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.
|ジャーナル||Journal of Experimental and Clinical Cancer Research|
|出版ステータス||出版済み - 3月 2003|
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