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 alpha-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.
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 alpha-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.
Authors: Eliezer M Van Allen; Vivian W Y Lui; Ann Marie Egloff; Eva M Goetz; Hua Li; Jonas T Johnson; Umamaheswar Duvvuri; Julie E Bauman; Nicolas Stransky; Yan Zeng; Breean R Gilbert; Kelsey P Pendleton; Lin Wang; Simion Chiosea; Carrie Sougnez; Nikhil Wagle; Fan Zhang; Yu Du; David Close; Paul A Johnston; Aaron McKenna; Scott L Carter; Todd R Golub; Gad Getz; Gordon B Mills; Levi A Garraway; Jennifer R Grandis Journal: JAMA Oncol Date: 2015-05 Impact factor: 31.777
Authors: Carmen M Klass; Mi Sun Choe; Selwyn J Hurwitz; Mourad Tighiouart; Xin Zhang; Zhuo Georgia Chen; Dong M Shin Journal: Head Neck Date: 2009-10 Impact factor: 3.147
Authors: Maha S Almutairi; Gehan H Hegazy; Mogedda E Haiba; Hamed I Ali; Nagy M Khalifa; Abd El-mohsen M Soliman Journal: Int J Mol Sci Date: 2014-12-05 Impact factor: 5.923