Cetuximab plus oridonin showed a synergistic way to kill laryngeal squamous cell carcinoma (LSCC), as been reported previously. The present work further mechanistically extended action of the synergistic effects of combination treatment. Firstly, two LSCC cells displayed higher sensitivity to oridonin, whereas both low EGFR expression tumor cells and EGFR knockdown LSCC cells were less sensitive to oridonin. Next, cetuximab/oridonin significantly enhanced the mitochondrial apoptosis through NF-κB. Meanwhile, PI3K/Akt and JAK2/STAT3 pathways are associated with the nucleus translocation of NF-κB by combination treatment. Additionally, cetuximab enhanced oridonin-promoted ER stress-related apoptosis. Interestingly, both ER stress and mitochondrial apoptosis by combination treatment are abrogated by ROS scavenger. Furthermore, oridonin/cetuximab induced ROS production after 1.5 h, followed by G2/M arrest and apoptosis, indicating that ROS generation might be an early and key event. Taken together, cetuximab enhances oridonin-induced ER stress and mitochondrial apoptotic pathway, which contributes to the synergistic antitumor effects of cetuximab/oridonin.

中文翻译：

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西妥昔单抗通过线粒体途径和内质网应激作用，增强了Oridonin诱导的细胞凋亡。

如先前报道，西妥昔单抗加冬凌草甲素显示出杀死喉鳞状细胞癌（LSCC）的协同方式。本工作进一步在机械上扩展了联合治疗的协同作用。首先，两个LSCC细胞对Oridonin的敏感性较高，而低EGFR表达的肿瘤细胞和EGFR敲低的LSCC细胞对Oridonin的敏感性均较低。接下来，西妥昔单抗/奥多菌素通过NF-κB明显增强了线粒体的凋亡。同时，PI3K / Akt和JAK2 / STAT3通路与联合治疗NF-κB的核易位相关。此外，西妥昔单抗增强了冬凌草甲素促进的内质网应激相关的细胞凋亡。有趣的是，ROS清除剂废除了通过联合处理的ER应激和线粒体凋亡。此外，1.5小时后，冬凌草甲素/西妥昔单抗诱导ROS产生，随后G2 / M停滞和细胞凋亡，表明ROS的产生可能是早期和关键事件。两者合计，西妥昔单抗可增强Oridonin诱导的内质网应激和线粒体细胞凋亡途径，从而有助于西妥昔单抗/奥里多宁的协同抗肿瘤作用。