Ketoconazole inhibition and glucocorticoid action in the human lymphoblastic leukemia cell line CEM-C7.
The antifungal drug, ketoconazole, was reported to antagonize the induction of the enzyme tyrosine aminotransferase (TAT) by glucocorticoids in hepatoma tissue culture (HTC) cells, and to compete with glucocorticoids for binding to the glucocorticoid receptor. Since glucocorticoids inhibit the growth of the human leukemia cell line CEM-C7, ketoconazole might be expected to reverse this inhibition. Unexpectedly, ketoconazole inhibited CEM-C7 cell growth without utilizing glucocorticoid receptors. This was confirmed by ketoconazole inhibition of the growth of a receptor-less subline of CEM-C7 cells which are insensitive to glucocorticoids. Ketoconazole competed with triamcinolone acetonide (TA) for binding to the glucocorticoid receptor in cell-free supernatant prepared from CEM-C7 cells, but this was greatly reduced if ketoconazole and TA were incubated with intact cells prior to preparation of the cell-free supernatant. Ketoconazole inhibited induction by TA of the enzyme glutamine synthetase only at concentrations of 45-90 microM. We conclude that ketoconazole antagonism of glucocorticoid activity in CEM-C7 cells is probably not of pharmacologic significance due to the large concentrations required, and its reduced interaction with receptors in intact cells. The growth inhibitory activity of ketoconazole may be of interest in cancer chemotherapy.
D002460:Cell Line; D003907:Dexamethasone / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D004357:Drug Synergism; D005974:Glutamate-Ammonia Ligase / Q000096:biosynthesis; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology*; D007945:Leukemia, Lymphoid / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000187:drug effects; D014222:Triamcinolone Acetonide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*
D006131:Growth Inhibitors; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D005974:Glutamate-Ammonia Ligase; D014222:Triamcinolone Acetonide; D007654:Ketoconazole