Wang Jiankang, Luo Bingling, Li Xiaobing, Lu Wenhua, Yang Jing, Hu Yumin, Huang Peng, Wen Shijun
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, China.
Cell Death Dis. 2017 Jun 22;8(6):e2887. doi: 10.1038/cddis.2017.272.
Reactive oxygen species (ROS) have a crucial role in cell signaling and cellular functions. Mounting evidences suggest that abnormal increase of ROS is often observed in cancer cells and that this biochemical feature can be exploited for selective killing of the malignant cells. A naturally occurring compound phenethyl isothiocyanate (PEITC) has been shown to have promising anticancer activity by modulating intracellular ROS. Here we report a novel synthetic analog of PEITC with superior in vitro and in vivo antitumor effects. Mechanistic study showed that LBL21 induced a rapid depletion of intracellular glutathione (GSH), leading to abnormal ROS accumulation and mitochondrial dysfunction, evident by a decrease in mitochondrial respiration and transmembrane potential. Importantly, LBL21 exhibited the ability to abrogate stem cell-like cancer side population (SP) cells in non-small cell lung cancer A549 cells associated with a downregulation of stem cell markers including OCT4, ABCG2, SOX2 and CD133. Functionally, LBL21 inhibited the ability of cancer cells to form colonies in vitro and develop tumor in vivo. The therapeutic efficacy of LBL21 was further demonstrated in mice bearing A549 lung cancer xenografts. Our study suggests that the novel ROS-modulating agent LBL21 has promising anticancer activity with an advantage of elimination of stem-like cancer cells. This compound merits further study to evaluate its potential for use in cancer treatment.
活性氧（ROS）在细胞信号传导和细胞功能中起着至关重要的作用。越来越多的证据表明，癌细胞中常常观察到ROS异常增加，并且这种生化特征可被用于选择性杀死恶性细胞。一种天然存在的化合物苯乙基异硫氰酸酯（PEITC）已被证明通过调节细胞内ROS具有有前景的抗癌活性。在此，我们报告了一种新型的PEITC合成类似物，其具有优异的体外和体内抗肿瘤作用。机制研究表明，LBL21诱导细胞内谷胱甘肽（GSH）迅速消耗，导致ROS异常积累和线粒体功能障碍，线粒体呼吸和跨膜电位降低即为明证。重要的是，LBL21表现出消除非小细胞肺癌A549细胞中干细胞样癌侧群（SP）细胞的能力，这与包括OCT4、ABCG2、SOX2和CD133在内的干细胞标志物下调有关。在功能上，LBL21抑制癌细胞在体外形成集落和在体内形成肿瘤的能力。LBL21的治疗效果在携带A549肺癌异种移植瘤的小鼠中得到进一步证实。我们的研究表明，新型ROS调节剂LBL21具有有前景的抗癌活性，其优势在于能够消除干细胞样癌细胞。该化合物值得进一步研究以评估其在癌症治疗中的应用潜力。
