COX-2 Inhibitor Celecoxib Suppresses Tumor Growth and Lung Metastasis of a Murine Mammary Cancer

Abstract

Background: The antitumor growth and antimetastatic actions of celecoxib [a selective cyclooxygenase-2 (COX-2) inhibitor] were investigated in a metastatic murine mammary cancer model. Materials and Methods: Mice bearing mammary tumors, developed after inoculation of syngeneic BALB/c mice with a mammary carcinoma cell line carrying a p53 mutation, were treated with celecoxib at 0, 7.5 and 15 mg/kg five times a week for seven weeks. Results: Tumor volumes were significantly reduced in association with an increase in apoptosis and a decrease in DNA synthesis in tumor tissues. In vitro studies demonstrated a significant increase in the number of cells undergoing apoptosis, with significantly elevated activities of caspase-3 and caspase-9, but not caspase-8, and a dose-dependent decrease in mitochondrial membrane potential, indicating the mitochondrial pathway of apoptosis. In addition, treatment with celecoxib showed cell cycle arrest in the G₁-phase and decreased cell population in the S- and G₂/M-phases. Furthermore, tumor microvessel formation and mRNA levels for VEGF-A and COX-2 were markedly decreased. Conclusion: Celecoxib may be useful as an adjuvant therapy for breast cancer containing p53 mutations due to its ability to both induce p53-independent mitochondria-mediated apoptosis and exert anti-angiogenic potential.