Effect of herbimycin A, an antagonist of tyrosine kinase, on bcr/abl oncoprotein-associated cell proliferations: abrogative effect on the transformation of murine hematopoietic cells by transfection of a retroviral vector expressing oncoprotein P210bcr/abl and preferential inhibition on Ph1-positive leukemia cell growth.

Abstract

Herbimycin A, a benzoquinoid ansamycin antibiotic, was demonstrated to decrease intracellular phosphorylation by protein tyrosine kinase (PTK). In Philadelphia chromosome (Ph1)-positive leukemias such as chronic myelogenous leukemia (CML) and Ph1-positive acute lymphoblastic leukemia (ALL), both of which express bcr-abl fused gene products (P210bcr-abl or P190bcr-abl protein kinase) with augmented tyrosine kinase activities, herbimycin A markedly inhibited the in vitro growth of the Ph1-positive ALL cells and the leukemic cells derived from CML blast crisis. However, the same dose of herbimycin A did not inhibit in vitro growth of a broad spectrum of Ph1-negative human leukemia cells, and several other protein kinase antagonists also displayed no preferential inhibition. Furthermore, we demonstrated that herbimycin A has an antagonizing effect on the growth of transformed cells by a transfection of retroviral amphotrophic vector expressing P210bcr/abl into a murine interleukin (IL)-3-dependent myeloid FDC-P2 cell line. This inhibition was abrogated by the addition of sulfhydryl compounds, similar to the reaction previously described for Rous sarcoma virus transformation. The inhibitory effect of herbimycin A on the growth of Ph1-positive cells was associated with decreased bcr/abl tyrosine kinase activity, but no decrease of bcr-abl mRNA and protein, suggesting that the inactivation of bcr-abl tyrosine kinase activity by herbimycin A may be induced by its binding to the bcr-abl protein portion that is rich with sulfhydryl groups. The present study indicates that herbimycin A is a beneficial agent for the investigation of the role of the bcr-abl gene in Ph1-positive leukemias and further suggests that the development of agents inhibiting the bcr-abl gene product may offer a new therapeutic potential for Ph1-positive leukemias.

• Authors: M Okabe, Y Uehara, T Miyagishima, T Itaya, M Tanaka, Y Kuni-Eda, M Kurosawa, T Miyazaki
• Journal: Blood (Blood) Vol. 80 Issue 5 Pg. 1330-8 (Sep 01 1992) ISSN: 0006-4971 [Print] United States
• PMID: 1515646 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Benzoquinones
• Lactams, Macrocyclic
• Quinones
• Sulfhydryl Compounds
• Rifabutin
• herbimycin
• Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl

Topics

• Benzoquinones
• Cell Division (drug effects)
• Cell Transformation, Neoplastic (drug effects)
• Fusion Proteins, bcr-abl (antagonists & inhibitors, genetics)
• Genetic Vectors
• Humans
• Lactams, Macrocyclic
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, pathology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Quinones (pharmacology)
• Retroviridae (genetics)
• Rifabutin (analogs & derivatives)
• Sulfhydryl Compounds (pharmacology)
• Transfection