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Non-Glucocorticoid Receptor-mediated Effects of the Potent Glucocorticoid Deacylcortivazol

Laboratory of Biochemistry, Division of Cancer Biology and Diagnosis, National Cancer Institute, NIH, Bethesda, Maryland 20205

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 µM 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.

¹ To whom requests for reprints should be addressed.

² Recipient of NIH Postdoctoral Fellowship 1F32 CA05447-01 from the National Cancer Institute. Present address: Fels Research Institute, Temple University School of Medicine, Philadelphia, Pa. 19140.

Received 10/ 9/81. Accepted 2/25/82.