Nuclear Factor-kappa B Inhibition by Parthenolide Potentiates the Efficacy of Taxol in Non-Small Cell Lung Cancer In vitro and In vivo

In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-kappa B (NF-kappa B) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-kappa B kinase activity. In A549 cells, inhibition of nuclear factor-kappa B by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochodria-dependent apoptosis in the treatment of non-small cell lung cancer cells. (Mol Cancer Res 2009;7(7):1139-49)