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ToxSci Advance Access originally published online on January 27, 2006
Toxicological Sciences 2006 91(1):59-69; doi:10.1093/toxsci/kfj114
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Apoptotic Effect of Brucine from the Seed of Strychnos nux-vomica on Human Hepatoma Cells is Mediated via Bcl-2 and Ca2+ Involved Mitochondrial Pathway

Xukun Deng*,{dagger}, Fangzhou Yin*, Xiaoyu Lu*, Baochang Cai* and Wu Yin{ddagger},1

* College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing,China, 210029; {dagger} College of Life Science, South-Central University for Nationalities, Wuhan, China, 430074; and {ddagger} State Key Lab of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China, 210093

Received December 28, 2005; accepted January 13, 2006

In an attempt to dissect the mechanism of Strychnos nux-vomica, a commonly used Chinese folk medicine in the therapy of liver cancer, the cytotoxic effects of four alkaloids in Strychnos nux-vomica, brucine, brucine N-oxide, strychnine, and isostrychnine, on human hepatoma cells (HepG2) were screened by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrasolium bromide (MTT) assay. Brucine, among the four alkaloids, exhibited the strongest toxic effect, the mechanism of which was found to cause HepG2 cell apoptosis, since brucine caused HepG2 cell shrinkage, the formation of apoptotic bodies, DNA fragmentation, cell cycle arrest, as well as phosphatidylserine externalization, all of which are typical characteristics of apoptotic programmed cell death. Brucine-induced HepG2 cell apoptosis was caspase dependent, with caspase-3 activated by caspase-9. Brucine also caused the proteolytic processing of caspase-9. In addition, brucine caused depolarization of the mitochondrial membrane of HepG2 cells, the inhibition of which by cyclosporine A completely abrogated the activation of casapses and release of cytochrome c in brucine-treated HepG2 cells. These findings suggested a pivotal role of mitochondrial membrane depolarization in HepG2 cell apoptosis elicited by brucine. Furthermore, brucine induced a rapid and sustained elevation of intracellular [Ca2+], which compromised the mitochondrial membrane potential and triggered the process of HepG2 cell apoptosis. Finally, Bcl-2 was found to predominately control the whole event of cell apoptosis induced by brucine. The elevation of [Ca2+]i caused by brucine was also suppressed by overexpression of Bcl-2 protein in HepG2 cells. From the facts given above, Ca2+ and Bcl-2 mediated mitochondrial pathway were found to be involved in brucine-induced HepG2 cell apoptosis.

Key Words: brucine; HepG2 cells; apoptosis; Bcl-2; caspases; Ca2+.


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