Inhibition of hemopoietic growth factor-induced proliferation by adenosine diphosphate-ribosylation inhibitors.
The effects of adenosine diphosphate (ADP) ribosylation inhibitors on hematopoietic growth factor-induced proliferation were examined. Significant inhibition of interleukin-3 (IL-3), colony-stimulating factor 1, and lung conditioned media-induced clonal agar growth of normal murine hematopoietic cells by 10 mmol/L nicotinamide (NAM), 10 mmol/L 3-aminobenzamide (3AB), and 5 mmol/L N1-methylnicotinamide (1MN) was noted. Nicotinic acid, a related compound that does not inhibit ADP ribosylation, failed to inhibit the growth factor-mediated proliferation. NAM (10 mmol/L), 3AB (10 mmol/L), and 1MN (5 mmol/L) also prevented IL-3 and phorbol ester-stimulated 3H-thymidine incorporation into the IL-3-responsive FDC-P1 cell line. Exposure of FDC-P1 cells to 10 mmol/L NAM led to a significant decrease in nuclear poly-(ADP-ribose) levels. Exposure of FDC-P1 cells to 5 mmol/L 1MN did not affect the interaction of the phorbol ester receptor, protein kinase-C (PK-C), with the cell membrane as determined by assay of phorbol ester binding in cytosol and membrane preparations. Nor did it affect the catalytic activity of PK-C as determined by assaying the in vitro phosphorylation of histone H1 by cytosolic kinase preparations from FDC-P1 as well as EL4 thymoma cells. 1MN markedly enhanced the inhibitory effects of phorbol esters on DNA synthesis of EL4 cells even at concentrations (1.25 mmol/L) that had no effects on DNA synthesis in the absence of phorbol esters. Our findings demonstrate that (a) active ADP ribosylation inhibitors interfere with growth factor-induced proliferation of murine hematopoietic cells and (b) the inhibition occurs at a step that follows the activation and translocation of PK-C and is more closely linked to DNA synthesis.
D000244:Adenosine Diphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D006131:Growth Inhibitors; D006133:Growth Substances / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D012266:Ribose / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism
D001549:Benzamides; D006131:Growth Inhibitors; D006133:Growth Substances; D016298:Hematopoietic Cell Growth Factors; D009536:Niacinamide; D000244:Adenosine Diphosphate; D012266:Ribose; C025160:3-aminobenzamide; D013936:Thymidine; C008472:N-methylnicotinamide