Research article

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

Frank Michael Klenke¹ , Martha-Maria Gebhard² , Volker Ewerbeck³ , Amir Abdollahi⁴ , Peter E Huber⁴ and Axel Sckell⁵

¹  Department of Orthopedic Surgery, Inselspital, University of Bern, CH-3010 Bern, Switzerland

²  Department of Experimental Surgery, University of Heidelberg, INF 365, D-69120 Heidelberg, Germany

³  Department of Orthopaedic Surgery, University of Heidelberg, Schlierbacher Landstrasse 200a, D-69118 Heidelberg, Germany

⁴  German Cancer Research Center, INF 280, D-69120 Heidelberg, Germany

⁵  Department of Trauma and Reconstructive Surgery, Charité – Campus Benjamin Franklin, Hindenburgdamm 30, D-12200 Berlin, Germany

author email corresponding author email

BMC Cancer 2006, 6:9doi:10.1186/1471-2407-6-9

Published:	12 January 2006

Abstract

Background

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. 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.

Methods

In 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.

Results

Treatment 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.

Conclusion

Celecoxib 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.