title: Cytotoxic activity to acute myeloid leukemia cells by Antp-TPR hybrid peptide targeting Hsp90.
abstract: We previously reported that Antp-TPR hybrid peptide inhibited the interaction of Hsp90 with TPR2A and had selective cytotoxic activity discriminating between normal and cancer cells to induce cancer cell death. In this study, we investigated the cytotoxic activity of Antp-TPR peptide toward acute myeloid leukemia (AML) cells. It was demonstrated that Antp-TPR peptide induced AML cell death in cell lines such as U937, K562, THP-1, and HL-60 via activation of caspases 3 and 7, and disruption of mitochondrial membrane potential. Conversely, Antp-TPR peptide did not reduce the viability of normal cells including peripheral blood mononuclear cells (PBMCs), although both geldanamycin and 17-AAG, small-molecule inhibitors of Hsp90, mediated cytotoxicity to these normal cells at low concentrations. In addition, mutation analysis of TPR peptide demonstrated that the highly conserved amino acids Lys and Arg were critical to the cytotoxic activity. These results indicated that Antp-TPR hybrid peptide would provide potent and selective therapeutic options in the treatment of AML.
authors.affiliation: Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Yoshida Konoecho, Sakyoku, Kyoto 606-8501, Japan. horibe.tomohisa.5z@kyoto-u.ac.jp
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Horibe
authors.forename: Megumi
authors.initials: M
authors.lastname: Kawamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kohno
authors.forename: Koji
authors.initials: K
authors.lastname: Kawakami
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003603:Cytotoxins / Q000494:pharmacology*; D057809:HEK293 Cells; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018398:Homeodomain Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects*; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D000077022:Survivin; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism; D020298:U937 Cells
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D003603:Cytotoxins; C476884:HOPX protein, human; D018841:HSP90 Heat-Shock Proteins; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; D025521:Tumor Suppressor Proteins; C558008:hybrid Antp-TPR peptide