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.
ABSTRACT 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.
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.
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).
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.
- SourceAvailable from: Jan B Vermorken[Show abstract] [Hide abstract]
ABSTRACT: The concept of chemoprevention whereby the use of a systemic agent is intended to halt the carcinogenesis process has been an attractive topic in head and neck squamous cell carcinoma (HNSCC). Yet, despite the significant efforts over the past decades and the substantial gain in knowledge of the biology of pre-malignant lesions of the head and neck, no tangible indications for chemoprevention have emerged for this disease. The negative results observed in the earlier larger studies using retinoids did not encourage further trials with these agents. Attention has been more recently focused on epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) as well as cyclo-oxygenase 2 (COX-2) inhibitors with early studies showing encouraging responses but rather poor tolerance to therapy. Natural compounds have gained more interest recently given preclinical evidence of activity as well as a low side effect profile. We herein offer a comprehensive overview of the field of chemoprevention in HNSCC with an in depth analysis of the challenges we face and discuss a road map for future directions. Copyright © 2014 Elsevier Ltd. All rights reserved.Oral Oncology. 11/2014;
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ABSTRACT: Epidermal growth factor receptor (EGFR) is extensively expressed in head and neck cancer. However, EGFR-targeted therapy has only modest efficacy in head and neck cancer, through mechanisms that are not fully understood. Here, we found that inhibition of EGFR by erlotinib stimulated phosphorylation and activation of STAT3 leading to increased Bcl2/Bcl-XL expression in head and neck cancer cells, which may dampen the therapeutic efficacy of erlotinib against head and neck cancer. Erlotinib-enhanced STAT3 phosphorylation results, at least in part, from suppression of its physiological phosphatase, PTPMeg2. Specific knockdown of STAT3 by RNA interference significantly sensitized head and neck cancer cells to erlotinib treatment. Pharmacological inhibition of STAT3 by niclosamide not only blocked erlotinib-stimulated STAT3 phosphorylation but also synergistically repressed head and neck cancer growth in vitro and in vivo. Combined inhibition of EGFR and STAT3 by erlotinib and niclosamide more effectively induced apoptosis in tumor tissues without toxicity for normal tissues. Based on our findings, treatment with erlotinib combined with niclosamide may offer an effective therapeutic approach to improve the prognosis of head and neck cancer.PLoS ONE 01/2013; 8(9):e74670. · 3.53 Impact Factor
- Oral Oncology 01/2014; · 3.03 Impact Factor