Anti-cancer effects of statins on castration- and chemotherapy- resistant prostate cancer cells

Abstract

In recent years, several clinical evidences have demonstrated that statin use improves the outcome of PCa. While various investigations suggested a potential preventive and therapeutic role for statins in PCa, limited evidence exists regarding their activity in aggressive PCa characterized by diverse therapy resistances. Furthermore, statins offer a therapeutic advantage of the confirmed safety and acceptable expenses by extensive clinical use in the general population over decades.

In order to evaluate the therapeutic potential of statins in CRPC, we investigated the efficacy and mechanisms of various statins in the androgen-insensitive PCa cell lines (PC3 and DU145) and their docetaxel-resistant sublines (PC3-DR and DU145-DR) mimicking castration-resistant and chemotherapy-resistant PCa. We observed that lipophilic statins (atorvastatin and simvastatin) effectively inhibited cell proliferation and migration in both castration- and chemotherapy- resistant PCa cells, which exhibit comparable drug sensitivity to statins. They also induced apoptosis and blocked cell cycle by arresting G1 phase through upregulating proteins p21 and downregulating Cyclin D1 and CDK1/CDK2 causing cell growth arrest. Statins strongly dephosphorylated AKT, which is able to promote apoptosis by inhibition of antiapoptotic proteins (Mcl-1L and p-GSK-3β) and upregulation of proapoptotic proteins (Mcl-1S). The most significant effects were consistently elicited by simvastatin in both androgen-insensitive and docetaxel-resistant sublines, while the docetaxel-resistant cells exhibited heightened sensitivity to simvastatin compared to the parental cells.

Our study provides evidence for the substantial anti-cancer potential of lipophilic statins in therapy-resistant PCa. Furthermore, it elucidates a remarkable amplification in treatment response of docetaxel-resistant cells, with a notable emphasis on the efficacy of simvastatin. Given the outcomes of our investigations, coupled with the economic advantages and established safety profile of these drugs, the adjunctive use of lipophilic statins for patients with CRPC should be carefully considered during hormone and chemotherapy interventions.