title: Selective cancer cell cytotoxicity of enantiomeric 9-mer peptides derived from beetle defensins depends on negatively charged phosphatidylserine on the cell surface.
abstract: Four enantiomeric 9-mer peptides named d-peptide A, B, C and D were designed and synthesized on the basis of 43-mer insect defensins from two beetles. The d-9-mer peptides maintained bacterial membrane disruptive activity similar to the original peptides and also showed various extents of growth inhibitory activity against different cancer cell lines. Of these peptides, d-peptide B exhibited the highest selective cancer cell cytotoxicity against the mouse myeloma cell line, P3-X63-Ag8.653. Flow cytometric and scanning electron microscopic analysis revealed d-peptide B disrupts mouse myeloma membrane construction, whereas no cytotoxic effect on normal leukocytes was observed. Moreover, a strong correlation between negatively charged phosphatidylserine (PS) density in cancer cell membrane surface and sensitivity to d-9-mer peptides were observed in various cancer cell lines. These results suggest that d-9-mer peptides have negative charge-dependent selective cancer cell cytotoxicity targeting PS in the cancer cell membrane. In addition, synergic growth inhibitory activity against mouse myeloma was observed in combinations of d-peptide B and dexamethasone. These results suggest d-9-mer peptides are promising candidates for novel anticancer drugs.
authors.affiliation: University of Tsukuba, Tennodai, Ibaraki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwasaki
authors.forename: Jun
authors.initials: J
authors.lastname: Ishibashi
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sato
authors.forename: Ai
authors.initials: A
authors.lastname: Asaoka
authors.forename: DeMar
authors.initials: D
authors.lastname: Taylor
authors.forename: Minoru
authors.initials: M
authors.lastname: Yamakawa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D001517:Coleoptera; D023082:Defensins / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry*; D051379:Mice; D008855:Microscopy, Electron, Scanning; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D023082:Defensins; D008563:Membrane Lipids; D010446:Peptide Fragments; D010718:Phosphatidylserines