Combination of icariin and oleanolic acid attenuates in vivo and in vitro glucocorticoid resistance through protecting dexamethasone-induced glucocorticoid receptor impairment

Abstract

Glucocorticoid resistance (GCR) remains a significant problem and is the most important reason for treatment failure of glucocorticoids (GCs). How to increase the sensitivity to GCs and exploring new agents to overcome GCR is of great significance. Herein, we report for the first time that the effects of combination of icariin and oleanolic acid (OA) on dexamethasone (Dex)-induced glucocorticoid receptor (GR) impairment in vivo and in vitro. Compared with the use of Dex or combination of icariin and OA alone, co-administration resulted in a significant increase in apoptosis, GR protein, GR binding and GRα protein both in GC-sensitive CEM-C7 and GC-resistant CEM-C1 cells and a decrease in GRβ protein and GRβ/GRα only in CEM-C1 cells. Furthermore, an ovalbumin-induced rat asthma model was chosen to evaluate the effects of co-administration of Dex and combination of icariin and OA in vivo. Compared with the use of Dex alone, co-administration could protect blood lymphocyte from excessive apoptosis, significantly increasing GR binding, GR protein and mRNA of GRα while decreasing GRβ protein and mRNA of GRβ. The results suggested that combination of icariin and OA could increase sensitivity to GCs through attenuating in vivo and in vitro Dex-induced GR impairment.