Transfer of IκBα gene increase the sensitivity of paclitaxel mediated with caspase 3 activation in human lung cancer cell

In oncogenic therapies, apoptosis seems to be the important mechanism of deciding chemotherapy effect. NF-κB transcription factors are implicated in the control of cell proliferation and apoptosis. NF-κB is activated by chemotherapy and by irradiation, and this pathway has been shown to protect cells potently from their stimuliinduced apoptosis. Furthermore, inhibition of NF-κB leads to enhanced apoptosis in response to various stimuli. However, because the role of NF-κB as a modifier of the intrinsic chemosensitivity of cancer cells is less clear, we have studied the impact of IκBα (an inhibitor of NF-κB) on the chemosensitivity of human lung cancer cells. We used adenoviral vectors expressing human IκBα (AdIκBα) and investigated the effects of IκBα gene transfer in combination with 6 anticancer agents on a human pulmonary adenocarcinoma cell line, A549. Solutions containing anticancer agents at various concentrations were added followed by the addition of recombinant adenovirus solutions, and each IC₅₀ was calculated based on the dose-response curves. The gene transfer of AdIκ-Bα decreased IC₅₀ from 12.0 to 2.2nM on paclitaxel and increased IC₅₀ from 0.27 to 16.0μM on SM5887 compared with the transfer of control gene, AdLacZ. The IC₅₀ did not change clearly on the other anticancer drugs. To investigate this molecular mechanism, we measured caspase 3 activity by the transfer of IκBα gene. On result, paclitaxel increased caspase 3 activity and SM5887 decreased the activity. These results indicate that the cell killing effect of anticancer drug is influenced by the inhibition of NF-κB activity and may, at least in part, depend on the regulation of caspase 3 activation. Adenovirus mediated IκBα gene transfer improve the anti-cancer effect of paclitaxel to lung cancer cells through the regulation of caspase 3 activation.