Effects of herbimycin A and its derivatives on growth and differentiation of Ph 1-positive acute lymphoid leukemia cell lines

Abstract

The molecular basis of the Philadelphia chromosome (Ph 1) is a structurally altered c-abl ( bcr/abl) gene which encodes an abnormally large protein with protein tyrosine kinase activity. Herbimycin A, an inhibitor of tyrosine kinase, preferentially inhibited the growth of Ph 1-positive acute lymphoid leukemia (ALL) cell lines, as well as Ph 1-positive chronic myeloid leukemia (CML) cell lines. Although noncytotoxic concentrations of herbimycin A induced erythroid differentiation of two CML-derived cell lines, K562 and KU812, in a previous study, the differentiation-inducing effect of herbimycin A on Ph 1-positive ALL cell lines was less strong. Herbimycin A enhanced some differentiation-associated properties of one Ph 1-positive ALL cell line, L2, but the effect of herbimycin A on the other Ph 1-positive ALL cell lines was cytotoxic rather than cytostatic (differentiation-inducing). Several derivatives of herbimycin A were synthesized and their effects on the cell proliferation of Ph 1-positive CML and ALL cell lines were examined. The sensitivities of the Ph 1-positive cell lines to herbimycin A derivatives were different from the data on the rat kidney cell line infected with Rous sarcoma virus (v- src) derived from a previous study, suggesting bcr/abl kinase may differ in sensitivity from other tyrosine kinases. Moreover, the sensitivities of the ALL cell lines were not the same as those of the CML cell lines. These results suggest that a specific inhibitor of bcr/abl kinase could be an effective antileukemic agent against Ph 1-positive CML or ALL.