EFFECTS OF H-7 AND STAUROSPORINE ON PROLIFERATION AND SELF-RENEWAL OFACUTE MYELOID-LEUKEMIA PROGENITORS

In this study, we compared the impact of two protein kinase (PK) inhib itors, H-7 and staurosporine, on the normal myeloid progenitors (CFU-G M) and acute myeloid leukemia progenitors (AML-CFU) proliferation meas ured by in vitro clonogenic assay. H-7 and staurosporine displayed a b iphasic dose-effect on both CFU-GM and AML-CFU recovery. At the lowest concentration range (0.1 muM to 20 muM for H-7 and 0.1 nM to 1 nM for staurosporine), we observed growth stimulation whereas higher concent rations induced dose-dependent growth inhibition. Moreover, AML-CFU pr oved to be significantly more sensitive to the inhibitory effect of bo th H-7 and staurosporine than CFU-GM (3.16- and 2.12-fold, respectivel y). These results were further confirmed with comparable murine cell l ine models (FDC-P1, a hematopoietic cell line generated from normal bo ne marrow and WEHI, a myelomonocytic leukemia cell line). Furthermore, we report that both H-7 and staurosporine present similar inhibitory effects on proliferation (PE1) as on self-renewal (PEs) of AML-CFU. In an attempt to understand more fully the mechanism of action of H-7 an d staurosporine, we investigated their impact (when used at their D50) on the human myelogenous leukemia cell line, K562. H-7 and staurospor ine induced a transient decrease of cell growth, between 0 and 24 hour s, and produced a transient blockade of K562 cells in the S-phase, eit her 24 or 48 hours after the addition of staurosporine and H-7, respec tively.