Effects of H-7 and staurosporine on proliferation and self-renewal of acute myeloid leukemia progenitors.
In this study, we compared the impact of two protein kinase (PK) inhibitors, H-7 and staurosporine, on the normal myeloid progenitors (CFU-GM) and acute myeloid leukemia progenitors (AML-CFU) proliferation measured by in vitro clonogenic assay. H-7 and staurosporine displayed a biphasic dose-effect on both CFU-GM and AML-CFU recovery. At the lowest concentration range (0.1 microM to 20 microM for H-7 and 0.1 nM to 1 nM for staurosporine), we observed growth stimulation whereas higher concentrations induced dose-dependent growth inhibition. Moreover, AML-CFU proved to be significantly more sensitive to the inhibitory effect of both H-7 and staurosporine than CFU-GM (3.16- and 2.12-fold, respectively). These results were further confirmed with comparable murine cell line models (FDC-P1, a hematopoietic cell line generated from normal bone 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 and staurosporine, we investigated their impact (when used at their D50) on the human myelogenous leukemia cell line, K562. H-7 and staurosporine induced a transient decrease of cell growth, between 0 and 24 hours, and produced a transient blockade of K562 cells in the S-phase, either 24 or 48 hours after the addition of staurosporine and H-7, respectively.
Laredo
J
J
Laboratoire de Pharmacologie et de Toxicologie Fondamentales, CNRS, Toulouse, France.
Demur
C
C
Muller
C
C
Saivin
S
S
Cassar
G
G
Bousquet
C
C
Dastugue
N
N
Jaffrézou
J P
JP
Colombies
P
P
Laurent
G
G
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000328:Adult; D000368:Aged; D000470:Alkaloids / Q000494:pharmacology*; D000970:Antineoplastic Agents; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002648:Child; D006131:Growth Inhibitors; D006410:Hematopoiesis / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D010879:Piperazines / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D019311:Staurosporine; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000473:pathology
D000470:Alkaloids; D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D007546:Isoquinolines; D010879:Piperazines; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine