Efficacy of gefitinib‑celecoxib combination therapy in docetaxel‑resistant prostate cancer

Abstract

Resistance to docetaxel is a major clinical problem in castration‑resistant prostate cancer (CRPC). We have previously reported that the combined inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase‑2 (COX‑2) led to an increased antitumor activity of docetaxel in CRPC. In the present study, we explored the efficacy of the combination of EGFR inhibition (by gefitinib) and COX‑2 inhibition (by celecoxib) as a potential treatment for docetaxel‑resistant CRPC. We established two docetaxel‑resistant prostate cancer cell lines, PC3/DR and DU145/DR, by culturing PC3 and DU145 cells in docetaxel in a dose‑escalating manner. The EGFR and COX‑2 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 Bcl‑2, FOXM1 and ABCB1 expression were analyzed. The expression of Ki‑67 and cleaved‑caspase‑3 was also examined in DU145/DR tumor tissue. The enhanced expression of EGFR and COX‑2 was observed in docetaxel‑resistant CRPC relative to the parental cell lines. MTT, clone formation and fluorescence‑activated 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 Bcl‑2, FOXM1 and ABCB1 expression levels. Furthermore, the gefitinib‑celecoxib combination inhibited DU145/DR tumor growth to a greater extent than either treatment used individually. The expression of Ki‑67 was reduced, whereas cleaved‑caspase‑3 protein expression was increased in the tumors from the combination therapy group. In conclusion, the combined inhibition of EGFR and COX‑2 by gefitinib and celecoxib may overcome docetaxel resistance in human CRPC. These findings provided a molecular basis for the clinical application of a novel combination therapy for docetaxel‑resistant CRPC.

Inferring therapeutic vulnerability within tumors through integration of pan-cancer cell line and single-cell transcriptomic profiles

“…Our in vitro experiments exposing vemurafenib in docetaxel resistant cells estimated an IC50 of 12.9 μM/L, which sits well below the safety dose, highlighting its clinical potential to be used in combination with docetaxel to control CRPC progression. Furthermore, two EGFR inhibitors have been proposed to combat docetaxel resistance by our computational pipeline (Figure 4D), consistent with previous studies suggesting that EGFR inhibitors mediate docetaxel resistance in CRPC 57,58 . To sum up, our scIDUC powered computational pipelines were able to quickly propose drug candidates with clinical impact.…”

Innate Immunity and Cancer Pathophysiology

“…COX2 inhibition increases TNF-α, IL-12, and iNOS expression, shifting the macrophages to an antitumor phenotype (222,223). In a phase I clinical trial for the treatment of docetaxel-resistant prostate cancer, patients treated with a COX2 inhibitor (celecoxib) and an epidermal growth factor receptor inhibitor (gefitinib) showed reduced tumor growth and invasion (224). HDAC inhibitors modify the epigenetic profile of monocytes and macrophages, resulting in altered gene expression and polarization toward an antitumor phenotype.…”

Molecular Repolarisation of Tumour-Associated Macrophages

“…Lastly, combination of celecoxib with EGFR inhibitor gefitinib was reported in a phase I clinical for the treatment of docetaxel-resistant prostate cancer. Combination treatment was well tolerated and inhibited tumour growth and tumour invasion in patients [134].…”