Paclitaxel Efficacy is Increased by Parthenolide via Nuclear Factor- KappaB Pathways in In Vitro and In Vivo Human Non–Small Cell Lung Cancer Models

Author(s): Z. W. Gao , D. L. Zhang , C. B. Guo .

Journal Name: Current Cancer Drug Targets

Volume 10 , Issue 7 , 2010

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Abstract:

The focus of this study was to develop additive or synergistic agents to chemosensitize the existing chemotherapeutic drug in human non – small cell lung cancer (NSCLC). In this study employing analyses of the NF-κB/ I-κB kinase (IKK) signal cascade in a number of NSCLC cell lines, we report the identification and characterization of parthenolide. Parthenolide is a sesquiterpene lactone that can antagonize paclitaxel-mediated NF-κB nuclear translocation and activation through selectively targeting I-κB kinase (IKK) activity. Our results showed that parthenolide dramatically lowered the effective dose of Paclitaxel needed to induce cytotoxicity of a wide range of NSCLC cell lines. An examination of pathways common to Paclitaxel and parthenolide signaling revealed that this synergy was related to modulation of the NF-κB/ I-κB kinase (IKK) signal cascade through IKKß. Parthenolide alone induced apoptosis via the mitochondria/ caspase pathway. Moreover, in a human orthotopic NSCLC xenograft model, a well-tolerated combination induces tumor regression. These data strengthen the rationale for the use of parthenolide to decrease the apoptotic threshold via a caspase-dependent process and support the use of concurrent low doses of paclitaxel in the treatment of NSCLC with paclitaxel chemoresistance.

Keywords: Synergy, IKK, NF-κB, caspase dependent.

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Article Details

VOLUME: 10
ISSUE: 7
Year: 2010
Page: [705 - 715]
Pages: 11
DOI: 10.2174/156800910793605776
Price: $58

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