Tumor Growth Inhibition by Simultaneously Blocking Epidermal Growth Factor Receptor and Cyclooxygenase-2 in a Xenograft Model

Abstract

Purpose: Our previous study revealed that simultaneously targeting epidermal growth factor receptor (EGFR) tyrosine kinase and cyclooxygenase-2 (COX-2) additively or synergistically inhibited growth of squamous cell carcinoma of the head and neck (SCCHN) in vitro. However, an in vivo efficacy of this combined treatment in SCCHN has not been studied. Experimental Design: Nude mice were pretreated with control (1% Tween 80), ZD1839 (50 mg/kg) alone, celecoxib (50 mg/kg) alone, or a combination of ZD1839 and celecoxib at the same dosages for 7 days before injection of a human SCCHN cell line Tu212.The animals were continuously treated with the agents 5 days a week for about 11weeks. Results: Tumor growth in the combined treatment was significantly inhibited compared with the control (P < 0.001), ZD1839 (P = 0.005), or celecoxib (P < 0.001). At the same time, a dramatic delay of tumor progression was observed in the combined treatment compared with all other three groups. Molecular analysis showed that the combined treatment significantly decreased prostaglandin E metabolite production. The cooperative effect of these two agents in combination was also associated with down-regulation of phosphorylated EGFR, phosphorylated extracellular signal-regulated kinase, and phosphorylated signal transducers and activators of transcription 3 levels and reduction of vascular endothelial growth factor and Ki-67 expression. Specifically, gene silencing of both EGFR and COX-2 by small interfering RNA further confirmed the cooperative antitumor effect. Conclusion:The current results strongly suggest that a cooperative effect of the combined treatment on tumor progression is mediated through blocking both EGFR-and COX-2-related pathways. This combination regimen may provide a promising strategy for cancer therapy and chemoprevention in SCCHN.

Cyclooxygenase-2 (COX-2) Negatively Regulates Expression of Epidermal Growth Factor Receptor and Causes Resistance to Gefitinib in COX-2–Overexpressing Cancer Cells

“…EGFR is known to induce COX-2 expression, and PGE 2 , the major end product of COX-2, is also known to activate EGFR through various pathways (1). In addition, we, as well as other researchers, have reported that inhibitors of COX-2 and EGFR can exert a synergistic antineoplastic effect when administered together in some cancer cells (16,17). Although it has been verified that the actions of COX-2 and EGFR are closely related in cells, as described above, expression patterns of COX-2 and EGFR are highly variable among cancer cell types and frequently seem to be independent of each other.…”

“…To inhibit production of PGE 2 by COX-2, cells were treated with celecoxib, a COX-2-specific inhibitor. Celecoxib effectively blocks production of PGE 2 from COX-2 (2,5,17). Although PGE 2 production was blocked by celecoxib, EGFR expression was still down-regulated in both HCT-116-COX-2 and H460-COX-2 cells (Fig.…”

“…Overexpression or mutation of EGFR activates cellular signaling pathways that induce characteristics of cancer cells, including angiogenesis, metastasis, and invasiveness (1,13,16,17). In cancer patients, EGFR-induced signaling pathways have been implicated in disease progression, decreased survival, and resistance to cytotoxic agents or radiation (16)(17)(18).…”

“…Many studies have been done about the separate functions of either COX-2 or EGFR, and there is growing evidence that these two molecules are intimately related in cancer cells (1,2,16,17,19). However, a precise correlation between the two proteins is still not well understood.…”

Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells

“…As their use in combination has been shown to block tumorigenesis in both APC Min/þ mice [34] and headand-neck carcinoma xenografted mice [35], but has not been examined for GBM, we tested the efficacy of their combination in NSC-L61, OPC-L61, hGIC1, and hGIC2. Gefitinib, an EGFR inhibitor, and Celecoxib, a Ptgs2 inhibitor, prevented the proliferation of NSC-L61, OPC-L61, and hGIC cells in a dose-dependent manner, and the combination had additive effects, although control NSCs and OPCs were also affected ( Fig.…”