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.
Smets
L
L
Dept Experimental Therapy, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
Metwally
E A
EA
Knol
E
E
Martens
M
M
D019797:3-Iodobenzylguanidine; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D007462:Iodobenzenes / Q000494:pharmacology*; D007700:Kinetics; D007939:Leukemia L1210 / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism; D015735:Mifepristone
D004963:Estrenes; D005938:Glucocorticoids; D007462:Iodobenzenes; D000246:Adenosine Diphosphate Ribose; D015735:Mifepristone; D019797:3-Iodobenzylguanidine; D003907:Dexamethasone