RESUMO
Resistance to docetaxel is a major clinical problem in castrationresistant prostate cancer (CRPC). We have previously reported that the combined inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase2 (COX2) led to an increased antitumor activity of docetaxel in CRPC. In the present study, we explored the efï¬cacy of the combination of EGFR inhibition (by gefitinib) and COX2 inhibition (by celecoxib) as a potential treatment for docetaxelresistant CRPC. We established two docetaxelresistant prostate cancer cell lines, PC3/DR and DU145/DR, by culturing PC3 and DU145 cells in docetaxel in a doseescalating manner. The EGFR and COX2 protein expression levels were determined. The effects of gefitinib and celecoxib on cell proliferation, apoptosis and invasion in vitro and in vivo were evaluated. In vitro changes in Bcl2, FOXM1 and ABCB1 expression were analyzed. The expression of Ki67 and cleavedcaspase3 was also examined in DU145/DR tumor tissue. The enhanced expression of EGFR and COX2 was observed in docetaxelresistant CRPC relative to the parental cell lines. MTT, clone formation and fluorescenceactivated cell sorting (FACS) analyses demonstrated that gefitinib and celecoxib in combination decreased cell viability and enhanced the rate of apoptosis when compared with either drug used alone. Additionally, the combination treatment was superior in inhibiting cell invasion and induced significant decreases in Bcl2, FOXM1 and ABCB1 expression levels. Furthermore, the gefitinibcelecoxib combination inhibited DU145/DR tumor growth to a greater extent than either treatment used individually. The expression of Ki67 was reduced, whereas cleavedcaspase3 protein expression was increased in the tumors from the combination therapy group. In conclusion, the combined inhibition of EGFR and COX2 by gefitinib and celecoxib may overcome docetaxel resistance in human CRPC. These ï¬ndings provided a molecular basis for the clinical application of a novel combination therapy for docetaxelresistant CRPC.
