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Srinivasan S, Ranga RS, Burikhanov R, Han SS, Chendil D.
Cancer Res. 2007 Jan 1;67(1):246-53
Par-4-dependent apoptosis by
withaferin A in prostate cancer cells.
Department of Clinical Sciences, College of Health Sciences, University of
Kentucky, 900 South Limestone Street, Lexington, KY 40536, USA.
Deletion or mutation of the androgen receptor (AR) renders prostate tumors
refractory to apoptosis by androgen ablation, the mainstay of prostate cancer
therapy. To identify novel therapeutics that can induce apoptosis regardless of
the AR status of prostate cancer cells, we screened dietary herbal compounds
using a reporter assay for the prostate apoptosis response-4 (Par-4) gene, which
induces p53- and PTEN-independent and cancer-selective apoptosis. One of the
compounds, withaferin A (WA), a major constituent of the dietary compound
Withania somnifera, induced Par-4-dependent apoptosis in androgen-refractory
prostate cancer cells and regression of PC-3 xenografts in nude mice.
Interestingly, restoration of wild-type AR in PC-3 (AR negative) cells abrogated
both Par-4 induction and apoptosis by WA. Individually, WA and anti-androgens
induced neither Par-4 nor apoptosis in androgen-responsive prostate cancer
cells, yet in combination, WA and anti-androgen synergistically induced Par-4
and apoptosis in androgen-responsive prostate cancer cells. Thus, when
judiciously combined with anti-androgens, WA inhibits survival of both
androgen-responsive and androgen-refractory prostate cancer cells by a
Par-4-dependent mechanism. As Par-4 up-regulation induces apoptosis in most
tumor cells, our findings can be extended to high-throughput screens to identify
synergistic combinations for both therapy-sensitive and therapy-resistant
cancers.
PMID: 17185378
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