Carcinogenesis Advance Access originally published online on March 20, 2008
Carcinogenesis 2008 29(5):1049-1056; doi:10.1093/carcin/bgn078
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Fisetin, a novel dietary flavonoid, causes apoptosis and cell cycle arrest in human prostate cancer LNCaP cells
Department of Dermatology, University of Wisconsin–Madison, 1300 University Avenue, Medical Sciences Center, B-25, Madison, WI 53706, USA
* To whom correspondence should be addressed. Tel: +608 263 3927; Fax: +608 263 5223;Email: hmukhtar{at}wisc.edu
Novel dietary agents for prevention and therapy of prostate cancer (PCa) 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 PCa cells. Treatment of fisetin (10–60 µM, 48 h) was found to result in a decrease in the viability of LNCaP, CWR22R
1 and PC-3 cells but had only minimal effects on normal prostate epithelial cells as assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazoliumbromide assay. Treatment of LNCaP cells with fisetin also resulted in G1-phase arrest that was associated with a marked decrease in the protein expression of cyclins D1, D2 and E and their activating partner cyclin-dependent kinases 2, 4 and 6 with concomitant induction of WAF1/p21 and KIP1/p27. Fisetin treatment also resulted in induction of apoptosis, poly (ADP-ribose) polymerase (PARP) cleavage, modulation in the expressions of Bcl-2 family proteins, inhibition of phosphatidyl inositol 3-kinase and phosphorylation of Akt at Ser473 and Thr308. There was also induction of mitochondrial release of cytochrome c into cytosol, downregulation of X-linked inhibitor of apoptosis protein and upregulation of second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI on treatment of cells with fisetin. Treatment of cells with fisetin also resulted in significant activation of caspases-3, -8 and -9. Pretreatment of cells with caspase inhibitor (Z-VAD-FMK) blocked fisetin-induced activation of caspases. These data provide the first evidence that fisetin could be developed as an agent against PCa.
Abbreviations: cdk, cyclin-dependent kinase; DEVD, aspartylglutamylalanylaspartic acid; DIABLO, direct inhibitor of apoptosis-binding protein with low pI; NF-
B, nuclear factor-B; PARP, poly (ADP-ribose) polymerase; PBS, phosphate-buffered saline; PCa, prostate cancer; PI3K, phosphatidyl inositol 3-kinase; PrECs, prostate epithelial cells; siRNA, small interfering RNA; Smac, second mitochondria-derived activator of caspase; XIAP, X-linked inhibitor of apoptosis protein
Received October 17, 2007; revised January 30, 2008; accepted March 11, 2008.
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