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; 51(2). DOI:10.1016/j.oraloncology.2014.11.002 · 3.03 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Despite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors. Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Herein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells. In addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.British Journal of Cancer 07/2012; 107(4):707-12. DOI:10.1038/bjc.2012.203 · 4.82 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cyclooxygenase (COX)-2 is one of two isoforms of COX that is the rate-limiting enzyme in the production of prostaglandin from arachidonic acid. It is induced by stimuli such as mitogens, cytokines, growth factors and tumor promoters, and has been elucidated to be up-regulated not only at the sites of inflammation but also in various cancer tissues such as colon, stomach, breast, lung and head and neck including oral cavity. Overexpression of COX-2 is known to inhibit apoptosis and immune surveillance, promote angiogenesis, increase cancer invasiveness and metastasis. Therefore, COX-2 is considered to be strongly involved in carcinogenesis and tumor growth. In fact, immunohistochemical and Western blot analyses in oral precancerous and cancerous lesions demonstrated that COX-2 expression is increased from epithelial dysplasia to squamous cell carcinoma through carcinoma in situ, with the elevation of cell proliferating activity. The patients with overexpression of COX-2 showed poor prognosis and their overall 5-year survival rate was decreased. Inhibition of COX-2 activity with selective COX-2 inhibitors or antisense RNA resulted in suppression of tumor cell growth and invasion in vitro and prevention of oral carcinogenesis by chemical carcinogens in animal models. In addition, combined use of selective COX-2 inhibitors was found to enhance synergistically the cytocidal effects of anti-cancer drugs and irradiation. From these evidences, it is indicated that COX-2 becomes a potent molecular target for prevention and therapy of oral cancer.Japanese Dental Science Review 11/2007; 44(1). DOI:10.1016/j.jdsr.2007.10.003