Study summary · research use only
Anti-cancer peptides from ras-p21 and p53 proteins
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This laboratory study used computer-based molecular modeling to design peptides from the ras-p21 and p53 proteins intended to alter tumor cell behavior. The peptides ras 35-47 (PNC-7) and 96-110 (PNC-2), attached to a membrane-penetrating peptide (MRP), were reported to block oncogenic ras-p21-induced oocyte maturation without affecting insulin-induced oocyte maturation, and to induce phenotypic reversion or necrosis in several ras-transformed cell lines while sparing normal cells. Separately, peptides PNC-27 and 28, containing HDM-2-binding sequences from p53 linked to MRP, were reported to form pores in the membranes of a range of cancer cell lines but not normal cells tested, attributed to HDM-2 expression on cancer cell membranes. In nude mice, these peptides were reported to eradicate a malignant tumor with no apparent side effects noted.
Abstract
We have employed computer-based molecular modeling approaches to design peptides from the ras-p21 and p53 proteins that either induce tumor cell reversion to the untransformed phenotype or induce tumor cell necrosis without affecting normal cells. For rasp21, we have computed and superimposed the average low energy structures for the wild-type protein and oncogenic forms of this protein and found that specific domains change conformation in the oncogenic proteins. We have synthesized peptides corresponding to these and found that ras peptides, 35-47 (PNC-7) and 96-110 (PNC-2), block oncogenic ras-p21-induced oocyte maturation but have no effect on insulin-induced oocyte maturation that requires activation of endogenous wild-type ras-p21. These results show signal transduction pathway differences between oncogenic and activated wild-type ras-p21. Both peptides, attached to a membrane-penetrating peptide (membrane residency peptide or MRP), either induce phenotypic reversion to the untransformed phenotype or tumor cell necrosis of several ras-transformed cell lines, but have no effect on the growth of normal cells. Using other computational methods, we have designed two peptides, PNC-27 and 28, containing HDM-2-protein-binding domain sequences from p53 linked on their C-termini to the MRP that induce pore formation in the membranes of a wide range of cancer cells but not any normal cells tested. This is due to the expression of HDM-2 in the cancer cell membrane that does not occur in normal cells. These peptides eradicate a highly malignant tumor in nude mice with no apparent side effects. Both ras and p53 peptides show promise as anti-tumor agents in humans.
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