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Yang H, Shi G, Dou QP.
Mol Pharmacol. 2007 Feb;71(2):426-37.
The tumor proteasome is a
primary target for the natural anticancer compound Withaferin A isolated from
"Indian winter cherry"
The Prevention Program, Barbara Ann Karmanos Cancer Institute, and Department
of Pathology, School of Medicine, Wayne State University, 640.1 HWCRC, 4100 John
R Road, Detroit, MI 48201, USA.
Withaferin A (WA) is a steroidal lactone purified from medicinal plant
"Indian Winter Cherry" that is widely researched for its variety of properties,
including antitumor effects. However, the primary molecular target of WA is
unknown. By chemical structure analysis, we hypothesized that Withaferin A might
be a natural proteasome inhibitor. Computational modeling studies consistently
predict that C1 and C24 of WA are highly susceptible toward a nucleophilic
attack by the hydroxyl group of N-terminal threonine of the proteasomal
chymotrypsin subunit beta5. Furthermore, WA potently inhibits the
chymotrypsin-like activity of a purified rabbit 20S proteasome (IC50=4.5 microM)
and 26S proteasome in human prostate cancer cultures (at 5-10 microM) and
xenografts (4-8 mg/kg/day). Inhibition of prostate tumor cellular proteasome
activity in cultures and in vivo by WA results in accumulation of ubiquitinated
proteins and three proteasome target proteins (Bax, p27, and IkappaB-alpha)
accompanied by androgen receptor protein suppression (in androgen-dependent
LNCaP cells) and apoptosis induction. Treatment of WA under conditions of the
aromatic ketone reduction, or reduced form of Celastrol, had significantly
decreased the proteasome-inhibitory and apoptosis-inducing activities. Treatment
of human prostate PC-3 xenografts with WA for 24 days resulted in 70% inhibition
of tumor growth in nude mice, associated with 56% inhibition of the tumor tissue
proteasomal chymotrypsinlike activity. Our results demonstrate that the tumor
proteasome beta5 subunit is the primary target of WA, and inhibition of the
proteasomal chymotrypsin-like activity by WA in vivo is responsible for, or
contributes to, the antitumor effect of this ancient medicinal compound.
PMID: 17093135
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