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

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 a-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.

Targeting Cyclooxygenase-2 and the Epidermal Growth Factor Receptor for the Prevention and Treatment of Intestinal Cancer

“…The inhibition of COX-2 and EGFR has proven effective in squamous cell carcinoma of the head and neck (SCCHN). In vitro data suggest that this combination alone or in the presence of docetaxel synergistically inhibited the growth of several SCCHN cell lines (20,21). This effect was observed through G 1 arrest and increased apoptosis.…”

Phase II Study of Docetaxel and Gefitinib as Second-Line Therapy in Gemcitabine Pretreated Patients with Advanced Pancreatic Cancer

“…In a single-arm phase II study, a median survival of 5.9 months with docetaxel was comparable to historical results reported with gemcitabine [22], and toxicity of the combination has been acceptable [23]. Based on preclinical data demonstrating synergy in cell lines [24], we performed a single-arm trial of docetaxel and gefitinib to assess median survival time after failure with a gemcitabine-based regimen in patients with APC.…”

Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future

“…In the preclinical setting, gefitinib has shown to have synergistic cytotoxic effects when combined with either docetaxel or cisplatin in head and neck cancer cell lines [46,47]. A combination of docetaxel, gefitinib, and celecoxib (a Cox-2 inhibitor) showed in preclinical studies to be active, and the dual action of gefitinib with celecoxib seemed to have similar synergistic effects in the clinical setting [46,48].…”

“…A combination of docetaxel, gefitinib, and celecoxib (a Cox-2 inhibitor) showed in preclinical studies to be active, and the dual action of gefitinib with celecoxib seemed to have similar synergistic effects in the clinical setting [46,48]. Docetaxel and cisplatin were used in conjunction with gefitinib in a phase II trial by Belón et al [14].…”