Table_1_Antitumor and Radiosensitization Effects of a CXCR2 Inhibitor in Nasopharyngeal Carcinoma.docx

CXCR2, a member of the G-protein-coupled cell surface chemokine receptor family, is commonly found on leukocytes, endothelial cells and tumor cells including nasopharyngeal carcinoma cells. However, how the activity of CXCR2 and its ligand CXCL8 affects the development of nasopharyngeal carcinoma (NPC) remains unknown. Here, we found that CXCR2 and CXCL8 were both predicted poor prognosis in NPC patients. Furthermore, we identified that treatment with CXCR2 antagonist SB225002 of nasopharyngeal carcinoma cell lines resulted tumorigenesis inhibition in vitro and in vivo. In addition, we found that SB225002 could enhance NPC cells radiosensitivity through regulating cell circle distribution and interfering with cellular DNA damage repair. SB225002 also exhibited an efficient radiosensitization effect in C666-1 and HONE-1 bearing mice. Functionally, we showed that SB225002 reduced microvessel density and proliferation and induced tumor apoptosis. Furthermore, changes in the tumor microenvironment were also observed in this study. We observed that SB225002 reduced tumor-associated neutrophils (TANs) in the tumors tissue which were recruited especially after irradiation. Taken together, our results suggested that targeting the CXCL8-CXCR2 pathway is a promising therapeutic strategy for comprehensive NPC treatment.

CXC趋化因子受体2（CXCR2）是G蛋白偶联细胞表面趋化因子受体家族成员，广泛表达于白细胞、内皮细胞及包括鼻咽癌细胞在内的多种肿瘤细胞。然而，CXCR2及其配体CXCL8的活性如何影响鼻咽癌（nasopharyngeal carcinoma, NPC）的发生发展，目前尚未明确。本研究发现，CXCR2与CXCL8的异常高表达均预示鼻咽癌患者预后不良。进一步实验显示，采用CXCR2拮抗剂SB225002处理鼻咽癌细胞系，可在体外及体内有效抑制肿瘤发生。此外，本研究证实SB225002可通过调控细胞周期分布、干扰细胞DNA损伤修复过程，增强鼻咽癌细胞的放射敏感性；在接种C666-1与HONE-1细胞的荷瘤小鼠模型中，SB225002同样展现出显著的放射增敏效应。功能学实验表明，SB225002可降低肿瘤组织微血管密度、抑制肿瘤细胞增殖并诱导肿瘤细胞凋亡。同时，本研究还观察到肿瘤微环境的显著改变：经SB225002处理后，放疗后在肿瘤组织内募集的肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）数量明显减少。综上，本研究结果提示，靶向CXCL8-CXCR2通路是一种极具应用前景的鼻咽癌综合治疗策略。