Abstract
BackgroundThe inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors.MethodsIn 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay.ResultsTreatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls.ConclusionCelecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases.
Highlights
The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation
Besides hypoxia which is the main inducer of vascular endothelial growth factor (VEGF), prostaglandins mediated by Cox-2 have been reported to regulate VEGF expression [6,7,8] which demonstrates an important link between Cox-2 activity and VEGF expression [9]
The enzyme is localized in neoplastic cells, endothelial cells, and stromal tissues [9,11,12,13] and contributes to tumor angiogenesis and tumor growth by (1) an increased expression of the angiogenic growth factor VEGF [14], (2) the production of eicosanoid products which can directly stimulate endothelial cell growth factor induced angiogenesis [15], and (3) the inhibition of tumor and endothelial cell apoptosis by up regulating the antiapoptotic protein bcl-2 [16,17]
Summary
The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. The enzyme is localized in neoplastic cells, endothelial cells, and stromal tissues [9,11,12,13] and contributes to tumor angiogenesis and tumor growth by (1) an increased expression of the angiogenic growth factor VEGF [14], (2) the production of eicosanoid products which can directly stimulate endothelial cell growth factor induced angiogenesis [15], and (3) the inhibition of tumor and endothelial cell apoptosis by up regulating the antiapoptotic protein bcl-2 [16,17]. Due to the multiple links between tumor angiogenesis, tumor growth and Cox-2 expression, selective pharmacological inhibition of Cox-2 represents a promising therapeutic strategy for the treatment of malignant solid tumors
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