Open AccessChemosensitization in non‐small cell lung cancer cells by IKK inhibitor occurs via NF‐κB and mitochondrial cytochrome c cascade
Author(s) -
Jin Xianqing,
Qiu Lin,
Zhang Dianliang,
Zhang Mingman,
Wang Ziming,
Guo Zhenhua,
Deng Chun,
Guo Chunbao
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2008.00601.x
Subject(s) - parthenolide , caspase , apoptosis , cytochrome c , iκb kinase , nf κb , chemistry , iκbα , celastrol , caspase 3 , signal transduction , cancer research , pharmacology , biology , microbiology and biotechnology , programmed cell death , biochemistry
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.