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Induction of apoptosis and cell cycle arrest by a chalcone panduratin A isolated from Kaempferia pandurata in androgen-independent human prostate cancer cells PC3 and DU145

2006; Oxford University Press; Volume: 27; Issue: 7 Linguagem: Inglês

10.1093/carcin/bgi348

1460-2180

Jung‐Mi Yun, Mee-Hyang Kweon, Hoonjeong Kwon, Jae‐Kwan Hwang, Hasan Mukhtar,

Cholesterol and Lipid Metabolism

Because of unsatisfactory treatment options for prostate cancer (CaP) there is a need to develop novel preventive approaches for this malignancy. One such strategy is through chemoprevention by the use of non-toxic dietary substances and botanical products. We have shown previously that panduratin A isolated from the extract of Kaempferia pandurata ( Zingiberaceae ) is a strong inhibitor of cyclooxygenase-2 in RAW264.7 cells and induces apoptosis in HT-29 cells. In the present study, we provide evidence that panduratin A treatment to androgen-independent human CaP cells PC3 and DU145 result in a time and dose-dependent inhibition of cell growth with an IC 50 of 13.5–14 μM and no to little effect on normal human prostate epithelial cells. To define the mechanism of these anti-proliferative effects of panduratin A, we determined its effect on critical molecular events known to regulate the cell cycle and the apoptotic machinery. Annexin V/propidium iodide staining provided the evidence for the induction of apoptosis which was further confirmed by the observation of cleavage of poly (ADP-ribose) polymerase and degradation of acinus. Panduratin A treatment to cells was found to result in inhibition of procaspases 9, 8, 6 and 3 with significant increase in the ratio of Bax:Bcl-2, suggesting the involvement of a mitochondrial-dependent apoptotic pathway. Panduratin A-mediated apoptosis was accompanied with upregulation of Fas death receptor and TNF-related apoptosis-inducing ligand (TRAIL). Furthermore, cell cycle analysis using flow cytometry showed that panduratin A treatment of cells resulted in a G 2 /M arrest in a dose-dependent manner. The immunoblot analysis data revealed that in both cell lines panduratin A treatment resulted in a dose-dependent (i) induction of p21 WAF1/Cip1 and p27 Kip1 , (ii) downregulation of cdks 2, 4 and 6 and (iii) decrease in cyclins D1 and E. These findings suggest that panduratin A may be an effective chemopreventive or therapeutic agent against CaP.