Blockage of NF-κB by IKKβ- or RelA-siRNA rather than the NF-κB super-suppressor IκBα mutant potentiates adriamycin-induced cytotoxicity in lung cancer cells

Ambiguous roles of genotoxic anticancer therapeutic-induced NF-kappa B activation in regulating gene expression (activation or suppression) and apoptosis (anti- or pro-apoptosis) have recently been suggested. In order to clarify this controversy and determine the usefulness of NF-kappa B blockage for sensitizing anticancer therapy, we have systematically investigated the effect of distinct NF-kappa B-blocking approaches on lung cancer cells' responses to Adriamycin-induced cytotoxicity. The results show that Adriamycin-induced NF-kappa B activation functions as a transcriptional activator triggering the expression of anti-apoptotic genes. Blocking NF-kappa B with IKK beta- or RelA siRNA substantially sensitized Adriamycin-induced cytotoxicity, suggesting that the NF-kappa B pathway could be a target for sensitizing lung cancer cells to Adriamycin's anticancer effect. Surprisingly, although it effectively blocks NF-kappa B activation, the I kappa B alpha super-suppressor (I kappa B alpha AA) antagonized Adriamycin-induced cell death. Additionally, the induction of death receptor 5 (DR5), which contributes to Adriamycin-induced cytotoxicity, was not affected by NF-kappa B blockage. Thus, our results suggest that Adriamycin-induced NF-KB is a transcriptional activator that protects lung cancer cells against apoptosis, and IKK beta- or RelA siRNA rather than I kappa B alpha AA is an appropriate NF-KB blocking approach for sensitizing lung cancer cells to Adriamycin-induced cytotoxicity.