title: Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site.
abstract: p53 is the most frequently altered gene in human cancer and therefore represents an ideal target for cancer therapy. Several amino terminal p53-derived synthetic peptides were tested for their antiproliferative effects on breast cancer cell lines MDA-MB-468 (mutant p53), MCF-7 (overexpressed wild-type p53), and MDA-MB-157 (null p53). p53(15)Ant peptide representing the majority of the mouse double minute clone 2 binding site on p53 (amino acids 12-26) fused to the Drosophila carrier protein Antennapedia was the most effective. p53(15)Ant peptide induced rapid, nonapoptotic cell death resembling necrosis in all breast cancer cells; however, minimal cytotoxicity was observed in the nonmalignant breast epithelial cells MCF-10-2A and MCF-10F. Bioinformatic/biophysical analysis utilizing hydrophobic moment and secondary structure predictions as well as circular dichroism spectroscopy revealed an alpha-helical hydrophobic peptide structure with membrane disruptive potential. Based on these findings, p53(15)Ant peptide may be a novel peptide cancer therapeutic because it induces necrotic cell death and not apoptosis, which is uncommon in traditional cancer therapy.
authors.affiliation: Experimental Therapeutics Program, Division of Medical Oncology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
authors.forename: Tamara N
authors.initials: TN
authors.lastname: Do
authors.forename: Ramon V
authors.initials: RV
authors.lastname: Rosal
authors.forename: Lisa
authors.initials: L
authors.lastname: Drew
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Raffo
authors.forename: Josef
authors.initials: J
authors.lastname: Michl
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pincus
authors.forename: Fred K
authors.initials: FK
authors.lastname: Friedman
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Petrylak
authors.forename: Nicholas
authors.initials: N
authors.lastname: Cassai
authors.forename: Joseph
authors.initials: J
authors.lastname: Szmulewicz
authors.forename: Gurdip
authors.initials: G
authors.lastname: Sidhu
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
authors.forename: Paul W
authors.initials: PW
authors.lastname: Brandt-Rauf
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D051943:Antennapedia Homeodomain Protein; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001940:Breast / Q000166:cytology / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002942:Circular Dichroism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009336:Necrosis; D009687:Nuclear Proteins; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051943:Antennapedia Homeodomain Protein; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; D007770:L-Lactate Dehydrogenase; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D020169:Caspases