1-(3′,4′,5′-Trimethoxyphenyl)-3-(3″,4″-dimethoxy-2″-hydroxyphenyl)-propane with microtubule-depolymerizing ability induces G2/M phase arrest and apoptosis in HepG2 cells

Abstract

1-(3′,4′,5′-Trimethoxyphenyl)-3-(3″,4″-dimethoxy-2″-hydroxyphenyl)-propane (DP), a novel synthesized 1,3-diarylpropanes compound, showed growth inhibitory effect on human hepatoma HepG2 cells in a concentration-dependent manner. The growth inhibitory effect of DP on HepG2 cells was associated with microtubule depolymerization, G2/M phase arrest and apoptosis induction. The G2/M phase arrest induced by DP resulted from its microtubule-depolymerizing ability, and DP-treated HepG2 cells finally underwent caspase-dependent apoptosis. DP increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) and pro-apoptotic protein Bax, but decreased the levels of anti-apoptotic protein Bcl-2. Meanwhile, the decrease in the mitochondrial membrane potential (MMP) and the release of cytochrome c from mitochondria were observed in DP-treated HepG2 cells. DP increased the levels of reactive oxygen species (ROS) in HepG2 cells, and antioxidant N-acetylcysteine (NAC) completely blocked DP-induced ROS accumulation and the disruption of the balance between Bax and Bcl-2 proteins, and effectively blocked the decreased MMP and apoptosis, but had no effect on the activation of caspase-8 and the up-regulations of DR4 and DR5 induced by DP. These results suggest that DP induces G2/M phase arrest through interruption of microtubule network followed by the death receptor- and ROS-mediated apoptosis in HepG2 cells.