Nakayama H, Sekine Y, Oka D, et al. - Findings showed that simvastatin alters the expression of many genes implicated in the cell cycle in castration-resistant prostate cancer (CRPC) cells. Therefore, CRPC growth can potentially be impacted by the combination of novel androgen receptor (AR) antagonists (darolutamide) and simvastatin, via both androgen-dependent and androgen-independent mechanisms.

• This study involved LNCaP, 22Rv1, and PC-3 human prostate cancer cell lines, and androgen-independent LNCaP cells (LNCaP-LA) were developed, to ultimately test a combination therapy of novel AR antagonists and statin, simvastatin, for CRPC.

• In LNCaP-LA and 22Rv1 cells, the observed suppression of proliferation was most significant with the combination of darolutamide and simvastatin.

• Decrease in mRNA expression of the androgen-stimulated genes, KLK2 and PSA, was induced by the combination of darolutamide and simvastatin in LNCaP-LA cells; such reduction in expression did not happen in 22Rv1 cells.

• As revealed by microarray data and pathway analyses, in the darolutamide and simvastatin-treated 22Rv1 cells, the number of differentially expressed genes was the highest in the pathway named “role of cell cycle.”

• The mRNA and protein expression of three genes [polo-like kinase 1 (PLK1), cyclin-dependent kinase 2 (CDK2), and cell cycle division 25C (CDC25C)] was suppressed by the combination of darolutamide and simvastatin, in 22Rv1 cells.

• Enhancement in the suppression of cell proliferation and expression of these genes was brought about by the combination of simvastatin and darolutamide, in PC-3 cells (which lack AR expression).