Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone (DEX), a synthetic glucocorticoid, is routinely prescribed with anti-neoplastic agents to alleviate pain associated with chemotherapy and reduce intra-cranial pressure. We investigated whether DEX treatment increased the expression and activity of multi-drug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with sub-micromolar concentrations of DEX induced significantly higher levels of drug efflux transporters such as BCRP, p-gp, and MRP-2 at transcriptional, translational, and functional levels. The inductive effect of DEX was significant within 6 hour of treatment, was dose-dependent, and was reversible. DEX-induced up-regulation of BCRP and P-gp was partially prevented by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the DEX-induced up-regulation of MRP-2, suggestive of a GR-independent regulation of MRP-2, and a GR-dependent regulation of P-gp and BCRP. In addition to the DEX-induced up-regulation of MDR transporters, there was a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). DEX treatment in rats caused increased expression of PXR in microvessels of the brain within 24 hours. These results suggest that adjuvant therapy with corticosteroids in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR. Supported by NIH grant GM071321.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA