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.

Abstract

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.

• Authors: M Makishima, Y Yamamoto-Yamaguchi, Y Honma
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1272 Issue 3 Pg. 199-205 (Dec 12 1995) ISSN: 0006-3002 [Print] Netherlands
• PMID: 8541353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Benzoquinones
• DNA Probes
• Lactams, Macrocyclic
• Quinones
• RNA, Messenger
• Sulfhydryl Compounds
• Rifabutin
• Mercaptoethanol
• herbimycin
• Granulocyte-Macrophage Colony-Stimulating Factor
• 19-allylaminoherbimycin A
• Protein-Tyrosine Kinases
• Glutathione

Topics

• Antibiotics, Antineoplastic (pharmacology)
• Base Sequence
• Benzoquinones
• Cell Division (drug effects)
• DNA Probes
• Gene Expression (drug effects)
• Genes, myc (genetics)
• Glutathione (metabolism, pharmacology)
• Granulocyte-Macrophage Colony-Stimulating Factor (pharmacology)
• Humans
• Lactams, Macrocyclic
• Leukemia, Monocytic, Acute (pathology)
• Mercaptoethanol (metabolism, pharmacology)
• Molecular Sequence Data
• Phosphorylation (drug effects)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinones (pharmacology)
• RNA, Messenger (genetics, metabolism)
• Rifabutin (analogs & derivatives)
• Sulfhydryl Compounds (metabolism, pharmacology)
• Tumor Cells, Cultured