Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck.
OBJECTIVE
Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (Cox-2) contribute to development of squamous cell carcinoma of the head and neck (SCCHN). Simultaneously blocking both EGFR and Cox-2-mediated pathways may be an efficient means of inhibiting cancer cell growth in SCCHN.


METHODS
A combination of EGFR-selective tyrosine kinase inhibitors (TKIs) AG1478 or ZD1839 (Iressa or gefitinib) with a Cox-2 inhibitor (Cox-2I) celecoxib (Celebrex) was studied for its effects on cell growth, cell cycle progression, and apoptosis in SCCHN cell lines by cell growth assay, clonogenic assay, flow cytometric analysis, and terminal deoxynucleotidyl transferase-mediated nick end labeling assay. A potential effect of EGFR TKIs and Cox-2I on angiogenesis was examined by endothelial capillary tube formation assay. Primary and secondary targets of EGFR TKIs and Cox-2I were also examined using immunoblotting and immunoprecipitation after the combined treatment.


RESULTS
The combination of AG1478 or ZD1839 with celecoxib either additively or synergistically inhibited growth of the five SCCHN cell lines examined, significantly induced G(1) arrest and apoptosis, and suppressed capillary formation of endothelium. Furthermore, the combination showed strong reductions of p-EGFR, p-extracellular signal-regulated kinase 1/2, and p-Akt in SCCHN cells as compared with the single agents. Both AG1478 and ZD1839 inhibited expression of Cox-2 protein, whereas celecoxib mainly blocked the production of prostaglandin E(2).


CONCLUSIONS
These results suggest that cell growth inhibition induced by a combination of EGFR TKIs and Cox-2I is mediated through simultaneously blocking EGFR and Cox-2 pathways. This combination holds a great potential for the treatment and/or prevention of SCCHN.
Chen
Zhuo
Z
Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.
Zhang
Xin
X
Li
Mengfeng
M
Wang
Zhiqiang
Z
Wieand
H Samuel
HS
Grandis
Jennifer R
JR
Shin
Dong M
DM
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000201:enzymology; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020287:In Situ Nick-End Labeling; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007822:Laryngeal Neoplasms / Q000188:drug therapy / Q000201:enzymology; D008207:Lymphatic Metastasis / Q000473:pathology; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D020032:Tyrphostins / Q000494:pharmacology
D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D020032:Tyrphostins; C101044:RTKI cpd; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D066246:ErbB Receptors; D000068579:Celecoxib; D000077156:Gefitinib