Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition (Retracted Article)
Diosmetin induces apoptosis and enhances the chemotherapeutic efficacy of paclitaxel in non-small cell lung cancer cells via Nrf2 inhibition (Retracted Article)
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DOI：
10.1111/bph.14652
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发表时间：
2019-06-01
影响因子：
7.3
通讯作者：
Liu, Bing
中科院分区：
文献类型：
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作者：
Chen, Xiangcui;Wu, Qipeng;Liu, Bing
背景与目的非小细胞肺癌（non-small cell lung cancer，NSCLC）占肺癌的80-85%，预后较差。黄酮类化合物发挥抗癌特性，主要涉及刺激ROS产生而对正常细胞没有显著毒性。本研究的目的是描述薯蓣皂苷，一种天然黄酮，对非小细胞肺癌细胞的影响，并提高紫杉醇的抗肿瘤活性的能力。实验方法以非小细胞肺癌细胞、正常细胞系HLF-1和BEAS-2B以及免疫缺陷小鼠为模型，研究薯蓣皂苷的作用。采用MTT法、流式细胞仪、荧光探针DCFH-DA检测细胞活力、凋亡和活性氧的变化，Western blotting和real-time RT-PCR检测蛋白质和mRNA的表达。测量异种移植肿瘤的生长。脾脏和其他重要器官进行了分析，组织学和免疫组织化学技术。Diosmetin通过ROS积累诱导NSCLC细胞选择性凋亡，但不影响正常细胞。薯蓣皂苷可能通过破坏PI 3 K/Akt/GSK-3 β途径降低Nrf 2稳定性而诱导NSCLC细胞中的ROS产生。体外和体内异种移植研究表明，薯蓣皂苷和紫杉醇联合治疗可协同抑制NSCLC细胞。重要器官的组织学分析显示薯蓣皂苷没有明显的毒性，这与我们的体外研究结果相匹配。Diosmetin通过破坏PI 3 K/Akt/GSK-3 β/Nrf 2通路，通过ROS积累选择性诱导NSCLC细胞凋亡，增强紫杉醇的疗效。因此，薯蓣皂苷可能是一个有前途的候选人，辅助治疗NSCLC。
Background and Purpose Non-small-cell lung cancer (NSCLC) accounts for up to 80-85% of all lung cancers and has a disappointing prognosis. Flavonoids exert anticancer properties, mostly involving stimulation of ROS production without significant toxicity to normal cells. This study was aimed to delineate the effect of diosmetin, a natural flavonoid, on NSCLC cells and its ability to enhance the antitumour activity of paclitaxel. Experimental Approach NSCLC cells, normal cell lines HLF-1 and BEAS-2B, and immunodeficient mice were chosen as models to study the effects of diosmetin. Changes in cell viability, apoptosis, and ROS were analysed by MTT assay, flow cytometry assay, and fluorescent probe DCFH-DA. Expression of proteins and mRNA was determined by Western blotting and real-time RT-PCR. Growth of xenografted tumours was measured. Spleens and other vital organs were analysed with histological and immunohistochemical techniques. Key Results Diosmetin induced selective apoptotic death in NSCLC cells but spared normal cells, via ROS accumulation. Diosmetin induced ROS production in NSCLC cells probably via reducing Nrf2 stability through disruption of the PI3K/Akt/GSK-3 beta pathway. The in vitro and in vivo xenograft studies showed that combined treatment of diosmetin and paclitaxel synergistically suppressed NSCLC cells. Histological analysis of vital organs showed no obvious toxicity of diosmetin, which matched our in vitro findings. Conclusions and Implications Diosmetin selectively induced apoptosis and enhanced the efficacy of paclitaxel in NSCLC cells via ROS accumulation through disruption of the PI3K/Akt/GSK-3 beta/Nrf2 pathway. Therefore, diosmetin may be a promising candidate for adjuvant treatment of NSCLC.