19-Allylaminoherbimycin A, an analog of herbimycin A that is stable against treatment with thiol compounds or granulocyte-macrophage colony-stimulating factor in human leukemia cells.
Herbimycin A, a benzoquinonoid ansamycin antibiotic, reduces intracellular phosphorylation by some protein tyrosine kinases and inhibits the proliferation of malignant cells which express high tyrosine kinase activity. Herbimycin A inhibited the proliferation of human monoblastic leukemia U937 cells, but this inhibition was abrogated by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF). On the other hand, a derivative of herbimycin A, 19-allylaminoherbimycin A, inhibited the proliferation of such cells without interference by the addition of GM-CSF. Phosphorylation of MAP kinase and c-myc expression induced by GM-CSF in U937 cells were inhibited by both herbimycin A and 19-allylaminoherbimycin A. The time courses of growth inhibition showed that the growth-inhibitory activity of herbimycin A in U937 cells was initially potent, but gradually decreased in the presence of GM-CSF. Thiol compounds, glutathione (GSH) and 2-mercaptoethanol, abrogated the inhibition of the growth of U937 cells by herbimycin A, but not by 19-allylaminoherbimycin A, like GM-CSF. Intracellular GSH content in U937 cells was increased by treatment with GM-CSF, and decreased with herbimycin A, but returned to the control level with the addition of GM-CSF to herbimycin A. In thin-layer chromatography, after in vitro incubation with herbimycin A and GSH, nothing could be detected at the position of intact herbimycin A, while 19-allylaminoherbimycin A was stably detected. These findings suggest that changes in the intracellular concentration of GSH play a role in the abrogation of the inhibition of U937 cell growth by herbimycin A. In the presence of GSH, 19-allylaminoherbimycin A inhibited the proliferation of U937 cells and Philadelphia chromosome-positive K562 cells more effectively than herbimycin A. Since GSH plays a role in detoxicating several anticancer drugs, 19-allylaminoherbimycin A may have therapeutic advantages over herbimycin A against some types of leukemia.
Department of Chemotherapy, Saitama Cancer Center Research Institute, Japan.
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M
Makishima
Y
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Yamamoto-Yamaguchi
Y
Y
Honma
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D016227:Benzoquinones; D002455:Cell Division / Q000187:drug effects; D015342:DNA Probes; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc / Q000235:genetics; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D047029:Lactams, Macrocyclic; D007948:Leukemia, Monocytic, Acute / Q000473:pathology*; D008623:Mercaptoethanol / Q000378:metabolism / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017828:Rifabutin / Q000031:analogs & derivatives; D013438:Sulfhydryl Compounds / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D015342:DNA Probes; D047029:Lactams, Macrocyclic; D011809:Quinones; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D017828:Rifabutin; D008623:Mercaptoethanol; C020754:herbimycin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C097561:19-allylaminoherbimycin A; D011505:Protein-Tyrosine Kinases; D005978:Glutathione