Tung Chun-Liang, Chen Jyh-Cheng, Wu Chia-Hung, Peng Yi-Shuan, Chen Wen-Ching, Zheng Hao-Yu, Jian Yi-Jun, Wei Chia-Li, Cheng Ya-Ting, Lin Yun-Wei
Department of Pathology, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan; Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.
Department of Food Science, National Chiayi University, Chiayi, Taiwan.
Exp Cell Res. 2017 Aug 1;357(1):59-66. doi: 10.1016/j.yexcr.2017.04.026. Epub 2017 Apr 25.
Erlotinib (Tarceva) is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in the treatment of human non-small cell lung cancer (NSCLC). Salinomycin, a polyether antibiotic, has been promising a novel therapeutic agent for lung cancer, and down-regulated the expression of thymidylate synthase (TS) in NSCLC cell lines. Previous study showed that against EGFR and TS was strongly synergistic cytotoxicity in NSCLC cells. In this study, we showed that erlotinib (1.25-10μM) treatment down-regulating of TS expression in an AKT inactivation manner in two NSCLC cell lines, human lung squamous cell carcinoma H1703 and adenocarcinoma H1975 cells. Knockdown of TS using small interfering RNA (siRNA) or inhibiting AKT activity with PI3K inhibitor LY294002 enhanced the cytotoxicity and cell growth inhibition of erlotinib. A combination of erlotinib and salinomycin resulted in synergistic enhancement of cytotoxicity and cell growth inhibition in NSCLC cells, accompanied with reduced protein levels of phospho-AKT(Ser473), phospho-AKT(Thr308), and TS. Overexpression of a constitutive active AKT (AKT-CA) or Flag-TS expression vector reversed the salinomycin and erlotinib-induced synergistic cytotoxicity. Our findings suggested that the down-regulation of AKT-mediated TS expression by salinomycin enhanced the erlotinib-induced cytotoxicity in NSCLC cells. These results may provide a rationale to combine salinomycin with erlotinib for lung cancer treatment.
厄洛替尼（特罗凯）是一种选择性表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，用于治疗人类非小细胞肺癌（NSCLC）。沙利霉素是一种聚醚抗生素，有望成为一种新型肺癌治疗药物，它能下调NSCLC细胞系中胸苷酸合成酶（TS）的表达。先前的研究表明，针对EGFR和TS在NSCLC细胞中具有强烈的协同细胞毒性作用。在本研究中，我们发现厄洛替尼（1.25 - 10μM）处理可通过AKT失活的方式下调两种NSCLC细胞系（人肺鳞癌H1703细胞和腺癌H1975细胞）中TS的表达。使用小干扰RNA（siRNA）敲低TS或用PI3K抑制剂LY294002抑制AKT活性可增强厄洛替尼的细胞毒性和细胞生长抑制作用。厄洛替尼和沙利霉素联合使用可协同增强NSCLC细胞的细胞毒性和细胞生长抑制作用，同时降低磷酸化AKT（Ser473）、磷酸化AKT（Thr308）和TS的蛋白水平。组成型活性AKT（AKT-CA）的过表达或Flag-TS表达载体可逆转沙利霉素和厄洛替尼诱导的协同细胞毒性。我们的研究结果表明，沙利霉素通过下调AKT介导的TS表达增强了厄洛替尼在NSCLC细胞中的细胞毒性。这些结果可能为沙利霉素与厄洛替尼联合用于肺癌治疗提供理论依据。
