Breast cancer (BC), especially the inflammatory subtype (IBC), represents a highly aggressive form of cancer, often marked by the overexpression of cyclooxygenase-2 (COX-2). COX-2 contributes significantly to the inflammatory process, driving tumor growth and metastasis. Its overexpression correlates with poor prognosis because it supports the epithelial-mesenchymal transition (EMT), a process that increases the invasiveness and spread of cancer cells.
Celecoxib: A Selective COX-2 Inhibitor for Breast Cancer Research
Celecoxib is a selective COX-2 inhibitor that works by suppressing COX-2 activity, which in turn reduces the production of prostaglandin E2 (PGE2). This inhibition affects multiple downstream signaling pathways, including the stabilization of E-cadherin, a protein essential for cell-to-cell adhesion. By targeting this pathway, celecoxib disrupts cell adhesion, thus impairing the metastatic potential of cancer cells.
The Effect of Celecoxib
In vitro experiments with IBC cell lines, such as SUM149, showed that celecoxib at a concentration of 50 μM for 48 hours significantly lowered the protein levels of E-cadherin, β-catenin, and p120 catenin. The treatment also increased cell death, as indicated by propidium iodide (PI) staining. Celecoxib also inhibited the phosphorylation of AKT and GSK3β, key regulators of cell survival. Moreover, it disrupted cell aggregation in 3D cultures, leading to increased cell death by day 3.
In vivo studies in mice with established SUM149 xenograft tumors demonstrated that treatment with 1000 mg/kg of celecoxib for 7 days significantly reduced tumor growth, as measured by tumor volume. Western blot analysis showed decreased levels of E-cadherin and other proteins like pGSK3βS9 in treated tumors. Celecoxib also reduced the number of circulating tumor cells (CTCs) in the blood, suggesting its potential to hinder metastasis.
In BCM-5471 patient-derived xenograft (PDX) models, celecoxib alone or in combination with paclitaxel reduced lung metastases. Experimental studies on lung metastasis showed that both celecoxib alone and in combination with paclitaxel significantly reduced metastatic burden.
In conclusion, celecoxib is a selective COX-2 inhibitor that downregulates E-cadherin complex proteins. It represents a promising therapeutic approach for metastatic breast cancer.
Reference
[1] Balamurugan, Kuppusamy et al. JCI Insight. 2023 Mar 22;8(6):e156057.
