Paclitaxel Efficacy is Increased by Parthenolide via Nuclear Factor- KappaB Pathways in In Vitro and In Vivo Human Non – Small Cell Lung Cancer Models
Z. W. Gao,
D. L. Zhang,
C. B. Guo.
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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