therefore, the novel therapeutic strategies and combination therapy are needed to overcome this resistance. In this study, we examined whether histone deacetylase inhibitor (HDACI), suberoylanilide hydroxamic acid (SAHA) might enhance the effect of docetaxel in CRPC. Hormone-independent 22Rv1 cells harboring AR were treated with docetaxel and/or SAHA. Co-treatment of docetaxel and SAHA inhibited the growth of 22Rv1 cells synergistically. Combination treatment decreased the levels of AR, prostate specific antigen (PSA), and anti-apoptotic Bcl-2 proteins (Mcl-1, Bcl-xl) more efficiently compared with docetaxel or SAHA alone, when it analyzed by Western blot. And combination treatment increased activation of caspase-3 remarkably, while docetaxel or SAHA alone increased it slightly. Moreover, immunocytochemistry and analysis of nuclear fractionated proteins showed that combination treatment induced acetylation and bundling of tubulin, inhibiting nuclear accumulation of AR significantly. These results suggested that docetaxel in combination with SAHA inhibited cell growth efficiently and induced apoptosis by repressing expression and translocation to nucleus of AR in 22Rv1 cells, and this combination can be a useful therapeutics for the treatment of CRPC patients. Citation Format: Ha-Gyeong Kim, Jung Jin Hwang, Choung-Soo Kim. Combination of docetaxel with histone deacetylase inhibitor inhibits AR signaling synergistically in hormone-independent 22Rv1 prostate cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr B16.