Enhancement of docetaxel-induced cytotoxicity by blocking epidermal growth factor receptor and cyclooxygenase-2 pathways in squamous cell carcinoma of the head and neck.
OBJECTIVE
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.


METHODS
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.
Choe
Mi Sun
MS
Department of Hematology/Oncology, Emory University Winship Cancer Institute, Atlanta, Georgia 30322, USA.
Chen
Zhuo
Z
Klass
Carmen M
CM
Zhang
Xin
X
Shin
Dong M
DM
D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology; D000068579:Celecoxib; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage; D000077143:Docetaxel; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D043823:Taxoids / Q000627:therapeutic use*
D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D043823:Taxoids; D000077143:Docetaxel; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib