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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Amino Acid Sequence
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Animals
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Antennapedia Homeodomain Protein
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Binding Sites
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Breast / cytology
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Breast / drug effects
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Breast Neoplasms / drug therapy
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Breast Neoplasms / pathology*
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Caspases / drug effects
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Caspases / metabolism
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Cell Death / drug effects
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Circular Dichroism
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Cysteine Proteinase Inhibitors / pharmacology
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Epithelial Cells / drug effects
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Female
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Homeodomain Proteins / genetics
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Humans
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L-Lactate Dehydrogenase / drug effects
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L-Lactate Dehydrogenase / metabolism
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Mice
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Molecular Sequence Data
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Mutation
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Necrosis
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Nuclear Proteins*
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Peptide Fragments / chemistry*
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Peptide Fragments / pharmacology*
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Protein Conformation
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Transcription Factors*
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Amino Acid Chloromethyl Ketones
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Antennapedia Homeodomain Protein
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Antineoplastic Agents
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Cysteine Proteinase Inhibitors
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Homeodomain Proteins
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Nuclear Proteins
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Peptide Fragments
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Proto-Oncogene Proteins
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Recombinant Proteins
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Transcription Factors
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Tumor Suppressor Protein p53
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butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone
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L-Lactate Dehydrogenase
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MDM2 protein, human
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Mdm2 protein, mouse
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Proto-Oncogene Proteins c-mdm2
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Caspases