Li Bo, Yu Yin, Jiang Yanan, Zhao Lili, Li Ang, Li Mingzhu, Yuan Baoyin, Lu Jing, Dong Ziming, Zhao Jimin, Liu Kangdong
The Pathophysiology Department, School of Basic Medical Sciences, College of Medicine, Zhengzhou University, Zhengzhou, 450000, China.
China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, China.
Cell Death Discov. 2021 Jun 21;7(1):166. doi: 10.1038/s41420-021-00509-w.
Esophageal squamous cell carcinoma (ESCC) is a major type of esophageal cancer. The prognosis of patients with ESCC remains poor because of the high morbidity and mortality of the disease. One strategy for drug discovery for ESCC treatment or prevention is screening FDA-approved drugs. In the present study, we found that the antitussive agent cloperastine can inhibit the proliferation of ESCC cells. However, the underlying mechanism was unclear. To determine the mechanism of this inhibitory effect, we performed proteomic analysis using KYSE150 cells treated with cloperastine and DMSO. The results identified several down-regulated signaling pathways included those of three key proteins (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex 1, NADH ubiquinone oxidoreductase subunit S5, and cytochrome C oxidase subunit 6B1) involved in oxidative phosphorylation. Meanwhile, we observed that oxidative phosphorylation in mitochondria was inhibited by the drug. Importantly, cloperastine suppressed ESCC growth in a xenograft mouse model in vivo. Our findings revealed that cloperastine inhibits the proliferation of ESCC in vivo and in vitro by suppressing mitochondrial oxidative phosphorylation.
食管鳞状细胞癌（ESCC）是食管癌的主要类型。由于该疾病的高发病率和死亡率，ESCC患者的预后仍然很差。筛选美国食品药品监督管理局（FDA）批准的药物是一种用于ESCC治疗或预防的药物发现策略。在本研究中，我们发现镇咳药氯哌斯汀可以抑制ESCC细胞的增殖。然而，其潜在机制尚不清楚。为了确定这种抑制作用的机制，我们对用氯哌斯汀和二甲基亚砜（DMSO）处理的KYSE150细胞进行了蛋白质组学分析。结果确定了几个下调的信号通路，包括参与氧化磷酸化的三种关键蛋白（NADH脱氢酶[泛醌]1α亚复合体1、NADH泛醌氧化还原酶亚基S5和细胞色素C氧化酶亚基6B1）的信号通路。同时，我们观察到该药物抑制了线粒体中的氧化磷酸化。重要的是，氯哌斯汀在体内异种移植小鼠模型中抑制了ESCC的生长。我们的研究结果表明，氯哌斯汀通过抑制线粒体氧化磷酸化在体内和体外抑制ESCC的增殖。
