The Antiproliferative Effects And The Mechanisms Of Action Of 1,3-Diarylpropanes In Human Hepatoma And Leukemia Cells In Vitro

1,3-Diarylpropanes are a set of natural products present in many plants, and some of which exhibit anti-cancer activity. In the present study, a series of 1,3-diarylpropanes were synthesized and evaluated for their antiproliferative activities. The results showed that 1-(3’,4’,5’-trimethoxyphenyl)-3-(3",4"-dimethoxy-2"-hydroxyphenyl)-propane (DP) displayed high antiproliferative activities against the human hepatoma and leukemia cells, and therefore, was chosen to explore the mechanisms of action of 1,3-diarylpropanes in human hepatoma and leukemia cells in vitro.The growth inhibitory effects of DP in HepG2 cells and BEL7402 cells were 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. Western blot analyses indicated that DP did not influence the levels of cyclin B1 and Cdkl proteins in HepG2 cells. DP-treated cells finally underwent caspase-dependent apoptosis following G2/M phase arrest. DP increased the levels of death receptor 4 (DR4), death receptor 5 (DR5) in HepG2 cells. DP also increased the levels of 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, 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 in HepG2 cells. 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.In HL60 cells, G2/M phase arrest was invloled in the growth inhibitory effects of DP and associated with the microtubule-depolymerizition and the upregulation of cyclin B1 and Cdkl proteins. DP induced apoptosis in HL60 cells through the similar mechanisms with HepG2 cells; however, DP decreased the levels of survivin proteins and did not influence the levels of DR4 and DR5 proteins. These results suggest that DP induces ROS-mediated but not death receptor-mediated apoptosis in HL60 cells.In conclusion, DP produces the growth inhibitory effects in the different tumor cell lines through induction of G2/M phase arrest and apoptosis. The effect of the microtubule-depolymerizition explains G2/M phase arrest induced by DP, and the different apoptosis signalings are then activated to induce cell apoptosis.