Aminopeptidase inhibitors inhibit proliferation and induce apoptosis of K562 and STI571-resistant K562 cell lines through the MAPK and GSK-3beta pathways.
A tyrosine kinase inhibitor, STI571, has been demonstrated to be effective for the treatment of chronic myelogenous leukemia (CML). STI571 inhibits tyrosine kinase activity of ABL and induces apoptosis of CML cells. However, drug resistance develops commonly in patients with blast phase CML, and has become a significant therapeutic problem. We examined the effects of aminopeptidase inhibitors on CML cell line (K562) and a STI571-resistant subline of K562. Ubenimex and the more potent aminopeptidase inhibitor, actinonin, inhibited proliferation of both K562 cells and STI571-resistant K562 cells and also induced their apoptosis in dose- and time-dependent manners. Ubenimex and actinonin induced the activation of caspase-3, and the induction of apoptosis was inhibited by pan-caspase inhibitor, indicating this apoptosis is caspase-dependent. We found that serine phosphorylation of both MAPK and glycogen synthase kinase-3beta were suppressed by aminopeptidase inhibitors in parent K562 and STI571-resistant K562 cells. The expression level of cyclin D1 protein was also reduced by ubenimex and actinonin in both cell lines. These results indicated STI571-resistance does not confer the cross-resistance to aminopeptidase inhibitors in K562 cells and revealed the new findings of aminopeptidase inhibitor-induced intracellular signaling pathways.
Sawafuji
Kanoko
K
Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Miyakawa
Yoshitaka
Y
Weisberg
Ellen
E
Griffin
James D
JD
Ikeda
Yasuo
Y
Kizaki
Masahiro
M
D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D000068877:Imatinib Mesylate; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D006877:Hydroxamic Acids; D010879:Piperazines; D011480:Protease Inhibitors; D011743:Pyrimidines; D019938:Cyclin D1; D012694:Serine; D000068877:Imatinib Mesylate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000626:Aminopeptidases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D007930:Leucine; C012211:ubenimex; C010531:actinonin