Abstract 5576: Rhamnetin inhibits human prostate cancer cell growth through cell-cycle arrest by modulating expression and function of key cell-cycle regulators and survival molecules

Abstract

Abstract Development of effective agents for treatment of prostate cancer has become a national medical priority. Rhamnetin (3,5,3,4-tetrahydroxy-7-methoxyflavone), a natural compound known as O-methylated flavonol, abundantly present in cloves, sweet annie, annual wormwood, green vegetables and orchard grass has shown to possess anti-inflammatory and antioxidant properties. However, the anticancer properties of rhamnetin have not been fully elucidated. In the present study we demonstrated the molecular mechanism of cell growth inhibition and induction of apoptosis in human prostate carcinoma LNCaP and PC-3 cells by rhamnetin. Treatment of these cells with rhamnetin resulted in a dose (5, 10, 20, 40 microM) and time (24, 48 and 72 h) dependent inhibition of growth, G2-S phase arrest of the cell cycle and DNA fragmentation. This effect was associated with a marked decrease in the protein expression of cyclin D1, D2, and E and their activating partner, cyclin-dependent kinase (cdk) 2, 4, and 6, with concomitant upregulation of WAF1/p21, KIP1/p27, INK4a/p16, and INK4c/p18. Rhamnetin treatment also resulted in alteration in Bax/Bcl2 ratio in favor of apoptosis, which was associated with the release of cytochrome-c and induction of apoptotic protease-activating factor-1 (Apaf-1). This effect was found to result in a significant increase in cleaved fragments of caspase-9, -3, and poly (ADP-ribose) polymerase (PARP). Further, rhamnetin treatment resulted in down modulation of XIAP, survivin, and c-Myc protein expressions. Taken together, we concluded that molecular mechanisms during rhamnetin-mediated growth inhibition and induction of apoptosis in both androgen-responsive, LNCaP and androgen-refractory, PC-3 cells was due to modulation in cell-cycle machinery, disruption of mitochondrial function, and inhibition of cell survival machinery. For the first time we provide evidence that rhamnetin acts on potential molecular targets of cell cycle regulation and survival to elicit anticancer effects in prostate cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5576. doi:10.1158/1538-7445.AM2011-5576