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.
Current Cancer Drug Targets
Title:Paclitaxel Efficacy is Increased by Parthenolide via Nuclear Factor- KappaB Pathways in In Vitro and In Vivo Human Non–Small Cell Lung Cancer Models
Volume: 10 Issue: 7
Author(s): Z. W. Gao, D. L. Zhang and C. B. Guo
Affiliation:
Keywords: Synergy, IKK, NF-κB, caspase dependent.
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.
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Cite this article as:
W. Gao Z., L. Zhang D. and B. Guo C., Paclitaxel Efficacy is Increased by Parthenolide via Nuclear Factor- KappaB Pathways in In Vitro and In Vivo Human Non–Small Cell Lung Cancer Models, Current Cancer Drug Targets 2010; 10 (7) . https://dx.doi.org/10.2174/156800910793605776
DOI https://dx.doi.org/10.2174/156800910793605776 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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