LZ-106, a novel analog of enoxacin, inducing apoptosis via activation of ROS-dependent DNA damage response in NSCLCs
LZ-106, a novel analog of enoxacin, inducing apoptosis via activation of ROS-dependent DNA damage response in NSCLCs
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LZ-106，一种新型依诺沙星类似物，通过激活 NSCLC 中 ROS 依赖性 DNA 损伤反应诱导细胞凋亡
DOI：
10.1016/j.freeradbiomed.2016.03.007
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发表时间：
2016
影响因子：
7.4
通讯作者：
Wei Libin
中科院分区：
文献类型：
--
作者：
Yang Lin;Yuan Yinan;Fu Chengyu;Xu Xuefen;Zhou Jieying;Wang Shuhao;Kong Lingyi;Li Zhiyu;Guo Qinglong;Wei Libin
肺癌，尤其是非小细胞肺癌（NSCLC），在癌症中占据主导地位，与多种致命结果密切相关。不幸的是，尽管过去二十年已经进行了深入的研究，但目前 NSCLC 的分子机制和临床治疗仍有待探索。最近，人们对寻找可利用的抗癌药物来源的关注重新集中在喹诺酮类化合物上。喹诺酮类化合物是一种长期临床应用的抗生素，因其不仅对细菌而且对真核生物具有显着的细胞杀伤活性。在这项研究中，我们发现 LZ-106（依诺沙星的类似物）在培养细胞和异种移植小鼠模型中对 NSCLC 表现出有效的抑制作用。我们通过膜联蛋白-V/PI双染色测定、膜电位检测、钙水平检测和关键凋亡蛋白的表达分析，确定了LZ-106通过线粒体和内质网（ER）应激凋亡途径在NSCLC细胞中诱导凋亡的作用。通过彗星实验、活性氧（ROS）检测、DNA损伤反应（DDR）标记γ-H2AX和其他DDR相关蛋白的表达分析，我们还证明LZ-106显着诱导ROS过量产生和DDR。有趣的是，我们的研究结果中的其他证据表明，在 ROS 清除剂 N-乙酰半胱氨酸 (NAC) 存在的情况下，DDR 和细胞凋亡可以得到缓解，表明 ROS 依赖性 DDR 参与 LZ-106 诱导的细胞凋亡。因此，我们的数据不仅为NSCLC提供了新的治疗候选药物，而且为喹诺酮类药物的药理学研究提供了新的见解。
Lung cancer, especially non-small-cell lung cancer (NSCLC), plays the leading role in cancer which is closely related to a myriad of fatal results. Unfortunately, current molecular mechanisms and clinical treatment of NSCLC still remain to be explored despite the fact that intensive investigations have been carried out in the last two decades. Recently, growing attention to finding exploitable sources of anticancer agents is refocused on quinolone compounds, an antibiotic with a long period of clinic application, for their remarkable cell-killing activity against not only bacteria, but eukaryotes as well. In this study, we found LZ-106, an analog of enoxacin, exhibiting potent inhibitory effects on NSCLC in both cultured cells and xenograft mouse model. We identified apoptosis-inducing action of LZ-106 in NSCLC cells through the mitochondrial and endoplasmic reticulum (ER)-stress apoptotic pathways via Annexin-V/PI double-staining assay, membrane potential detection, calcium level detection and the expression analysis of the key apoptotic proteins. Through comet assay, reactive oxygen species (ROS) detection, the expression analysis of DNA damage response (DDR) marker γ-H2AX and other DDR-related proteins, we also demonstrated that LZ-106 notably induced ROS overproduction and DDR. Interestingly, additional evidence in our findings revealed that DDR and apoptosis could be alleviated in the presence of ROS scavenger N-acetyl-cysteine (NAC), indicating ROS-dependent DDR involvement in LZ-106-induced apoptosis. Thus our data not only offered a new therapeutic candidate for NSCLC, but also put new insights into the pharmacological research of quinolones.