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

Cancer Biol Ther. Jan-Feb 2002;1(1):47-55. doi: 10.4161/cbt.1.1.41.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / biosynthesis
  • Cyclins / 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
  • Neoplasm Proteins / drug effects*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / 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
  • Retinoblastoma Protein / genetics
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / pathology
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / physiology

Substances

  • 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