Induction of erythroid differentiation of K562 human leukemic cells by herbimycin A, an inhibitor of tyrosine kinase activity

Abstract

Herbimycin A, a benzoquinonoid ansamycin antibiotic, is found to reduce intracellular phosphorylation by tyrosine protein kinase. The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. When K562 cells are induced to undergo erythroid differentiation by hemin, reduction in the intracellular level of tyrosine phosphorylation occurs. In order to understand the relationship between induction of differentiation and reduction of tyrosine phosphorylation by the c-abl gene product, the effect that herbimycin A, a selective inhibitor of intracellular tyrosine kinase activity, exerts on the differentiation of K562 cells was examined. Reduction of tyrosine phosphorylation in K562 cells by herbimycin A was observed within 1 h. Noncytotoxic concentrations of herbimycin A induced erythroid differentiation of K562 cells but not of murine erythroleukemia 745A cells. The other human myeloid leukemia cell lines (HL-60, THP-1, and U937) tested were not induced to undergo cell differentiation by this antibiotic. Herbimycin A and the other well-known inducers such as hemin, butyric acid, Adriamycin, and 1-beta-D-arabinofuranosylcytosine had additive or more than additive effects on induction of erythroid differentiation of K562 cells. With respect to inhibition of cell growth, the sensitivity of K562 cells to herbimycin A was highest in the human leukemia cell lines we tested. Noncytotoxic concentrations of herbimycin enhanced the antiproliferative effect of Adriamycin or 1-beta-D-arabinofuranosylcytosine on K562 cells. Combination therapy with herbimycin A and its derivatives may be considered for use in the treatment of some types of leukemia where tyrosine kinase activities are implicated as determinants of the oncogenic state.