Identification of chelerythrine as an inhibitor of BclXL function

Chan, Shing-Leng, Lee, Mei Chin, Tan, Kuan Onn, Yang, Lay-Kien, Lee, Alex S. Y., Flotow, Horst, Fu, Nai Yang, Butler, Mark S., Soejarto, Doel D., Buss, Antony D. and Yu, Victor C. (2003) Identification of chelerythrine as an inhibitor of BclXL function. Journal of Biological Chemistry, 278 23: 20453-20456. doi:10.1074/jbc.C300138200

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Author Chan, Shing-Leng
Lee, Mei Chin
Tan, Kuan Onn
Yang, Lay-Kien
Lee, Alex S. Y.
Flotow, Horst
Fu, Nai Yang
Butler, Mark S.
Soejarto, Doel D.
Buss, Antony D.
Yu, Victor C.
Title Identification of chelerythrine as an inhibitor of BclXL function
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2003-06-06
Sub-type Article (original research)
DOI 10.1074/jbc.C300138200
Open Access Status File (Publisher version)
Volume 278
Issue 23
Start page 20453
End page 20456
Total pages 4
Editor Herbert Tabor
Place of publication Bethesda, MD, U.S.A.
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Subject 0601 Biochemistry and Cell Biology
0904 Chemical Engineering
Formatted abstract
The identification of small molecule inhibitors of antiapoptotic Bcl-2 family members has opened up new therapeutic opportunities, while the vast diversity of chemical structures and biological activities of natural products are yet to be systematically exploited. Here we report the identification of chelerythrine as an inhibitor of BclXL-Bak Bcl.2 homology 3 (BH3) domain binding through a high throughput screening of 107,423 extracts derived from natural products. Chelerythrine inhibited the BclXL-Bak BH3 peptide binding with IC50 of 1.5 μM and displaced Bax, a BH3-containing protein, from BclXL. Mammalian cells treated with chelerythrine underwent apoptosis with characteristic features that suggest involvement of the mitochondrial pathway. While staurosporine, H7, etoposide, and chelerythrine released cytochrome c from mitochondria in intact cells, only chelerythrine released cytochrome c from isolated mitochondria. Furthermore BelXL-overexpressing cells that were completely resistant to apoptotic stimuli used in this study remained sensitive to chelerythrine. Although chelerythrine is widely known as a protein kinase C inhibitor, the mechanism by which it mediates apoptosis remain controversial. Our data suggest that chelerythrine triggers apoptosis through a mechanism that involves direct targeting of Bcl-2 family proteins.
© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Keyword Small- molecule inhibitors
Sex-determining protein
Cytochrome-C release
BCL-2 family
BH3 domain
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 123 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 23 Mar 2010, 11:00:58 EST by June Temby on behalf of Institute for Molecular Bioscience