Oxidative stress in NSC-741909-induced apoptosis of cancer cells.
Oxidative stress in NSC-741909-induced apoptosis of cancer cells.
复制标题
NSC-741909 诱导的癌细胞凋亡中的氧化应激
DOI：
10.1186/1479-5876-8-37
复制
发表时间：
2010-04-16
影响因子：
7.4
通讯作者：
Fang B
中科院分区：
文献类型：
--
作者：
Wei X;Guo W;Wu S;Wang L;Huang P;Liu J;Fang B
NSC-741909是一种新型的抗癌药物，能有效抑制肺癌、结肠癌、乳腺癌、卵巢癌和肾癌等多种肿瘤细胞的生长。我们最近发现，NSC-741909诱导的抗肿瘤活性与持续的Jun N-末端激酶（JNK）激活有关，这是由于抑制了与MAPK磷酸酶-1蛋白水平降低相关的JNK去磷酸化。然而，NSC-741909诱导的抗肿瘤活性的机制仍不清楚。由于JNK在细胞内经常被氧化应激激活，我们推测活性氧（ROS）可能参与抑制JNK去磷酸化和NSC-741909的细胞毒性。方法采用细胞可渗透的非荧光化合物H2 DCF-DA和流式细胞术检测ROS的产生。通过磺酰罗丹明B测定法测定细胞活力。结果NSC-741909处理后，NSC-741909敏感细胞株ROS产生明显增加，MAPK磷酸酶-1和-7聚集明显，呈剂量和时间依赖性，耐药细胞株则无明显变化。早在30分钟就可检测到ROS的产生，并且处理后ROS水平高达基础水平的6至8倍。此外，NSC-741909诱导的ROS产生可以通过用抗氧化剂如去甲二氢愈创木酸、七叶皂苷、黄芩素和咖啡酸预处理来阻断，结论NSC-741909诱导的JNK活化和细胞凋亡与ROS产生增加有关。NSC-741909诱导的抗肿瘤活性，ROS产生和随后的JNK活化是NSC-741909介导的抗肿瘤细胞活性的主要机制之一。
BackgroundNSC-741909 is a novel anticancer agent that can effectively suppress the growth of several cell lines derived from lung, colon, breast, ovarian, and kidney cancers. We recently showed that NSC-741909-induced antitumor activity is associated with sustained Jun N-terminal kinase (JNK) activation, resulting from suppression of JNK dephosphorylation associated with decreased protein levels of MAPK phosphatase-1. However, the mechanisms of NSC-741909-induced antitumor activity remain unclear. Because JNK is frequently activated by oxidative stress in cells, we hypothesized that reactive oxygen species (ROS) may be involved in the suppression of JNK dephosphorylation and the cytotoxicity of NSC-741909.MethodsThe generation of ROS was measured by using the cell-permeable nonfluorescent compound H2DCF-DA and flow cytometry analysis. Cell viability was determined by sulforhodamine B assay. Western blot analysis, immunofluorescent staining and flow cytometry assays were used to determine apoptosis and molecular changes induced by NSC-741909.ResultsTreatment with NSC-741909 induced robust ROS generation and marked MAPK phosphatase-1 and -7 clustering in NSC-741909-sensitive, but not resistant cell lines, in a dose- and time-dependent manner. The generation of ROS was detectable as early as 30 min and ROS levels were as high as 6- to 8-fold above basal levels after treatment. Moreover, the NSC-741909-induced ROS generation could be blocked by pretreatment with antioxidants, such as nordihydroguaiaretic acid, aesculetin, baicalein, and caffeic acid, which in turn, inhibited the NSC-741909-induced JNK activation and apoptosis.ConclusionOur results demonstrate that the increased ROS production was associated with NSC-741909-induced antitumor activity and that ROS generation and subsequent JNK activation is one of the primary mechanisms of NSC-741909-mediated antitumor cell activity.
登录
查看更多内容
影响因子：
5.3
作者：
Benhar, M;Dalyot, I;Levitzki, A
通讯作者：
Levitzki, A
影响因子：
4.6
作者：
Berndt, G;Grosser, N;Schröder, H
通讯作者：
Schröder, H
影响因子：
1.7
作者：
Maciag, A;Anderson, LM
通讯作者：
Anderson, LM
影响因子：
4.8
作者：
Ling, YH;Liebes, L;Perez-Soler, R
通讯作者：
Perez-Soler, R
影响因子：
64.5
作者：
Kohanski, Michael A.;Dwyer, Daniel J.;Collins, James J.
通讯作者：
Collins, James J.