Triptolide and chemotherapy cooperate in tumor cell apoptosis - A role forthe p53 pathway

Triptolide (PG490), a diterpene triepoxide, is a potent immunosuppressive a gent extracted from the Chinese herb Tripterygium wilfordii. We have previo usly shown that triptolide blocks NF-kappaB activation and sensitizes tumor necrosis factor (TNF-alpha)-resistant tumor cell lines to TNF-alpha -induc ed apoptosis. We show here that triptolide enhances chemotherapy-induced ap optosis. In triptolide-treated cells, the expression of p53 increased but t he transcriptional function of p53 was inhibited, and we observed a down-re gulation of p21(waf1/cip1), a p53-responsive gene. The increase in levels o f the p53 protein was mediated by enhanced translation of the p53 protein. Additionally, triptolide induced accumulation of cells in S phase and block ed doxorubicin-mediated accumulation of cells in G(2)/M and doxorubicin-med iated induction of p21. Our data suggest that triptolide, by blocking p21-m ediated growth arrest, enhances apoptosis in tumor cells.