The curcuminoid CLEFMA selectively induces cell death in H441 lung adenocarcinoma cells via oxidative stress

被引:0
作者
Kaustuv Sahoo
Mikhail G. Dozmorov
Shrikant Anant
Vibhudutta Awasthi
机构
[1] University of Oklahoma Health Science Center,Department of Pharmaceutical Sciences
[2] Oklahoma Medical Research Foundation,Arthritis & Immunology Department
[3] University of Kansas Medical Center,Department of Molecular and Integrative Physiology
来源
Investigational New Drugs | 2012年 / 30卷
关键词
CLEFMA; Curcumin; Cancer; Reactive oxygen species; Oxidative stress;
D O I
暂无
中图分类号
学科分类号
摘要
CLEFMA or 4-[3,5-bis(2-chlorobenzylidene-4-oxo-piperidine-1-yl)-4-oxo-2-butenoic acid] is a curcuminoid being developed as an anticancer drug. We recently reported that it potently inhibits proliferation of various cancer cells. In this project, we investigated the effect of CLEFMA on gene expression profile in H441 lung adenocarcinoma cells, and studied its mechanism of action. In microarray data, we observed a deregulation of genes involved in redox and glutamate metabolism. Based on the affected ontologies, we hypothesized that antiproliferative activity of CLEFMA could be a result of the induction of reactive oxygen species (ROS). We tested this hypothesis by determining the levels of glutathione (GSH) and ROS in H441 cells treated with CLEFMA. We observed a rapid depletion of intracellular GSH/GSSG ratio. Using a cell-permeable fluorogenic substrate, we found that CLEFMA significantly induced ROS in a time- and dose-dependent manner (p < 0.05). Flow-cytometry with a mitochondria-selective fluorescent reporter of ROS indicated that the CLEFMA-induced ROS was of mitochondrial origin. In contrast to the cancer cells, the normal lung fibroblasts (CCL-151) did not show any increase in ROS and were resistant to CLEFMA-induced cell death. Furthermore, the addition of antioxidants, such as catalase, superoxide dismutase and N-acetylcysteine, rescued cancer cells from CLEFMA-induced cell death. Gene expression pathway analysis suggested that a transcription factor regulator Nrf2 is a pivotal molecule in the CLEFMA-induced deregulation of redox pathways. The immunoblotting of Nrf2 showed that CLEFMA treatment resulted in phosphorylation and nuclear translocation of Nrf2 in a time-dependent fashion. Based on these results, we conclude that induction of ROS is critical for the antiproliferative activity of CLEFMA and the Nrf2-mediated oxidative stress response fails to salvage H441 cells.
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页码:558 / 567
页数:9
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