Nuclear factor-kappaB inhibition by parthenolide potentiates the efficacy of Taxol in non-small cell lung cancer in vitro and in vivo.

Abstract

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.

• Authors: Dianliang Zhang, Lin Qiu, Xianqing Jin, Zhenhua Guo, Chunbao Guo
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 7 Pg. 1139-49 (Jul 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19584264 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bcl2l1 protein, mouse
• NF-kappa B
• Sesquiterpenes
• bcl-X Protein
• parthenolide
• Cytochromes c
• I-kappa B Kinase
• Caspases
• Paclitaxel

Topics

• Analysis of Variance
• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Survival
• Cytochromes c (metabolism)
• Drug Synergism
• Histocytochemistry
• I-kappa B Kinase (antagonists & inhibitors, metabolism)
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, metabolism)
• Mice
• Mitochondrial Membranes (drug effects)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Paclitaxel (administration & dosage, pharmacology)
• Sesquiterpenes (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• bcl-X Protein (metabolism)