Cytotoxic effect of a non-peptidic small molecular inhibitor of the p53-HDM2 interaction on tumor cells

Abstract

To investigate if non-peptidic small molecular inhibitors of the p53-HDM2 interaction could restore p53 function and kill tumor cells. A series of non-peptidic small HDM2 inhibitors were designed by computer-aided model and synthesized by chemical method. Syl-155 was one of these inhibitors. Cytotoxic effect of syl-155 on three tumor cell lines with various states of p53, HT1080 (wild-type p53), KYSE510 (mutant p53), MG63 (p53 deficiency) was evaluated by MTT assay, Western blot and flow cytometry. Syl-155 stimulated the accumulation of p53 and p21 protein in HT1080 cells expressing wild-type p53, but not in KYSE510 and MG63 cells. Consequently, syl-155 induced cell cycle arrest and apoptosis in HT1080 cells. Non-peptidic small molecular inhibitors of the p53-HDM2 interaction show promise in treatment of tumors expressing wild-type p53.