RT Journal Article
SR Electronic
T1 A Critical Role of Luteolin-Induced Reactive Oxygen Species in Blockage of Tumor Necrosis Factor-Activated Nuclear Factor-κB Pathway and Sensitization of Apoptosis in Lung Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1381
OP 1388
DO 10.1124/mol.106.032185
VO 71
IS 5
A1 Wei Ju
A1 Xia Wang
A1 Honglian Shi
A1 Wenshu Chen
A1 Steven A. Belinsky
A1 Yong Lin
YR 2007
UL http://molpharm.aspetjournals.org/content/71/5/1381.abstract
AB Nuclear factor κB (NF-κB) activated by tumor necrosis factor (TNF) attenuates the TNF-induced apoptosis pathway. Therefore, blockage of NF-κB should improve the anticancer activity of TNF. Luteolin, a naturally occurring polyphenol flavonoid, has been reported to sensitize colorectal cancer cells to TNF-induced apoptosis through suppression of NF-κB; however, the mechanisms of this effect have not been well elucidated. In this article, we provide evidence showing a critical role of reactive oxygen species (ROS) accumulation induced by luteolin in modulating TNF-activated pathways in lung cancer cells. Luteolin effectively suppressed NF-κB, whereas it potentiated the c-Jun N-terminal kinase (JNK) to increase apoptosis induced by TNF in lung cancer cells. Our results further demonstrate that luteolin induced an early phase ROS accumulation via suppression of the cellular superoxide dismutase activity. It is noteworthy that suppression of ROS accumulation by ROS scavengers butylated hydroxyanisole, and N-acetyl-l-cysteine prevented the luteolin-induced suppression of NF-κB and potentiation of JNK and significantly suppressed the synergistic cytotoxicity seen with cotreatment of luteolin and TNF. Taken together, these results suggest that the accumulation of ROS induced by luteolin plays a pivotal role in suppression of NF-κB and potentiation of JNK to sensitize lung cancer cells to undergo TNF-induced apoptosis. The American Society for Pharmacology and Experimental Therapeutics