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Tumor growth inhibition by simultaneously blocking epidermal growth factor receptor and cyclooxygenase-2 in a
Xin Zhang1, Zhuo Georgia Chen, Mi Sun Choe
1Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
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 11 weeks.
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.
Insights
Combining EGFR tyrosine kinase and COX-2 inhibitors significantly inhibited squamous cell carcinoma of the head and neck (SCCHN) tumor growth in vivo. This dual targeting strategy shows promise for SCCHN cancer therapy and chemoprevention.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Previous in vitro studies demonstrated additive or synergistic inhibition of squamous cell carcinoma of the head and neck (SCCHN) growth by simultaneously targeting epidermal growth factor receptor (EGFR) tyrosine kinase and cyclooxygenase-2 (COX-2).
- The in vivo efficacy of this combined treatment in SCCHN remained uninvestigated.
Purpose of the Study:
- To evaluate the in vivo efficacy of combined EGFR tyrosine kinase and COX-2 inhibition in SCCHN.
- To investigate the molecular mechanisms underlying the cooperative antitumor effect of this combination therapy.
Main Methods:
- Nude mice bearing human SCCHN xenografts (Tu212) were treated with EGFR inhibitor (ZD1839) and/or COX-2 inhibitor (celecoxib) for approximately 11 weeks.
- Tumor growth, progression, and relevant molecular markers including phosphorylated EGFR, phosphorylated ERK, phosphorylated STAT3, prostaglandin E metabolite, vascular endothelial growth factor, and Ki-67 were assessed.
- Gene silencing of EGFR and COX-2 using small interfering RNA was employed to confirm the cooperative effect.
Main Results:
- Combined treatment with ZD1839 and celecoxib significantly inhibited tumor growth and delayed tumor progression in SCCHN xenografts compared to monotherapy or control groups.
- Molecular analysis revealed that the combination therapy downregulated prostaglandin E metabolite production, reduced levels of phosphorylated EGFR, ERK, and STAT3, and decreased vascular endothelial growth factor and Ki-67 expression.
- Gene silencing experiments confirmed the cooperative antitumor effect of targeting both EGFR and COX-2 pathways.
Conclusions:
- The combined inhibition of EGFR and COX-2 exhibits a cooperative antitumor effect in SCCHN, mediated by blocking related signaling pathways.
- This combination regimen represents a promising therapeutic strategy for SCCHN cancer therapy and chemoprevention.
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