Peptides from the amino terminal mdm-2-binding domain of p53, designed from conformational analysis, are selectively cytotoxic to transformed cells

We have synthesized three peptides from the mdm-2 binding domain of human p 53, residues 12-26 (PPLSQETFSDLWKLL), residues 12-20, and 17-26. To enable transport of the peptides across the cell membrane and at the same time to maximize the active mdm-2 binding a-helical conformation for these peptides , each was attached at its carboxyl terminus to the penetratin sequence, KK WKMRRNQFWVKVQRG, that contains many positively charged residues that stabil ize an a-helix when present on its carboxyl terminal end. All three peptide s were cytotoxic to human cancer cells in culture, whereas a control, unrel ated peptide attached to the same penetratin sequence had no effect on thes e cell lines. The same three cytotoxic peptides had no effect on the growth of normal cells, including human cord blood-derived stem cells. These pept ides were as effective in causing cell death in p53-null cancer cells as in those having mutant or normal p53. Peptide-induced cell death is not accom panied by expression of apoptosis-associated proteins such as Bax and waf(p 21). Based on these findings, we conclude that the antiproliferative effect s of these p53-derived peptides are not completely dependent on p53 activit y and may prove useful as general anticancer agents.