RT Journal Article
SR Electronic
T1 Induction of CDK Inhibitors (p21<sup>WAF1</sup> and p27<sup>Kip1</sup>) and Bak in the β-Lapachone-Induced Apoptosis of Human Prostate Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 784
OP 794
DO 10.1124/mol.59.4.784
VO 59
IS 4
A1 Ming-Jaw Don
A1 Yen-Hwa Chang
A1 Kuang-Kuo Chen
A1 Li-Kang Ho
A1 Yat-Pang Chau
YR 2001
UL http://molpharm.aspetjournals.org/content/59/4/784.abstract
AB β-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that β-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that β-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold β-lapachone-induced increase in H2O2production seen in HL-60 cells, only a 2- to 4-fold increase was observed in HPC cells. N-acetyl-l-cysteine (NAC), a thiol antioxidant, inhibited the apoptosis in DU145 cells after 12 h exposure to β-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to β-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in β-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by β-lapachone. According to our results, β-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. β-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21WAF1 and p27Kip1), induces bak expression, and subsequently stimulates the activation of caspase-7 but not of caspase-3 or caspase-8 during the apoptosis of HPC cells. Taken together, these results suggest that the signaling pathway involving the β-lapachone-induced apoptosis of HPC cell may be by DNA damage, induction of cdk inhibitors (p21 and p27), and then subsequent stimulation of caspase-7 activation.