The p53 stabilizing compound CP-31398 induces apoptosis by activating the intrinsic Bax/mitochondrial/caspase-9 pathway

Exp Cell Res. 2002 Jun 10;276(2):214-22. doi: 10.1006/excr.2002.5526.

Abstract

p53 is considered the guardian of the genome and has a number of biological functions, including cell cycle arrest, DNA repair, and apoptosis. In a recent study by Foster and colleagues, the pharmacological compound CP-31398 was found to stabilize wild-type p53 to enhance its transcriptional activity and inhibit tumor growth in mice. We hypothesize that CP-31398 induces apoptosis by stabilizing the p53 protein and activating the mitochondrial-mediated pathway. Using the wild-type p53 HCT116+/+ and the p53-deficient HCT116-/- colon carcinoma cell lines, we demonstrate here that CP-31398 induces apoptosis in a dose-, time-, and p53-dependent manner. CP-31398 dramatically elevated p53 and p21(Waf1) protein levels in HCT116+/+, while a smaller p53-independent p21(Waf1) induction by CP-31398 in HCT116-/- cells was also observed. Moreover, we also found that CP-31398 increased Bax expression, altered mitochondrial membrane potential causing the release of cytochrome c, and induced the cleavage of caspases-9 and -3. Taken together, our results indicate that CP-31398 induces p53-dependent apoptosis by activating the Bax/mitochondrial/caspase-9 pathway. Elucidating the mechanism by which CP-31398 induces cell death may establish it as an anticancer agent.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Carcinoma / drug therapy
  • Carcinoma / genetics
  • Carcinoma / metabolism
  • Caspase 3
  • Caspase 9
  • Caspases / drug effects
  • Caspases / genetics
  • Caspases / metabolism*
  • Cell Division / drug effects
  • Cell Division / genetics
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Colonic Neoplasms / drug therapy
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Cytochrome c Group / drug effects
  • Cytochrome c Group / metabolism
  • Eukaryotic Cells / cytology
  • Eukaryotic Cells / drug effects
  • Eukaryotic Cells / metabolism
  • Humans
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / metabolism
  • Proto-Oncogene Proteins / drug effects
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-bcl-2*
  • Pyrimidines / pharmacology*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • bcl-2-Associated X Protein

Substances

  • Antineoplastic Agents
  • BAX protein, human
  • Cytochrome c Group
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • Tumor Suppressor Protein p53
  • bcl-2-Associated X Protein
  • CASP3 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 9
  • Caspases
  • CP 31398