Effects of sorafenib on proliferation of hormone-sensitive and hormone-insensitive prostate cancer cells

Abstract

e16092 Background: Sorafenib is a multi-targeted kinase inhibitor approved for treatment of renal and hepatocellular cancer. In patients with castration therapy-resistant prostate cancer sorafenib treatment is associated with discordant prostate-specific antigen (PSA) and clinical responses, possibly due to an effect on PSA expression. The mechanisms of its action in advanced prostate tumors are not investigated so far. The aim of the present study was to evaluate the effects of sorafenib in androgen-sensitive (LNCaP) and -insensitive (PC 3) prostate cancer cell lines. Methods: Proliferation was evaluated by measurement of cell number and protein. Expression of cell cycle and apoptosis regulatory proteins of the Bcl-2 family was determined by Western blot. Results: Treatment of those cells by sorafenib for 48 hours resulted in a concentration-dependent inhibition of proliferation. Maximal inhibition was achieved with 25 μM of the compound. Cell number was reduced by 50% in both cell lines. We observed inhibition of expression of cyclin-dependent kinase 2 in LNCaP and PC3 cells. In addition, Mcl-1 protein, that is frequently overexpressed in prostate cancer, was down-regulated by sorafenib in both cellular models. Conclusions: Sorafenib caused inhibition of growth of prostate cancer cells regardless of their androgen sensitivity. Its inhibitory effects on cyclin- dependent kinase 2 and Mcl-1 imply that sorafenib regulates cell cycle progression and apoptosis in prostate cancer. On the basis of these results experiments with chemotherapy-resistant prostate cells are being performed. [Table: see text]