Chemosensitization in non-small cell lung cancer cells by IKK inhibitor occurs via NF-κB and mitochondrial cytochrome c cascade

Abstract

In this study, we demonstrated with mechanistic evidence that parthenolide, a sesquiterpene lactone, could antagonize paclitaxel-mediated NF-κB nuclear translocation and activation by selectively targeting I-κB kinase (IKK) activity. We also found that parthenolide could target IKK activity and then inhibit NF-κB; this promoted cytochrome c release and activation of caspases 3 and 9. Inhibition of caspase activity blocked the activation of caspase cascade, implying that the observed synergy was related to caspases 3 and 9 activation of parthenolide. In contrast, paclitaxel individually induced apoptosis via a pathway independent of the mitochondrial cytochrome c cascade. Finally, exposure to parthenolide resulted in the inhibition of several NF-κB transcript anti-apoptotic proteins such as c-IAP1 and Bcl-xl. These data strengthen the rationale for using parthenolide to decrease the apoptotic threshold via caspase-dependent processes for treatment of non-small cell lung cancer with paclitaxel chemoresistance. © 2008 The Authors Journal compilation © 2009 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.