title: Anti-cancer peptides from ras-p21 and p53 proteins.
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.
authors: Department of Pathology & Laboratory Medicine, New York Harbor VA Medical Center, Brooklyn, NY 11209, USA. matthew.pincus2@med.va.gov
authors: Matthew R
authors: MR
authors: Pincus
authors: Maly
authors: M
authors: Fenelus
authors: Ehsan
authors: E
authors: Sarafraz-Yazdi
authors: Victor
authors: V
authors: Adler
authors: Wilbur
authors: W
authors: Bowne
authors: Josef
authors: J
authors: Michl
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D015689:Oncogene Protein p21(ras) / Q000737:chemistry; D010455:Peptides / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D016159:Tumor Suppressor Protein p53; D015689:Oncogene Protein p21(ras)