Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells.
Inhibition of cancer growth in vitro and in vivo by a novel ROS-modulating agent with ability to eliminate stem-like cancer cells.
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一种能够消除干细胞样癌细胞的新型ROS调节剂在体外和体内抑制癌症生长
DOI：
10.1038/cddis.2017.272
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发表时间：
2017-06-22
影响因子：
9
通讯作者：
Wen S
中科院分区：
文献类型：
--
作者：
Wang J;Luo B;Li X;Lu W;Yang J;Hu Y;Huang P;Wen S
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，在癌细胞中经常观察到ROS的异常增加，这一生化特征可以被用来选择性地杀伤肿瘤细胞。一种天然存在的化合物异硫氰酸苯乙酯(PEITC)被证明通过调节细胞内ROS具有良好的抗癌活性。在这里，我们报道了一种新的合成的PEITC类似物，在体外和体内都有良好的抗肿瘤作用。机制研究表明，LBL21诱导细胞内谷胱甘肽(GSH)迅速耗竭，导致ROS异常积聚和线粒体功能障碍，明显表现为线粒体呼吸和跨膜电位下降。重要的是，LBL21能够通过下调干细胞标记物OCT4、ABCG2、SOX2和CD133的表达来消除非小细胞肺癌A549细胞中的干细胞样癌侧群(SP)细胞。在功能上，LBL21抑制了癌细胞在体外形成集落和在体内形成肿瘤的能力。LBL21对荷A549肺癌移植瘤小鼠的治疗作用进一步得到证实。我们的研究表明，新型ROS调节剂LBL21具有良好的抗癌活性，具有消除干细胞样癌细胞的优势。这种化合物值得进一步研究，以评估其在癌症治疗中的潜力。
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.
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