Chemosensitization in non-small cell lung cancer cells by IKK inhibitor occurs via NF-kappaB and mitochondrial cytochrome c cascade.
In this study, we demonstrated with mechanistic evidence that parthenolide, a sesquiterpene lactone, could antagonize paclitaxel-mediated NF-kappaB nuclear translocation and activation by selectively targeting I-kappaB kinase (IKK) activity. We also found that parthenolide could target IKK activity and then inhibit NF-kappaB; 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-kappaB 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.
Jin
Xianqing
X
Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, P.R. China.
Qiu
Lin
L
Zhang
Dianliang
D
Zhang
Mingman
M
Wang
Ziming
Z
Guo
Zhenhua
Z
Deng
Chun
C
Guo
Chunbao
C
D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D012717:Sesquiterpenes; D013450:Sulfones; D051996:Transcription Factor RelA; D051020:bcl-X Protein; C002669:parthenolide; D045304:Cytochromes c; D051550:I-kappa B Kinase; D017239:Paclitaxel