Mechanism of triptolide-induced apoptosis: Effect on caspase activation and Bid cleavage and essentiality of the hydroxyl group of triptolide.
Triptolide is a compound extracted from the Chinese herb Tripterygium wilfordii Hook. f. Triptolide has potent anticancer activity. However, the mechanisms by which triptolide exerts its anticancer activities remain unclear. To explore the molecular mechanisms involved in the anticancer activity of triptolide, we have examined the effect of triptolide on the growth of pancreatic carcinoma PANC-1 and cervical adenocarcinoma HeLa cells. We found that treatment of both HeLa and PANC-1 cells with triptolide potently suppressed cell growth and induced apoptosis, indicated by nuclear fragmentation and blebbing. In both HeLa and PANC-1 cells, apoptosis induced by triptolide was associated with activation of both caspase-3 and caspase-8, and cleavage of poly(ADP-ribose) polymerase and Bid. Moreover, in HeLa cells, caspase-9 is also significantly activated in response to triptolide. Overexpression of Bcl-2 in HeLa cells substantially attenuated triptolide-induced apoptosis. Interestingly, substitution of the 14-OH of triptolide with an acetyl group abrogated both its anticancer and its antiinflammatory activities. Our studies suggest that triptolide may exert its anticancer effects by initiating apoptosis through both death-receptor- and mitochondria-mediated pathways. Our results indicate that both the apoptosis-promoting and the antiinflammatory activities of triptolide depend on the 14-OH group.
Wang
Xianxi
X
Department of Pediatrics, Center for Developmental Pharmacology and Toxicology, Children's Research Institute, The Ohio State University, Columbus, OH 43205, USA.
Matta
Ranyia
R
Shen
Gang
G
Nelin
Leif D
LD
Pei
Dehua
D
Liu
Yusen
Y
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000187:drug effects / Q000378:metabolism*; D002277:Carcinoma / Q000188:drug therapy / Q000473:pathology; D020169:Caspases / Q000187:drug effects* / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004852:Epoxy Compounds; D006367:HeLa Cells; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D010616:Phenanthrenes / Q000737:chemistry* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018906:Antineoplastic Agents, Alkylating; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D004224:Diterpenes; D004852:Epoxy Compounds; D010616:Phenanthrenes; D019253:Proto-Oncogene Proteins c-bcl-2; C001899:triptolide; D020169:Caspases