Biological Activity |
PRIMA-1Met restores wild-type conformation and function to mutant p53, and triggers apoptosis in tumor cells. PRIMA-1Met also targets the selenoprotein thioredoxin reductase 1 (TrxR1), a key regulator of cellular redox balance. IC50 & Target: p53 activator[1] TrxR1 inhibitor[1] In Vitro: PRIMA-1Met inhibits both recombinant TrxR1 in vitro and TrxR1 in cells. Cellular TrxR1 activity is inhibited by PRIMA-1Met irrespective of p53 status. PRIMA-1Met can directly affect cellular redox status via targeting of TrxR1. Several small molecules have been shown to restore wild-type activity to mutant p53, including CP-31398, PRIMA-1 and PRIMA-1MET, MIRA, STIMA, PhiKan-083 and NSC319726. PRIMA-1 and its methylated analog PRIMA-1Met promote correct folding of mutant p53, induce cell death by apoptosis, and inhibit tumor growth in mice. PRIMA-1Met has also been shown to reactivate mutant forms of the p63 and p73 proteins that share high structural homology with p53[1]. PRIMA-1MET is a powerful apoptosis-inducing agent. PRIMA-1MET can enhance apoptosis in mutant p53 carrying cells, compared to the p53 null parental cells. Most p53 mutants are in complex with Hsp70 proteins. PRIMA-1MET treatment increases Hsp70 expression and nucleolar translocation, in parallel with the induction of nucleolar accumulation of mutant p53. Several lines of evidence suggest that PRIMA-1MET can also act independently of the p53 status of the cell. It can radiosensitize prostate carcinoma cell lines with mutant or wild type p53 and p53-/- cells as well. Introduction of mutant p53 (p53ser249 or p53gln248) into p53-/- hepatocarcinoma cells increases sensitivity to PRIMA-1MET without the induction of p53 target genes. PRIMA-1MET regularly induces apoptosis in mutant p53 expressing cells[2]. |