Preferential induction of necrosis in human breast cancer cells by a p53 peptide derived from the MDM2 binding site.
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.
Do
Tamara N
TN
Experimental Therapeutics Program, Division of Medical Oncology, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Rosal
Ramon V
RV
Drew
Lisa
L
Raffo
Anthony J
AJ
Michl
Josef
J
Pincus
Matthew R
MR
Friedman
Fred K
FK
Petrylak
Daniel P
DP
Cassai
Nicholas
N
Szmulewicz
Joseph
J
Sidhu
Gurdip
G
Fine
Robert L
RL
Brandt-Rauf
Paul W
PW
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*
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