Sensitization of tumor necrosis factor-induced lung cancer cell eath by luteolin

1371

Lung cancer is the leading cause of cancer-related death in the United States. Most lung cancer cells are resistant to chemotherapy, the mechanism of which is not well understood. Combinations of multiple anti-cancer drugs may be an effective strategy to improve the efficacy of lung cancer therapy. In this study, we examined the anti-cancer activity of tumor necrosis factor (TNF) combined with the flavonoid luteolin and found that luteolin treatment significantly sensitized lung cancer cells to TNF-induced cell death. The cell death induced by TNF and luteolin treatment is mainly apoptosis, which was detected both morphologically and biochemically. Although luteolin treatment had no effect on the expression levels of the key components of TNF receptor I signaling cascade including TRADD, RIP, TRAF2 and FADD, the TNF-induced NF-κB activation was effectively blocked, which is evidenced by NF-κB reporter assays and Western blots for the expression of NF-κB targeted anti-apoptosis genes. In the NF-κB-disabled cells expressing a non-degradable IκBα mutant (IκBαAA), the synergistic cytotoxicity induced by Luteolin and TNF treatment was abolished, suggesting that the potentiation of TNF-induced cell death by luteolin is achieved by blocking TNF-induced NF-κB activation. The target of the NF-κB pathway by luteolin appears to be downstream of IκB, since treatment with luteolin did not affect the TNF-induced IκBα phosphorylation and degradation. Altered modification of the RelA/p65 subunit of NF-κB in luteolin treated cells was detected, suggesting that modulation of the transcription activity contributes to the blockage of NF-κB by luteolin. In addition, we also found that luteolin augmented the TNF-induced c-Jun N-terminal protein kinase (JNK) activation, and suppression of JNK activity with a specific chemical inhibitor significantly inhibited the synergistic cytotoxicity induced by luteolin and TNF treatment. Thus activation of JNK may also contribute to the potentiation of cell death by luteolin. Taken together, our results suggest that luteolin potentiates TNF-induced lung cancer cell death through blockage of NF-κB and activation of JNK, and the combined treatment with luteolin and TNF could be useful for treating lung cancer.