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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
M Okabe, Y Uehara, T Miyagishima, T Itaya, M Tanaka, Y Kuni-Eda, M Kurosawa and T Miyazaki
Third Department of Internal Medicine, School of Medicine, Hokkaido
University, Sapporo, Japan.
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.
Volume 80,
Issue 5,
pp. 1330-1338,
09/01/1992
Copyright © 1992 by The American Society of Hematology
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