Diarylheptanoid hirsutenone enhances apoptotic effect of TRAIL on epithelial ovarian carcinoma cell lines via activation of death receptor and mitochondrial pathway.
Tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) induces apoptosis in various cancer cells. Diarylheptanoids such as hirsutenone and oregonin have been shown to have anti-inflammatory and anti-tumor effects. However, it is still unknown by which mechanism diarylheptanoids induce cell death. In addition, the effect of hirsutenone on TRAIL-induced apoptosis in the human epithelial ovarian carcinoma cell lines is unknown. To assess the apoptosis promoting effect of hirsutenone, we investigated the effect of hirsutenone on the apoptotic effect of TRAIL using the human epithelial carcinoma cell lines OVCAR-3 and SK-OV-3. TRAIL induced nuclear damage, decrease in Bid, Bcl-2 and Bcl-xL protein levels, increase in Bax levels, loss of the mitochondrial transmembrane potential, cytochrome c release, activation of caspases (8, 9 and 3) and increase in tumor suppressor p53 levels. Hirsutenone enhanced the TRAIL-induced apoptosis-related protein activation, nuclear damage and cell death. The results suggest that hirsutenone may enhance the apoptotic effect of TRAIL on ovarian carcinoma cell lines by increasing the activation of the caspase-8- and Bid-dependent pathways and the mitochondria-mediated apoptotic pathway, leading to caspase activation. Hirsutenone may confer a benefit in the TRAIL treatment of epithelial ovarian adenocarcinoma.
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul 156-756, South Korea. leecs@cau.ac.kr
Chung Soo
CS
Lee
Eun-Ra
ER
Jang
Yun Jeong
YJ
Kim
Soon Chul
SC
Myung
Wonyong
W
Kim
Min Won
MW
Lee
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D036381:Diarylheptanoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D053218:Receptors, Death Domain / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; D002396:Catechols; D036381:Diarylheptanoids; D053218:Receptors, Death Domain; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C508777:hirsutenone