PD59-08 COMBINATION THERAPY WITH NOVEL ANDROGEN RECEPTOR ANTAGONISTS AND STATIN FOR CASTRATION-RESISTANT PROSTATE CANCER

Abstract

INTRODUCTION AND OBJECTIVE: One of the growth mechanisms of castration-resistant prostate cancer is de novo androgen synthesis from intracellular cholesterol, and statins may be able to inhibit this mechanism. In addition, statins are reported to suppress the expression of androgen receptor (AR) in prostate cancer cell lines. In this study, we investigated whether the combination therapy with novel AR antagonists and statin (simvastatin) could inhibit castration-resistant prostate cancer cell growth. METHODS: Androgen independent 22Rv1 and androgen dependent LNCaP human prostate cancer cell lines were used. We have developed androgen-independent LNCaP cells (LNCaP-LA) by making a trade of FBS for charcoal stripped-FBS gradually. Microarray analyses were performed, followed by Ingenuity Pathway Analysis. mRNA and protein expressions were evaluated by quantitative real-time PCR and Western blot analysis, respectively. Cell viability was determined by MTS assay and cell counts. RESULTS: In LNCaP-LA cells, AR protein expression was suppressed by simvastatin in a dose dependent manner, but not in 22Rv1 cells, In comparison with enzalutamide and apalutamide, the combination with darolutamide and simvastatin significantly suppressed cell proliferation of both LNCaP-LA and 22Rv1 cells compared with treatment with either drug alone. The same applied to mouse xenograft model in 22Rv1 cells. In LNCaP-LA cells, the combination with darolutamide and simvastatin decreased both mRNA and proteinexpressions of KLK2, KLK3 and TMPRSS2, which are regulated by androgen, compared with treatment with either drug alone, but not in 22Rv1 cells. Microarray data and Ingenuity Pathway Analysis under combination therapy with darolutamide and simvastatin compared with simvastatin alonein 22Rv1 cells showed that the number of differentially expressed genes was the biggest in the pathway of “Role of cell cycle”. We focused on Polo-like Kinase 1 (PLK1), cyclin-dependent kinase 1 (CDK1) and CDC25C, which are listed in the pathway. The combination of darolutamide and simvastatin further decreased mRNA and protein expressions of PLK1, CDK1 and CDC25C compared with treatment with either drug alone. CONCLUSIONS: Simvastatin alters the expressions of many genes concerned with cell cycle in castration-resistant prostate cancer cells. The combination of novel AR antagonists and simvastatin can potentially affect castration-resistant prostate cancer growth in both androgen dependent and independent mechanisms.