Potentiation of glucocorticoid-induced cytolysis in sensitive human leukemic cells by an inhibitor of ADP-ribosylation.
3-Aminobenzamide, a general inhibitor of poly(ADP-ribose)polymerase, potentiated the triamcinolone acetonide-mediated growth inhibition and lysis of the glucocorticoid-sensitive CEM-C7 human leukemic cell line. This potentiation was dose-dependent with maximal response being detected at 3 mM 3-aminobenzamide, and was completely blocked by the glucocorticoid receptor antagonist RU 38486. Scatchard analysis of whole cell specific [3H]triamcinolone acetonide binding data did not reveal any effect of 3-aminobenzamide on either the number of intracellular receptor binding sites or their affinity for the agonist. Treatment of the ICR-27 cell line, which is a glucocorticoid resistant mutant isolated from CEM-C7, with 3-aminobenzamide did not restore triamcinolone acetonide sensitivity. Similarly, 3-aminobenzamide treatment of several other lymphoid cell lines (human HL60 and IM-9 and murine L1210 cells) which contain functional receptors but are not normally lysed by glucocorticoid agonists, failed to induce sensitivity to triamcinolone acetonide. Since treatment of sensitive lymphoid cells with glucocorticoid agonists results in DNA fragmentation prior to cell death, these data suggest that 3-aminobenzamide potentiates the cytolytic response of sensitive cells to glucocorticoid agonists by inhibiting DNA excision repair mechanisms.
Meyer
A S
AS
Department of Physiology and Biophysics, College of Medicine, University of Iowa, Iowa City 52242.
Schlechte
J A
JA
Schmidt
T J
TJ
D000244:Adenosine Diphosphate / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007945:Leukemia, Lymphoid / Q000378:metabolism / Q000473:pathology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014222:Triamcinolone Acetonide / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D000244:Adenosine Diphosphate; C025160:3-aminobenzamide; D014222:Triamcinolone Acetonide