Induction of CDK inhibitors (p21(WAF1) and p27(Kip1)) and Bak in the beta-lapachone-induced apoptosis of human prostate cancer cells

Mol Pharmacol. 2001 Apr;59(4):784-94. doi: 10.1124/mol.59.4.784.


beta-Lapachone, a novel anti-neoplastic drug, induces various cancer cells to undergo apoptosis. In a previous report, we showed that beta-lapachone-induced apoptosis of HL-60 cells is mediated by oxidative stress. However, in the present study, we found that beta-lapachone-induced apoptosis of human prostate cancer (HPC) cells may be independent of oxidative stress. In contrast to the 10-fold beta-lapachone-induced increase in H(2)O(2) production 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 beta-lapachone. Nonetheless, NAC, along with other antioxidants, failed to exert similar effect in HPC cells subjected to beta-lapachone treatment for 24 h. Under this premise, we suggest that the oxidative stress may not play a crucial role in beta-lapachone-mediated HPC cell apoptosis. Here we demonstrate that damage to genomic DNA is the trigger for the apoptosis of HPC cells induced by beta-lapachone. According to our results, beta-lapachone stimulates DNA dependent kinase expression and poly(ADP-ribose) polymerase cleavage in advance of significant morphological changes. beta-Lapachone promotes the expression of cyclin-dependent kinase (cdk) inhibitors (p21(WAF1) and p27(Kip1)), 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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology*
  • Antioxidants / pharmacology
  • Apoptosis
  • Caspases / metabolism
  • Cell Cycle / drug effects
  • Cell Cycle Proteins*
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclins / metabolism*
  • Cyclins / pharmacology
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins*
  • Enzyme Inhibitors / metabolism
  • Fluoresceins
  • Fluorescent Dyes
  • Genes, Tumor Suppressor
  • Humans
  • Male
  • Membrane Proteins / metabolism*
  • Microtubule-Associated Proteins / metabolism*
  • Microtubule-Associated Proteins / pharmacology
  • Naphthoquinones / pharmacology*
  • Nuclear Proteins
  • Phenanthridines
  • Poly(ADP-ribose) Polymerases / metabolism
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Serine-Threonine Kinases / metabolism
  • Reactive Oxygen Species / metabolism
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins*
  • bcl-2 Homologous Antagonist-Killer Protein


  • Antibiotics, Antineoplastic
  • Antioxidants
  • BAK1 protein, human
  • CDKN1A protein, human
  • Cell Cycle Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Fluoresceins
  • Fluorescent Dyes
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Naphthoquinones
  • Nuclear Proteins
  • Phenanthridines
  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • bcl-2 Homologous Antagonist-Killer Protein
  • Cyclin-Dependent Kinase Inhibitor p27
  • diacetyldichlorofluorescein
  • hydroethidine
  • beta-lapachone
  • Poly(ADP-ribose) Polymerases
  • DNA-Activated Protein Kinase
  • PRKDC protein, human
  • Protein Serine-Threonine Kinases
  • Cyclin-Dependent Kinases
  • Caspases