Effects of probucol on cell proliferation in human ovarian cancer cells

Probucol is considered to be an important agent in promoting anti-oxidative action and protecting against tissue injury. However, little is known about the effects of probucol on the progression of ovarian carcinoma. The aim of this study was to investigate the effects of probucol on cellular proliferation in human ovarian cancer cells (PA-1 and SKOV-3) and explore the anti-proliferative mechanism of probucol in these cells. We found that probucol decreased cell growth in PA-1 and SKOV-3 cells in a dose-dependent manner. Treatment with probucol had no effect on cytotoxicity, the percentages of Annexin V-FITC positive cells and caspase-3 activity when compared with the vehicle group. No significant differences in the protein expression of Bcl-2 and cytochrome c were observed, both of which were markers of cells undergoing apoptosis. The inhibition of cellular proliferation by probucol was caused by G1-phase arrest through regulating proteins associated with cell cycle progression, such as cyclin D1, p21^Waf1/Cip1, and p27^Kip1. A further study revealed that probucol strongly impaired the phosphorylation of IκBα and the nuclear translocation of NF-κB (p65). It also suppressed the activation of ERK/JNK/p38 MAPK signaling. Moreover, the NF-κB inhibitor (PDTC), the ERK inhibitor (PD98059), the JNK inhibitor (SP600125), and the p38 MAPK inhibitor (SB203580) markedly attenuated the growth of these cells. Our results indicate that probucol induces anti-proliferative effects via blocking of cell cycle progression and inactivation of NF-κB and MAPK pathways in human ovarian cancer cells.