title: Enhancement of sensitivity by bestatin of acute promyelocytic leukemia NB4 cells to all-trans retinoic acid.
abstract: All-trans retinoic acid (ATRA) induces the differentiation of acute promyelocytic leukemia (APL) cells into neutrophils. We found that bestatin, an inhibitor of CD13/aminopeptidase N, enhanced the sensitivity of APL NB4 cells to ATRA at concentrations of 0.1-1000ng/ml. A structurally different aminopeptidase N inhibitor, actinonin, also increased the effect of ATRA on differentiation, but an inactive stereoisomer of bestatin, (2R,3S)-AHPA-(R)-Leu, did not. Bestatin synergistically enhanced the cytostatic effect of ATRA on NB4 cells. Masking of the cell-surface CD13 by anti-CD13 antibody WM15 blocked the synergistic effect of bestatin and ATRA on differentiation. Thus bestatin, an immunomodulator clinically used for nonlymphocytic leukemia, synergistically increased the ATRA-induced differentiation of NB4 cells by inhibiting CD13/aminopeptidase N on the cell-surface.
authors.affiliation: Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Hirano
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kizaki
authors.forename: Kuniki
authors.initials: K
authors.lastname: Kato
authors.forename: Fuminori
authors.initials: F
authors.lastname: Abe
authors.forename: Natsuko
authors.initials: N
authors.lastname: Masuda
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umezawa
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D011480:Protease Inhibitors; D014212:Tretinoin; D000626:Aminopeptidases; D018826:CD13 Antigens; D007930:Leucine; C012211:ubenimex