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Enhancement of Docetaxel-Induced Cytotoxicity by Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 Pathways in Squamous Cell Carcinoma of the Head and Neck

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Author(s)
Mi Sun ChoeZhuo ChenCarmen M. KlassXin ZhangDong M. Shin
Keimyung Author(s)
Choe, Mi Sun
Department
Dept. of Pathology (병리학)
Journal Title
Clinical Cancer Research
Issued Date
2007
Volume
13
Issue
10
Abstract
Purpose: The addition of molecular targeted agents to enhance the cytotoxicity of chemotherapeutic agents is a promising strategy in cancer treatment. The combination of cyclooxygenase-2 inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors, such as celecoxib and ZD1839 (gefitinib), was reported to achieve synergistic cell growth inhibition in squamous cell carcinoma of the head and neck. Therefore, we postulated that the addition of celecoxib and ZD1839 to docetaxel, a cytotoxic agent, might further increase antitumor activity.

Experimental Design: The combination of celecoxib, ZD1839, and docetaxel was studied for its effect on cell growth and apoptosis by cell growth inhibition and Annexin V assays. The relevant molecular targets of these agents and apoptotic markers were examined by immunoblotting analyses in the presence or absence of these three drugs. Morphologic changes of the microtubule cytoskeleton, a known target of docetaxel, were also evaluated by staining for α-tubulin after the combination treatment.

Results: We showed that this triple combination significantly enhanced cell growth inhibition and docetaxel-induced apoptosis. Docetaxel mainly induced caspase-8 activation, whereas the addition of celecoxib and ZD1839 augmented the caspase-8 activation and enhanced caspase-9 activation. One of the underlying mechanisms for augmentation of docetaxel-induced apoptosis by celecoxib and ZD1839 is to further inhibit the activation of prosurvival pathway molecules, such as extracellular signal-regulated kinase and AKT, and the promotion of aberrant apoptosis.

Conclusions: Our studies suggest that the combination of docetaxel with a cyclooxygenase-2 inhibitor and an epidermal growth factor receptor tyrosine kinase inhibitor may further improve efficacy of docetaxel and other taxane-based therapies in squamous cell carcinoma of the head and neck.
Keimyung Author(s)(Kor)
최미선
Publisher
School of Medicine
Citation
Mi Sun Choe et al. (2007). Enhancement of Docetaxel-Induced Cytotoxicity by Blocking
Epidermal Growth Factor Receptor and Cyclooxygenase-2
Pathways in Squamous Cell Carcinoma of the Head and Neck. Clinical Cancer Research, 13(10), 3015–3023. doi: 10.1158/1078-0432.CCR-06-2959
Type
Article
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-06-2959
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35441
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Pathology (병리학)
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