Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells.

摘要: Development of effective agents for treatment hormone-refractory prostate cancer has become a national medical priority. We have reported recently that apigenin (4′,5,7-trihydroxyflavone), found in many common fruits and vegetables, shown remarkable effects inhibiting cell growth inducing apoptosis human carcinoma cells. Here we demonstrate the molecular mechanism inhibitory action on androgen-refractory DU145 cells mutations tumor suppressor gene p53 pRb. Treatment with resulted dose- time-dependent inhibition growth, colony formation, G1 phase arrest cycle. This effect was associated marked decrease protein expression cyclin D1, D2, E their activating partner, cyclin-dependent kinase (cdk)2, 4, 6, concomitant upregulation WAF1/p21, KIP1/p27, INK4a/p16, INK4c/p18. The induction WAF1/p21 its by appears to be independent pRb status these Apigenin also alteration Bax/Bcl2 ratio favor apoptosis, which release cytochrome c apoptotic protease-activating factor-1 (Apaf-1). result significant increase cleaved fragments caspase-9, -3, poly(ADP-ribose) polymerase (PARP). Further, downmodulation constitutive nuclear factor-kappaB (NF-κB)/p65 NF-κB/p50 fraction correlated an IkappaB-alpha (IκBα) cytosol. Taken together, concluded mechanisms during apigenin-mediated due (1) modulation cell-cycle machinery, (2) disruption mitochondrial function, (3) NF-κB inhibition. © 2004 Wiley-Liss, Inc.