Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines.
We investigated the growth inhibitory activity of bestatin, an inhibitor of aminopeptidase N (CD13), on six human leukemic cell lines. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentrations (IC50) close to the maximum serum concentration when bestatin was orally administered at 30 mg in clinical application. All cell lines except for K562 highly expressed CD13, but a clear correlation between the sensitivity to bestatin and expression of CD13 was not observed. Other aminopeptidase inhibitors such as amastatin A, arphamenine B and WM15 antibody showed no growth inhibitory effects. To confirm the growth inhibitory effects of bestatin, we quantitatively examined DNA fragmentation in five bestatin-sensitive cell lines. Bestatin dose-dependently induced DNA fragmentation in those cell lines. In case of U937, bestatin induced DNA fragmentation quantitatively and DNA ladder and enhanced caspase-3 activity. Furthermore, the growth inhibition by bestatin was reduced by the caspase inhibitor Z-Asp-CH2-DCB. These results suggested that bestatin exhibits direct antileukemic effects against human leukemic cell lines through the induction of apoptosis.
Sekine
K
K
Anticancer Drugs Department, Nippon Kayaku Co Ltd, Tokyo, Japan.
Fujii
H
H
Abe
F
F
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D017209:Apoptosis / Q000187:drug effects*; D018826:CD13 Antigens / Q000032:analysis; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D002455:Cell Division / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011480:Protease Inhibitors; D000626:Aminopeptidases; D018826:CD13 Antigens; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D007930:Leucine; C012211:ubenimex