Inhibition of cell cycle progression via p27^Kip1 upregulation and apoptosis induction by an ethanol extract of Rhus verniciflua Stokes in AGS gastric cancer cells

Botanical preparations are widely used by patient with cancer in Korea, Japan and China. Rhus verniciflua Stokes (RVS) has traditionally been used as a medicinal ingredient for the therapy of stomach and uterine cancer. In this study, we showed that exposure to an ethanol extract of RVS (50 μg/ml) resulted in a synergistic inhibitory effect on cell growth in AGS cells. Growth inhibition was related with the inhibition of proliferation and induction of apoptosis. The extract induces G₁-cell cycle arrest through the regulation of cyclins, the induction of p27^Kip1, and decrease the CDK2 kinase activity. The upregulated p27^Kip1 level is caused by protein stability increment by the reduction of Skp2, a key molecule related with p27^Kip1 ubiquitination and degradation, and de novo protein synthesis. RVS extract induces apoptosis through the expression of Bax, poly(ADP-ribose) polymerase (PARP) and activation of caspase-3. RVS extract induces G₁-cell cycle arrest via accumulation of p27^Kip1 controlled by Skp2 reduction and apoptosis passing through an intrinsic pathway in human gastric cancer cells but not in normal cells, therefore we suggest that this extract could be a candidate medicine or compound for the development of novel class of anti-cancer drugs.