Inhibition of abl oncogene tyrosine kinase induces erythroid differentiation of human myelogenous leukemia K562 cells.
The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. Erythroid differentiation of K562 cells was induced by tyrosine kinase inhibitors, but not by other kinase inhibitors. Treatment of K562 cells with 5'd(TACTGGCCGCTG-AAGGGC)3', complementary to the second exon (codons 2 to 7) of c-abl mRNA, inhibited cell growth and induced benzidine-positive cells in a dose-dependent manner. However, exposure to the sense oligomer did not induce erythroid differentiation of the cells. These results suggest that inhibition of abl tyrosine kinase activity is closely related to induction of erythroid differentiation of K562 cells. A multidrug-resistant subline (K562R) was induced to undergo erythroid differentiation by tyrosine kinase inhibitors such as genistein or herbimycin A as effectively as the parent K562 cells were. Therefore, tyrosine kinase inhibitors might be useful as cancer chemotherapeutic agents against some multidrug-resistant leukemias having abnormally high activity of oncogene tyrosine kinase(s).
Honma
Y
Y
Department of Chemotherapy, Saitama Cancer Research Institute.
Okabe-Kado
J
J
Kasukabe
T
T
Hozumi
M
M
Umezawa
K
K
D000470:Alkaloids / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001381:Azepines / Q000494:pharmacology; D016227:Benzoquinones; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004912:Erythrocytes / Q000473:pathology*; D016313:Genes, abl / Q000187:drug effects; D019833:Genistein; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D066298:In Vitro Techniques; D007529:Isoflavones / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D007951:Leukemia, Myeloid / Q000235:genetics / Q000473:pathology*; D009219:Myosin-Light-Chain Kinase / Q000037:antagonists & inhibitors; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D017828:Rifabutin / Q000031:analogs & derivatives; D013110:Sphingosine / Q000494:pharmacology; D019311:Staurosporine
D000470:Alkaloids; D000903:Antibiotics, Antineoplastic; D001381:Azepines; D016227:Benzoquinones; D006873:Hydroquinones; D007529:Isoflavones; D047029:Lactams, Macrocyclic; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011809:Quinones; D012333:RNA, Messenger; C056218:ML 9; D003609:Dactinomycin; D017828:Rifabutin; C020754:herbimycin; D004317:Doxorubicin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D016315:Proto-Oncogene Proteins c-abl; D009219:Myosin-Light-Chain Kinase; D019311:Staurosporine; D013110:Sphingosine; C048212:erbstatin