CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice

摘要: Mutations in the tumor suppressor p53 are detectable over 50% of all human malignancies. Mutant protein is incapable transactivating its downstream target genes that required for DNA repair and apoptosis. Chronic exposure to UVB induces mutations carcinogenic both murine skin. CP-31398, a styrylquinazoline compound, restores functions mutant forms cells. However, effectiveness vivo remains unclear. Here, we demonstrate CP-31398 blocked UVB-induced skin carcinogenesis was associated with increases p53, p21, BclXs. downregulated Bcl2, proliferating nuclear cell antigen, cyclin D1. Activation caspase-3 cleavage poly (ADP-ribose) polymerase also occurred perilesional following treatment. induced expression p53-dependent proteins, this followed by apoptosis UVB-irradiated wild-type mice but not their p53-deficient littermates. Similar effects were observed carcinoma A431 cells expressing p53. In addition, mitochondrial translocation leading changes membrane permeability pore transition (MPT) consequent cytochrome c release these Blocking MPT diminished These studies indicate reconstituting small molecular weight compounds may block pathogenesis progression cancer.