Kang Ning, Cao Shijie, Jiang Benke, Zhang Qiang, Donkor Paul Owusu, Zhu Yan, Qiu Feng, Gao Xiumei
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
Toxicol In Vitro. 2020 Sep;67:104885. doi: 10.1016/j.tiv.2020.104885. Epub 2020 May 12.
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.
如先前报道，西妥昔单抗联合冬凌草甲素对喉鳞状细胞癌（LSCC）具有协同杀伤作用。本研究进一步从机制上深入探讨了联合治疗协同效应的作用。首先，两种LSCC细胞对冬凌草甲素表现出更高的敏感性，而低表皮生长因子受体（EGFR）表达的肿瘤细胞和EGFR敲低的LSCC细胞对冬凌草甲素的敏感性较低。其次，西妥昔单抗/冬凌草甲素通过核因子κB（NF-κB）显著增强线粒体凋亡。同时，联合治疗通过PI3K/Akt和JAK2/STAT3信号通路与NF-κB的核转位相关。此外，西妥昔单抗增强了冬凌草甲素诱导的内质网应激相关凋亡。有趣的是，联合治疗引起的内质网应激和线粒体凋亡均被活性氧（ROS）清除剂消除。此外，冬凌草甲素/西妥昔单抗在1.5小时后诱导ROS产生，随后导致G2/M期阻滞和凋亡，表明ROS的产生可能是一个早期关键事件。综上所述，西妥昔单抗增强了冬凌草甲素诱导的内质网应激和线粒体凋亡途径，这有助于西妥昔单抗/冬凌草甲素的协同抗肿瘤作用。
