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Carcinogenesis Advance Access published online on March 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn078
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Fisetin, a novel dietary flavonoid causes apoptosis and cell-cycle arrest in human prostate cancer LNCaP cells

Naghma Khan, Farrukh Afaq, Deeba N. Syed and Hasan Mukhtar*

Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA

* Author for correspondence: Hasan Mukhtar, Ph.D., Helfaer Professor of Cancer Research, Director and Vice Chair of Research, Department of Dermatology, University of Wisconsin-Madison, 1300, University Avenue, Medical Sciences Center, B-25, Madison, WI, 53706. Phone: 608-263-3927, Fax: 608-263-5223, E-mail: hmukhtar{at}wisc.edu

Novel dietary agents for prevention and therapy of prostate cancer are desired. The aim of this study was to determine the effect of fisetin, a tetrahydroxyflavone, on inhibition of cell-growth and induction of apoptosis in human prostate cancer cells. Treatment of fisetin (10-60 µM; 48 h) was found to result in a decrease in the viability of LNCaP, CWR22R{upsilon}1 and PC-3 cells but had only minimal effects on normal prostate epithelial PrEC cells as assessed by MTT assay. Treatment of LNCaP cells with fisetin also resulted in G1-phase arrest which was associated with a marked decrease in the protein expression of cyclin D1, D2 and E and their activating partner cdk2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. Fisetin treatment also resulted in induction of apoptosis, PARP cleavage, modulation in the expressions of Bcl2-family proteins, inhibition of PI3K and phosphorylation of Akt at Ser473 and Thr308. There was also induction of mitochondrial release of cytochrome c into cytosol, downregulation of XIAP and upregulation of Smac/DIABLO on treatment of cells with fisetin. Treatment of cells with fisetin also resulted in significant activation of caspase-3, -8 and -9. Pretreatment of cells with caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced activation of caspases. These data provides the first evidence that fisetin could be developed as an agent against prostate cancer.

Received October 17, 2007; revised January 30, 2008; accepted March 11, 2008.


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