The mutant p53-conformation modifying drug, CP-31398, can induce apoptosis of human cancer cells and can stabilize wild-type p53 protein.

Abstract

CP-31398, a styrylquinazoline, emerged from a screen for therapeutic agents that restore a wild-type DNA-binding conformation of mutant p53 to suppress tumors in-vivo (Science 286, 2507, 1999). We investigated the growth inhibitory mechanism of CP-31398 using nine human cancer cell lines containing wild-type, mutant or no p53 expression. Six of nine cell lines underwent apoptosis after exposure to CP-31398, while two cell lines, DLD1 colon cancer and H460 lung cancer, underwent exclusively cell cycle arrest. Cell cycle arrest preceded the apoptosis in some cases. CP-31398 did not inhibit growth of the p53 non-expressing ovarian cancer cell line SKOV3. Interestingly, we found that wild-type p53 protein is stabilized upon CP-31398 exposure. p53 target genes such as p21WAF1/Cip1, and KILLER/DR5 were upregulated by CP-31398, but their expression did not correlate with arrest or apoptosis induction. Combination of CP-31398 and TRAIL or chemotherapeutic agents enhanced cancer cell killing effect possibly through upregulation of p53-regulated genes such as KILLER/DR5. Bax-/-, wild-type p53-expressing cells displayed reduced susceptibility to killing by CP-31398. An Affymetrix GeneChip Array screen revealed that CP-31398 alters expression of non-p53 target genes in addition to p53-responsive genes. Although our preliminary data suggest that CP-31398 does not alter wild-type p53:MDM2 interaction, further efforts are required to elucidate the mechanism of wild-type p53 stabilization by CP-31398. The results increase our understanding of CP-31398 action, and suggest strategies for improving its specificity, possibly through use of microarrays to screen related compounds with higher mutant p53-specificity.

• Authors: Rishu Takimoto, Wenge Wang, David T Dicker, Farzan Rastinejad, Joseph Lyssikatos, Wafik S el-Deiry
• Journal: Cancer biology & therapy (Cancer Biol Ther) 2002 Jan-Feb Vol. 1 Issue 1 Pg. 47-55 ISSN: 1538-4047 [Print] United States
• PMID: 12174820 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• CDKN1A protein, human
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins
• DNA, Neoplasm
• Growth Inhibitors
• Membrane Glycoproteins
• Neoplasm Proteins
• Nuclear Proteins
• Proto-Oncogene Proteins
• Pyrimidines
• Retinoblastoma Protein
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Tumor Necrosis Factor-alpha
• Tumor Suppressor Protein p53
• Doxorubicin
• Cycloheximide
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• CP 31398

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins
• Cyclin-Dependent Kinase Inhibitor p21
• Cyclins (biosynthesis, genetics)
• Cycloheximide (pharmacology)
• DNA, Neoplasm (metabolism)
• Doxorubicin (pharmacology)
• Female
• G1 Phase (drug effects)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Genes, p53
• Growth Inhibitors (pharmacology)
• Humans
• Male
• Membrane Glycoproteins (pharmacology)
• Neoplasm Proteins (chemistry, drug effects, genetics, physiology)
• Nuclear Proteins
• Protein Binding (drug effects)
• Protein Conformation (drug effects)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-mdm2
• Pyrimidines (pharmacology)
• Retinoblastoma Protein (biosynthesis, genetics)
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Cells, Cultured (drug effects, pathology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Tumor Suppressor Protein p53 (chemistry, drug effects, physiology)