Triptolide and chemotherapy cooperate in tumor cell apoptosis. A role for the p53 pathway.
Triptolide (PG490), a diterpene triepoxide, is a potent immunosuppressive agent extracted from the Chinese herb Tripterygium wilfordii. We have previously shown that triptolide blocks NF-kappaB activation and sensitizes tumor necrosis factor (TNF-alpha)-resistant tumor cell lines to TNF-alpha-induced apoptosis. We show here that triptolide enhances chemotherapy-induced apoptosis. In triptolide-treated cells, the expression of p53 increased but the transcriptional function of p53 was inhibited, and we observed a down-regulation of p21(waf1/cip1), a p53-responsive gene. The increase in levels of the p53 protein was mediated by enhanced translation of the p53 protein. Additionally, triptolide induced accumulation of cells in S phase and blocked doxorubicin-mediated accumulation of cells in G(2)/M and doxorubicin-mediated induction of p21. Our data suggest that triptolide, by blocking p21-mediated growth arrest, enhances apoptosis in tumor cells.
Chang
W T
WT
Division of Pulmonary and Critical Care Medicine, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Kang
J J
JJ
Lee
K Y
KY
Wei
K
K
Anderson
E
E
Gotmare
S
S
Ross
J A
JA
Rosen
G D
GD
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001483:Base Sequence; D002453:Cell Cycle / Q000187:drug effects; D017931:DNA Primers; D004273:DNA, Neoplasm / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D004852:Epoxy Compounds; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000473:pathology*; D015689:Oncogene Protein p21(ras) / Q000037:antagonists & inhibitors / Q000378:metabolism; D010616:Phenanthrenes; D011485:Protein Binding; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000970:Antineoplastic Agents; D017931:DNA Primers; D004273:DNA, Neoplasm; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D016159:Tumor Suppressor Protein p53; C001899:triptolide; D004317:Doxorubicin; D015689:Oncogene Protein p21(ras)