Oxidative stress in NSC-741909-induced apoptosis of cancer cells
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RESEARCH
Oxidative stress in NSC-741909-induced apoptosis of cancer cells Research
Xiaoli Wei†1,2, Wei Guo†2, Shuhong Wu2, Li Wang2, Peng Huang3, Jinsong Liu4 and Bingliang Fang*2
Abstract Background: NSC-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. Methods: The 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. Results: Treatment 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. Conclusion: Our 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 NSC741909-mediated antitumor cell activity. Background We recently identified a small molecule (oncrasin-1) through cell-based synthetic lethality screening that can effectively kill several lung cancer cell lines harboring mutant K-Ras genes [1]. Subsequent analyses of oncrasin1 analogues led us to identify several active compounds with similar chemical structures. NSC-741909 is one of the oncrasin-1 analogues that was highly active against several cell lines derived from lung, colon, breast, ovarian, and kidney cancers when tested in NCI-60 cancer cell lines by the Developmental Therapeutics Program at * Correspondence: [email protected] 2 Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA † Contributed equally
the National Cancer Institute. Using a reverse-phase protein microarray assay, we determined molecular changes in 77 protein biomarkers in an oncrasin-sensitive lung cancer cell line a
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