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
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- "Research over the last decade has indicated through clinical and preclinical studies that targeting the EGFR and COX-2 pathways can block progression of HNSCC growth   . The more recent generation of chemopreventive studies have therefore relied on Table 2 Trials using COX-2 and EGFR inhibitors in chemoprevention of HNSCC. "
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 · 3.61 Impact Factor
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- "Human SCCHN cell lines Tu212 and Tu686 were established from primary HNSCCs and maintained in DMEM/F12 (1:1) medium with 10% fetal bovine serum as described previously . These cell lines were employed for the described experiments without further authentication. "
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 09/2013; 8(9):e74670. DOI:10.1371/journal.pone.0074670 · 3.23 Impact Factor
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- "Studies have shown that the EGFR and COX-2 have an important role in the biology of HNSCC. Overexpression of COX-2 is associated with a poor prognosis in HNSCC, and COX-2 inhibitors have demonstrated synergy when combined with EGFR inhibitors in preclinical models (Chen et al, 2004; Chung et al, 2011). Inflammatory mediators can promote epithelial– mesenchymal transition (EST) and increase resistance to EGFR "
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 · 4.84 Impact Factor