Combined oridonin with cetuximab treatment shows synergistic anticancer effects on laryngeal squamous cell carcinoma: Involvement of inhibition of EGFR and activation of reactive oxygen species-mediated JNK pathway
Combined oridonin with cetuximab treatment shows synergistic anticancer effects on laryngeal squamous cell carcinoma: Involvement of inhibition of EGFR and activation of reactive oxygen species-mediated JNK pathway
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冬凌草甲素与西妥昔单抗联合治疗对喉鳞状细胞癌具有协同抗癌作用：参与抑制EGFR和激活活性氧介导的JNK通路
DOI：
10.3892/ijo.2016.3696
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发表时间：
2016-11-01
影响因子：
5.2
通讯作者：
Kang, Ning
中科院分区：
文献类型：
--
作者：
Cao, Shijie;Xia, Meijuan;Kang, Ning
表皮生长因子受体（EGFR）是一种跨膜糖蛋白，在大部分喉鳞状细胞癌（LSCC）中高水平表达。西妥昔单抗 (Cet) 是一种抗 EGFR 单克隆抗体，对于头颈鳞状细胞癌患者的临床效果有限。我们之前的研究表明冬凌草甲素 (ORI) 是一种从冬凌草中分离出来的天然安全的贝壳杉烯二萜类化合物，它通过抑制 EGFR 磷酸化来抑制 HEp-2 细胞的生长。本研究的目的是确定 ORI 是否可以提高 Cet 对 LSCC 的抗癌功效。我们观察到，在两种 LSCC 细胞系（HEp-2 和 Tu212 细胞）中，与 Cet 和 ORI 组合可协同抑制与 Fas 介导的细胞凋亡和 G2/M 期停滞相关的细胞生长。此外，联合治疗导致与 p-EGFR 抑制和活性氧 (ROS) 介导的 JNK 通路激活相关的细胞死亡。在携带 HEp-2 异种移植物的裸鼠中，ORI 加 Cet 通过诱导细胞凋亡和抑制增殖引起显着的肿瘤消退，且无副作用。总之，我们的研究结果表明 ORI 和 Cet 的组合有可能增强肿瘤反应，并可能显着改善 LSCC 的治疗结果。
Epidermal growth factor receptor (EGFR), a trans membrane glycoprotein, is expressed at high levels in a large proportion of laryngeal squamous cell carcinoma (LSCC). Cetuximab (Cet), an anti-EGFR monoclonal antibody, has limited clinical outcome for patients with head and neck squamous cell carcinoma. Our previous studies showed that oridonin (ORI), a natural and safe kaurene diterpenoid isolated from Rabdosia rubescens, inhibited cell growth in HEp-2 cells through inhibition of EGFR phosphorylation. The aim of the present study was to determine whether ORI could improve the anticancer efficacy of Cet on LSCC. We observed that the combination with Cet and ORI synergistically inhibited cell growth associated with Fas-mediated apoptosis and G2/M phase arrest in two LSCC cell lines (HEp-2 and Tu212 cells). Moreover, combination treatment caused cell death associated with suppression of p-EGFR and activation of reactive oxygen species (ROS)-mediated JNK pathway. In nude mice bearing HEp-2 xenografts, ORI plus Cet caused a significant tumor regression through induction of apoptosis and inhibition of proliferation with no side-effect. Together, our findings suggest that the combination of ORI and Cet has the potential to enhance tumor responses and may significantly improve therapeutic outcomes in LSCC.