rg7388 and Skin-Neoplasms

Cutaneous melanoma is the most serious skin malignancy and new therapeutic strategies are needed for advanced melanoma. TP53 mutations are rare in cutaneous melanoma and hence activation of wild-type p53 is a potential therapeutic strategy in cutaneous melanoma. Here, we investigated the WIP1 inhibitor, GSK2830371, and MDM2-p53 binding antagonists (nutlin-3, RG7388 and HDM201) alone and in combination treatment in cutaneous melanoma cell lines and explored the mechanistic basis of these responses in relation to the genotype and induced gene expression profile of the cells.. A panel of three p53. GSK2830371, at doses (⩽10 μM) that alone had no growth-inhibitory or cytotoxic effects on the cells, nevertheless significantly potentiated the growth-inhibitory and clonogenic cell killing effects of MDM2 inhibitors in p53. GSK2830371, a WIP1 inhibitor, at doses with no growth-inhibitory activity alone, potentiated the growth-inhibitory and cytotoxic activity of MDM2 inhibitors by increasing phosphorylation, acetylation and stabilisation of p53 in cutaneous melanoma cells in a functional p53-dependent manner.

Topics: Aminopyridines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dipeptides; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Imidazoles; Melanoma; Melanoma, Cutaneous Malignant; Mutagenesis, Site-Directed; para-Aminobenzoates; Phosphorylation; Piperazines; Protein Binding; Protein Phosphatase 2C; Protein Stability; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Skin Neoplasms; Tumor Suppressor Protein p53