Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106
USA

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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.

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, NF-B, caspase, (NSCLC), SCLC, taxane paclitaxel, tumorigenicity, Anti-apoptotic signals, NCI-H446, A549-T24, Z-VAD-fmk, MTT Assay, SDS, ELISA, EMSAautoradiography, western blotting kit, Cytochrome c Apoptosis Assay Kit, phospho-IB, anti-RelA, parthenolide, CI values, NF-B DNA-binding activity, EMSA, zVAD-fmk, cytochrome c, H460 cells, Kaplan, –, Meyer plot, proteasome inhibitor, cisplatin, doxorubicin, camptothecin

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Article Details

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