Potentiation of glucocorticoid-induced lysis in refractory and resistant leukemia cells by inhibitors of ADP-ribosylation.

Meta-iodo-benzylguanidine (MIBG; 3 x 10(-5) M), a novel inhibitor of mono(ADP-ribosylation)-and the general ribosylation inhibitor nicotinamide (NA; 5-20 mM) both stimulated the glucocorticoid-mediated lysis of sensitive L1210 leukemia cells and even induced susceptibility in various human and murine lines refractory or resistant to dexamethasone (DEX). Potentiation and induction of DEX-sensitivity by ADP-ribosylation inhibitors was accompanied by an increase in saturable 3H-DEX binding sites and by a 2-3 fold increase in the affinity of intracellular receptors for hormone binding. Moreover, the ribosylation inhibitors converted the glucocorticoid antagonist RU-486 into a potent agonist for cytolysis of L1210 cells. We conclude that the cytolytic action of glucocorticoid hormones in leukemic cells is negatively controlled by (mono)ADP-ribosylation of receptor proteins.