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

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.

• Authors: Yvonne Luu, Jason Bush, K-John Cheung Jr, Gang Li
• Journal: Experimental cell research (Exp Cell Res) Vol. 276 Issue 2 Pg. 214-22 (Jun 10 2002) ISSN: 0014-4827 [Print] United States
• PMID: 12027451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2002 Elsevier Science (USA).

Chemical References

• 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

Topics

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