Non-glucocorticoid receptor-mediated effects of the potent glucocorticoid deacylcortivazol.
Deacylcortivazol (DAC), a potent glucocorticoid, contains a phenyl-pyrazole moiety fused to the 2--3 position of the traditional steroid nucleus. When incubated with glucocorticoid-resistant mutants derived from the glucocorticoid-sensitive human leukemic cell line CEM-C7, DAC caused significant growth inhibition. However, this effect required 1 microM DAC, a concentration 50 times higher than that necessary for glucocorticoid receptor saturation. Cytotoxicity was observed in both mutants containing high-affinity glucocorticoid receptors defective in nuclear translocation and a mutant completely devoid of receptors. Further, in dexamethasone-resistant clones, DAC elicited only marginal increases in the activity of the glucocorticoid-inducible enzyme glutamine synthetase. Clones resistant to high concentrations of DAC could not be directly isolated from CEM-C7. However, stable DAC-resistant clones could be isolated from dexamethasone-resistant subclones of CEM-C7 with a frequency of 1 to 8 x 10(-4). These data are consistent with resistance to DAC being acquired in a two-step process. Our results suggest that the cytotoxicity of DAC at concentrations higher than necessary for glucocorticoid receptor saturation is not mediated by glucocorticoid receptors. Thus, DAC may be a bifunctional compound having both steroid receptor-mediated and receptor-independent cytotoxicity.
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002999:Clone Cells; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D007700:Kinetics; D007945:Leukemia, Lymphoid / Q000503:physiopathology*; D009154:Mutation; D011281:Pregnatrienes / Q000494:pharmacology*
D011281:Pregnatrienes; C029415:deacylcortivazol; D003907:Dexamethasone