Role of Glucocorticoid Receptor in the Regulation of Cellular Sensitivity to Irinotecan Hydrochloride

Abstract

In clinical practice, glucocorticoids are often used with the aim of modulating the efficacy and toxicity of chemotherapeutic agents. However, how glucocorticoids modulate the pharmacological action of chemotherapeutic agents remains to be clarified. In this study, we generated glucocorticoid receptor (GR)-deficient rat-1 cells to investigate the role of GR in the regulation of cellular sensitivity to irinotecan hydrochloride (CPT-11). Treatment of wild-type rat-1 cells with dexamethasone (DEX) significantly enhanced the cytotoxic effect of CPT-11, whereas the treatment had little effect on the cytotoxicity of CPT-11 in GR-deficient cells. Topoisomerase-I activity in wild-type cells after concomitant treatment with DEX and CPT-11 was significantly lower than that after treatment with CPT-11 alone. DEX treatment also enhanced the inhibitory action of CPT-11 on the phosphatidylinositol 3-kinase–Akt signaling pathway in wild-type cells, accompanied by facilitating caspase-3 activity. These modulatory effects of DEX on the CPT-11–induced cytotoxicity were not observed in GR-deficient cells. Our present findings reveal the underlying mechanism by which GCs enhance the chemotherapeutic effect of CPT-11 and indicate the possibility that the dosage of CPT-11 could be reduced by the combination treatment with GCs, which may attenuate the adverse effect without decreasing anti-tumor activity.[Supplementary Figures: available only at http://dx.doi.org/10.1254/jphs.08219FP] Keywords:: glucocorticoid receptor, dexamethasone, CPT-11, topoisomerase-I, phosphatidylinositol 3-kinase [PI(3)K]–Akt signaling