Bufalin and cinobufagin induce apoptosis of human hepatocellular carcinoma cells via Fas‐ and mitochondria‐mediated pathways

Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepat...

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Published inCancer science Vol. 102; no. 5; pp. 951 - 958
Main Authors Qi, Fanghua, Inagaki, Yoshinori, Gao, Bo, Cui, Xiaoyan, Xu, Huanli, Kokudo, Norihiro, Li, Anyuan, Tang, Wei
Format Journal Article
LanguageEnglish
Published Oxford, UK Blackwell Publishing Ltd 01.05.2011
Blackwell
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Summary:Bufadienolides bufalin and cinobufagin are cardiotonic steroids isolated from the skin and parotid venom glands of the toad Bufo bufo gargarizans Cantor. They have been shown to induce a wide spectrum of cancer cell apoptosis. However, the detailed molecular mechanisms of inducing apoptosis in hepatocellular carcinoma (HCC) are still unclear. In the present study, the apoptosis‐inducing effect of bufalin and cinobufagin on HCC cell line HepG2 was investigated. We found bufalin and cinobufagin induced marked changes in apoptotic morphology and significantly increased the proportion of apoptotic cells. This apoptotic induction was associated with an increase in Fas, Bax and Bid expression, a decrease in Bcl‐2 expression, disruption of the mitochondrial membrane potential, release of cytochrome c, activation of caspase‐3, ‐8, ‐9 and ‐10, and the cleavage of poly(ADP‐ribose)polymerase (PARP), which indicated that bufalin and cinobufagin induced apoptosis through both Fas‐ and mitochondria‐mediated pathways. In addition, caspase activation during bufalin‐ and cinobufagin‐induced apoptosis was further confirmed by caspase‐3 inhibitor Z‐DEVD‐FMK, caspase‐8 inhibitor Z‐IETD‐FMK, caspase‐9 inhibitor Z‐LEHD‐FMK and caspase‐10 inhibitor Z‐AEVD‐FMK. The results showed that bufalin‐ and cinobufagin‐induced apoptosis was blocked by these inhibitors and particularly by caspase‐10 inhibitor. Taken together, bufalin and cinobufagin induce apoptosis of HepG2 cells via both Fas‐ and mitochondria‐mediated pathways, and a Fas‐mediated caspase‐10‐dependent pathway might play a crucial role. (Cancer Sci 2011; 102: 951–958)
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ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/j.1349-7006.2011.01900.x