Icotinib hydrochloride enhances chemo- and radiosensitivity by inhibiting EGFR signaling and attenuating RAD51 expression and function in Hela S3 cells.
Icotinib hydrochloride enhances chemo- and radiosensitivity by inhibiting EGFR signaling and attenuating RAD51 expression and function in Hela S3 cells.
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盐酸埃克替尼通过抑制 EGFR 信号传导并减弱 Hela S3 细胞中的 RAD51 表达和功能来增强化疗和放射敏感性。
DOI：
10.2147/ott.s152613
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发表时间：
2018
影响因子：
4
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Wang X;Gu Y;Liu H;Shi L;Sun X
放射治疗和顺铂为基础的化疗目前被认为是标准的治疗晚期宫颈癌（CC）。然而，局部复发或远处转移的患者仍然预后不良。EGFR过表达与化疗/放疗耐药及疾病失败相关，已有研究证实。因此，本研究的目的是探讨高选择性EGFR酪氨酸激酶抑制剂（TKI）盐酸埃克替尼（IH）对人宫颈癌细胞系Hela S3的疗效及其对放疗或顺铂增敏的机制。CCK-8法检测细胞增殖;流式细胞仪分析细胞周期分布和凋亡。Western blot分析EGFR及其下游信号分子的磷酸化。免疫荧光染色观察细胞核内γ-H2 AX灶和RAD 51灶。检测全细胞和细胞下组分中RAD 51的表达水平，以证明IH对DNA修复的影响。IH可通过抑制EGFR信号通路的激活和降低同源重组（homologous recombination，HR）蛋白RAD 51的表达和功能，显著抑制Hela S3细胞在放射或顺铂处理后的细胞增殖、细胞周期重新分布、促进细胞凋亡和损害DNA损伤反应。这项研究表明，IH是一种潜在的敏化剂，在放射治疗和顺铂为基础的化学治疗CC和RAD 51可以作为一个预后的生物标志物，这种组合治疗。
Radiotherapy and cisplatin-based chemotherapy are currently considered as standard treatments employed for advanced cervical cancer (CC). However, patients with local recurrence or distant metastasis continue to have poor outcomes. EGFR overexpression correlated with chemo/radioresistance, and disease failure has been well proved in the previous studies. Hence, the aim of this study was to explore the therapeutic efficacy and underlying mechanism of the sensitization to radiation or cisplatin of icotinib hydrochloride (IH), a high-selective EGFR tyrosine kinase inhibitor (TKI), in the Hela S3 human CC cell line. Cell proliferation was measured with cell counting kit-8 (CCK-8) assay. Flow cytometry analysis was performed to examine cell cycle distribution and apoptosis. The phosphorylation of EGFR and its downstream signaling molecules were measured by Western blot analysis. γ-H2AX foci and RAD51 foci in the cellular nucleus were visualized using immunofluoresence staining. Expression levels of RAD51 in the whole cells and subceullar fractions were detected to demonstrate the impact of IH on DNA repair. IH can significantly inhibit cell proliferation, redistribute cell cycle, enhance apoptosis and impair DNA damage response of Hela S3 cells following radiation or cisplatin treatment through suppressing the activation of the EGFR signaling pathway and attenuating the expression and function of homologous recombination (HR) protein RAD51. This study suggests that IH is a potential sensitizer in radiotherapy and cisplatin-based chemotherapy for CC and RAD51 may serve as a prognosis biomarker for this combination treatment.