Chan SL, Lee MC, Tan KO, Yang LK, Lee AS, Flotow H, Fu NY,
Butler MS, Soejarto DD, Buss AD, Yu VC.Identification of
chelerythrine as an inhibitor of BclXL function.
J Biol Chem. 2003 Jun 6;278(23):20453-6
Institute of Molecular and Cell Biology, 30 Medical Drive,
Singapore 117609, Republic of Singapore.
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
micro m 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 BclXL-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.
PMID: 12702731 |
