Abstract
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.
Footnotes
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This work was partly supported by National Institutes of Health grants CA095568 and P30-ES012072.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.106.032185.
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ABBREVIATIONS: TNF, tumor necrosis factor; NF-κB, nuclear factor κB; ROS, reactive oxygen species; JNK, c-Jun N-terminal kinase; NAC, N-acetyl-l-cysteine; BHA, butylated hydroxyanisole; TNFR1, tumor necrosis factor receptor 1; IKK, IκB kinase; MnSOD, manganese superoxide dismutase; SOD, superoxide dismutase; CCS, copper chaperon for superoxide dismutase-1; LDH, lactase dehydrogenase; 1O2, ·OH, singlet oxygen; LOO ·, peroxyl radical; Cu-ZnSOD, copper-zinc superoxide dismutase; PARP, poly(ADP-ribose) polymerase; CM-H2DCFDA, 5-(and -6)-chloromethyl-2′,7′-dichlorodihydro-fluorescein diacetate acetyl ester; DHE, dihydroethidium; PAGE, polyacrylamide gel electrophoresis; MKP, mitogen-activated protein kinase phosphatase; SP600125, anthra[1,9-cd]pyrazol-6(2H)-one1,9-pyrazoloanthrone; zVAD-fmk, benzyloxy-carbonyl-Val-Ala-Asp fluoro-methylketone.
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The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
- Received October 24, 2006.
- Accepted February 12, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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