Abstract 3842: Methylseleninic acid, a novel potent and selective mutant-p53-rescue drug, reactivates mutant p53 by thiol modification

Abstract

Abstract Mutations of the p53 tumor suppressor gene constitute the most frequent genetic alteration known in human cancers. The vast majority (∼80%) of the mutations is missense mutations, and the DNA-binding domain is the most frequently mutable region of p53. p53 mutation leads to checkpoint defects, genomic instability, and propagation of cells with genetic damage. Developing therapeutic agents that could directly bind to the mutant p53 and reconstitute p53 function has been intensively pursued and proven to be feasible. However, the challenge remains to develop a drug that specifically reactivates mutant p53 without activating the pro-apoptotic function of wild-type p53 in normal tissues. In the present study, we show that a small-molecule drug, methylseleninic acid (CH3SeO2H, MSA), can selectively reactivate mutant p53 to induce apoptosis in cancer cells. MSA can be used at a concentration at least one order of magnitude lower than that of other mutant-p53-rescue agents to achieve the same p53-reactivating and growth-inhibitory effects. MSA reduces redox-active free thiols in mutant p53 without the requirement of other proteins, potentially through forming adducts with thiols in mutant p53. The modification restores wild-type conformation to mutant p53, leading to increased DNA binding and transactivation as well as expression of growth-suppressive and pro-apoptotic target genes in both cultured cancer cells and an orthotopic tumor model. Although MSA also redox modifies recombinant wild-type p53, the modification does not lead to the induction of growth-suppressive or pro-apoptotic target genes in normal fibroblasts. Instead, the expression of p53-regulated DNA-repair genes is significantly induced in normal fibroblasts, suggesting that MSA may selectively modify p53 for DNA repair or apoptosis depending on the level of endogenous or exogenous DNA damage. Our findings, therefore, demonstrate the effectiveness and selectivity of MSA as a novel potent mutant-p53-rescue drug. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3842. doi:1538-7445.AM2012-3842