Paclitaxel efficacy is increased by parthenolide via nuclear factor-kappaB pathways in in vitro and in vivo human non-small cell lung cancer models.
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 IKKβ. 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.
Gao
Z W
ZW
Department of Thoracic Surgery, Linyi People’s Hospital, Linyi, Shandong Province, PR China.
Zhang
D L
DL
Guo
C B
CB
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011897:Random Allocation; D012717:Sesquiterpenes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D016328:NF-kappa B; D012717:Sesquiterpenes; C002669:parthenolide; D017239:Paclitaxel