title: Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells.
abstract: Dysregulation of the discoidin domain receptors (DDRs) has been implicated in the development of numerous types of tumors, including head and neck cancer, and nasopharyngeal, breast, ovarian and esophageal carcinomas. Furthermore, agents that inhibit DDR1 activity are hypothesized to be useful for the treatment of nasopharyngeal carcinoma (NPC). The aim of the present study was to evaluate the effect of the DDR1 inhibitory (3-(2-(pyrazolo(1,5-a)pyrimidin-6-yl)-ethynyl)benzamide compound, 7RH, in NPC cells bothin vitroandin vivo, and its effect when used in combination with dasatinib, a SRC family kinase (SFK) inhibitor. The effects of 7RH alone or in combination with dasatinib on cell viability were assessed using MTT assays and apoptosis was detected by flow cytometry. In addition, western blotting was performed to analyze the relative protein expression levels of cell cycle-associated genes in human NPC cell lines (CNE1, CNE2, HONE1 and SUNE1). Cell migration was also assessed using cell adhesion assays. Furthermore, tumor xenografts of CNE2 NPC cells were established in nude mice and the growth inhibitory effects of 7RH treatment alone or in combination with dasatinib were evaluated. Finally, knockdown of DDR1 protein expression was achieved by transfection of CNE2 cells with DDR1-specific small interfering RNA. Treatment with 7RH effectively suppressed the proliferation and induced the apoptosis of NPC cells. In addition, the Janus kinase 1 (JAK1)/signal transducer and activator of transcription (STAT3) signaling pathway was downregulated by 7RH, whereas the activities of the Ras/Raf/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways were upregulated in response to 7RH treatment. Furthermore, the expression levels of phosphorylated SRC were increased in NPC cells treated with 7RH; thus indicating that SRC exhibits a vital function in the resistance of NPC cells to 7RH via activation of the PI3K/AKT signaling pathway. The results of the present study indicate that DDR1 and SFK inhibition may present a potential therapeutic strategy for patients with NPC.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Qiu-Ping
authors.initials: QP
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China.
authors.forename: Wen-Dan
authors.initials: WD
authors.lastname: Chen
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Jie-Ren
authors.initials: JR
authors.lastname: Peng
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Yao-Dong
authors.initials: YD
authors.lastname: Xu
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Cai
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China.
authors.forename: Gong-Kan
authors.initials: GK
authors.lastname: Feng
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong 510530, P.R. China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510275, P.R. China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510120, P.R. China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Guan
keywords: Janus kinase 1/signal transducer and activator of transcription 3; Src; dasatinib; discoidin domain receptor 1 inhibitor; nasopharyngeal carcinoma