cp-31398 and Melanoma

p53, a commonly mutated gene in human cancers, participates in cell cycle arrest, DNA repair and apoptosis. A small pharmacological compound, CP-31398, was found to have the ability to promote proper p53 protein folding, activate p53 transcription of downstream targets, and slow tumour growth in mice. Additionally, CP-31398 was found to be able to convert mutant p53 to wild-type conformation in several cell lines.. To examine if CP-31398 can revert all mutant p53 proteins to wild-type function.. We studied a series of apoptotic responses to CP-31398 in three melanoma cell lines varying in p53 mutation status.. Upon a moderate dose of CP-31398 treatment (15 microg mL(-1)), only the wild-type p53 MMRU and the single p53 point mutation MeWo cells exhibited apoptosis. Another melanoma cell line, Sk-mel-110, containing multiple p53 mutations, did not exhibit apoptosis. Although CP-31398 enhanced overall p53 protein level, its ability to promote proper folding of p53 protein was limited to CP-31398-sensitive MMRU and MeWo cells. These sensitive cells showed an increased Bax and PUMA transcription, altered mitochondrial membrane potential, followed by the release of cytochrome c, and cleaved caspase-9 and caspase-3. We also demonstrated that Apaf-1 was not involved in CP-31398-mediated apoptosis.. Our results suggest that the ability of CP-31398 to revert mutant p53 proteins to wild-type conformation may be correlated to p53 mutational status. More studies are necessary, to further investigate the effect of CP-31398 on mutant p53 and its potential applications as an anticancer agent.

Topics: Apoptosis; Apoptotic Protease-Activating Factor 1; Caspase 3; Caspase 9; Caspases; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Genes, p53; Humans; Intracellular Signaling Peptides and Proteins; Melanoma; Membrane Potentials; Mitochondria; Proteins; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Tumor Suppressor Protein p53

Topics: Apoptosis; Humans; Melanoma; Pyrimidines; Skin Neoplasms; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Ultraviolet Rays