AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species
AD-1, a novel ginsenoside derivative, shows anti-lung cancer activity via activation of p38 MAPK pathway and generation of reactive oxygen species
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AD-1 是一种新型人参皂苷衍生物，通过激活 p38 MAPK 通路和产生活性氧而具有抗肺癌活性
DOI：
10.1016/j.bbagen.2013.04.008
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发表时间：
2013-08-01
影响因子：
3
通讯作者：
Xie, Qiang-Min
中科院分区：
文献类型：
--
作者：
Zhang, Lin-Hui;Jia, Yong-Liang;Xie, Qiang-Min
背景：人参是一种传统的中草药，已经使用了数千年。方法：采用MTT法检测AD-1的细胞毒活性，流式细胞仪检测细胞周期、细胞凋亡和活性氧（ROS）的变化。Western blot和免疫组织化学分析信号通路。结果：AD-1浓度依赖性地降低肺癌细胞的存活率，但不影响正常人肺上皮细胞的存活率。在A549和H292肺癌细胞中，AD-1诱导G（0）/G（1）细胞周期停滞、凋亡和ROS产生。ROS清除剂-N-乙酰半胱氨酸（NAC）可减弱细胞凋亡。此外，AD-1上调p38的表达和ERK磷酸化。添加p38抑制剂SB 203580抑制AD-1诱导的细胞活力降低。此外，p38基因的沉默减弱了p38的表达，减少了AD-1诱导的细胞凋亡。用NAC处理减少AD-1诱导的p38磷酸化，这表明ROS产生参与AD-1诱导的p38活化。在小鼠中，口服AD-1（10-40 mg/kg）剂量依赖性地抑制异种移植肿瘤的生长而不影响体重，并降低肿瘤组织中VEGF、MMP-9和CD 34的表达。TUNEL染色证实，从AD-1治疗小鼠的肿瘤表现出显着更高的凋亡index.Conclusions和一般意义：这些数据支持AD-1作为一个潜在的代理肺癌治疗的发展。(c)2013爱思唯尔有限公司版权所有。
Background: Ginseng is a traditional Chinese herb that has been used for thousands of years. In the present study, effects and mechanisms of AD-1 were evaluated for its development as a novel anti-lung cancer drug.Methods: The cytotoxic activity was evaluated by MTT assay, Flow cytometry was employed to detect cell cycle, apoptosis and ROS. Western blot and immunohistochemistry were used to analyze signaling pathways. Lung cancer xenograft models were established by subcutaneous implantation of A549 or H292 cells into nude mice.Results: AD-1 concentration-dependently reduces lung cancer cell viability without affecting normal human lung epithelial cell viability. In A549 and H292 lung cancer cells, AD-1 induces G(0)/G(1) cell cycle arrest, apoptosis and ROS production. The apoptosis can be attenuated by a ROS scavenger - N-acetylcysteine (NAC). In addition, AD-1 up-regulates the expression of p38 and ERK phosphorylation. Addition of a p38 inhibitor SB203580, suppresses the AD-1-induced decrease in cell viability. Furthermore, genetic silencing of p38 attenuates the expression of p38 and decreases the AD-1-induced apoptosis. Treatment with NAC reduces AD-1-induced p38 phosphorylation, which indicates that ROS generation is involved in the AD-1-induced p38 activation. In mice, oral administration of AD-1 (10-40 mg/kg) dose-dependently inhibited the growth of xenograft tumors without affecting body weight and decreases the expression of VEGF, MMP-9 and CD34 in tumor tissue. TUNEL staining confirms that the tumors from AD-1 treated mice exhibit a markedly higher apoptotic index.Conclusions and general significance: These data support development of AD-1 as a potential agent for lung cancer therapy. (c) 2013 Elsevier B.V. All rights reserved.