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

Lin,Jian‑Zhong; Hameed,Irbaz; Xu,Zhen; Yu,Yang; Ren,Zhi‑Yun; Zhu,Jia‑Geng

doi:10.3892/or.2018.6595

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

Authors:
- Jian‑Zhong Lin
- Irbaz Hameed
- Zhen Xu
- Yang Yu
- Zhi‑Yun Ren
- Jia‑Geng Zhu
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Affiliations: Department of Urology and Central Laboratory, BenQ Medical Center, Nanjing Medical University, Nanjing, Jiangsu 210019, P.R. China, Department of Cancer Research, Southeast University, Nanjing, Jiangsu 210009, P.R. China, Department of Urology, Taizhou People's Hospital, Taizhou, Jiangsu 225300, P.R. China, Department of Cancer Research, The First Clinical Medical College, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China, Central Laboratory, BenQ Medical Center, Nanjing Medical University, Nanjing, Jiangsu 210019, P.R. China, Department of Urology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu 210006, P.R. China
Published online on: July 24, 2018 https://doi.org/10.3892/or.2018.6595
Pages: 2242-2250

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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.

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