Nuclear factor-kappaB 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-kappaB (NF-kappaB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-kappaB kinase activity. In A549 cells, inhibition of nuclear factor-kappaB 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 mitochondria-dependent apoptosis in the treatment of non-small cell lung cancer cells.
Zhang
Dianliang
D
Laboratory of Surgery, Children's Hospital of Chongqing Medical University, Chongqing, P.R. China.
Qiu
Lin
L
Jin
Xianqing
X
Guo
Zhenhua
Z
Guo
Chunbao
C
D000704:Analysis of Variance; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D045304:Cytochromes c / Q000378:metabolism; D004357:Drug Synergism; D006651:Histocytochemistry; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D016328:NF-kappa B; D012717:Sesquiterpenes; D051020:bcl-X Protein; C002669:parthenolide; D045304:Cytochromes c; D051550:I-kappa B Kinase; D020169:Caspases; D017239:Paclitaxel