Enhancing effect of ubenimex (bestatin) on proliferation and differentiation of hematopoietic progenitor cells, and the suppressive effect on proliferation of leukemic cell lines via peptidase regulation.
Ubenimex (Bestatin) significantly enhanced the G- and GM-CSF-induced colony formation of human bone marrow cells at concentrations of 0.001, 0.01, 0.1 and 1.0 microgram/ml (21-61% enhancement), but not at 10 micrograms/ml. Ubenimex did not influence the EPO-induced erythroid colony and burst formation between 0.0001-100 micrograms/ml. Against human and mouse leukemic cell lines, the growth-inhibitory activities of ubenimex were dose-dependently observed. Aminopeptidase activities on U937 and TF-1 cells were almost inhibited with 10 and 100 micrograms/ml of ubenimex, respectively. Cross-linking studies of 125I-GM-CSF binding to TF-1 cells demonstrated that the 150-kDa band of 2 major bands was enhanced after incubation with 0.01 microgram/ml ubenimex but decreased after that with 100 micrograms/ml, and that the 95-kDa band was not changed at any concentration of ubenimex. Change in density of the 150-kDa band on ubenimex-treated TF-1 cells was correlated with that in expression of CD10 (neutral endopeptidase) on them, whereas that in expression of CD13 (aminopeptidase N) was not changed at any concentration. These results suggest that one possible mechanism of ubenimex action in hematopoietic progenitor cells is the up-regulation of the high affinity receptor for GM-CSF and that in leukemic cell lines is suppression of amino acid incorporation via peptidase regulation.
Shibuya
K
K
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Chiba
S
S
Hino
M
M
Kitamura
T
T
Miyagawa
K
K
Takaku
F
F
Miyazano
K
K
D000626:Aminopeptidases / Q000378:metabolism*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007938:Leukemia / Q000473:pathology*; D051379:Mice
D000903:Antibiotics, Antineoplastic; D000626:Aminopeptidases; D007930:Leucine; C012211:ubenimex