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A Critical Role of Luteolin-Induced Reactive Oxygen Species in Blockage of Tumor Necrosis Factor-Activated Nuclear Factor-B Pathway and Sensitization of Apoptosis in Lung Cancer Cells

Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico (W.J., X.W., W.C., S.A.B., Y.L.); and College of Pharmacy, University of New Mexico, Albuquerque, New Mexico (H.S.)

Nuclear factor B (NF-B) activated by tumor necrosis factor (TNF) attenuates the TNF-induced apoptosis pathway. Therefore, blockage of NF-B 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-B; 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-B, 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-B 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-B and potentiation of JNK to sensitize lung cancer cells to undergo TNF-induced apoptosis.

Address correspondence to: Dr. Yong Lin, Molecular Biology and Lung Cancer Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Drive SE, Albuquerque, NM 87108. E-mail: ylin{at}lrri.org

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