Expression of an mdr gene is associated with a new form of resistance to dexamethasone-induced apoptosis

Abstract

A variant, MS23, of murine thymoma W7 cells, previously selected for its resistance to low concentrations of dexamethasone, is cross-resistant to unrelated drugs such as puromycin and colchicine. We report here that transcription of the mouse mdr1 gene is activated and P-glycoprotein is expressed in MS23 cells. Moreover, additional variants with increased resistance to dexamethasone and other drugs can be isolated from MS23 by stepwise selections in dexamethasone and colchicine. In one such variant (S7CD-5), the mdr1 gene is amplified and the mdr protein overexpressed. These variants have classical mdr characteristics: they accumulate reduced concentrations of drugs (including dexamethasone), and both drug sensitivity and intracellular accumulation can be restored by verapamil. The variants are most resistant to glucocorticoids with both 11- and 17-hydroxyl groups. The results indicate that we have identified a new form of glucocorticoid resistance, one associated with expression of the mouse mdr1 P-glycoprotein.