- Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig−Maximilians−University of Munich, Marchioninistr 15, 81377 Munich, Germany
- Department of Inner Medicin, Zentral Klinikum Augsburg, Strenglinstrase 2 86156 Augsburg, Germany
- Department Pharmazie−Zentrum für Pharmaforschung −, Ludwig−Maximilians−Universität München, Butenandtstr. 5−13, Haus B, D−81377 Munich, Germany
- Wilex AG München, Grillparzerstrasse 10, D−81675 Munich, Germany
- Clinical Cooperation Group Molecular Oncology, Helmholtz−Zentrum München, German Research Center for Environmental Health, and Head and Neck Research Dept, Ludwig−Maximilians−University of Munich, Germany
- Amper Kliniken AG, Abt für Hals−Nasen−Ohrenheilkunde, Krankenhausstr 15, D−85221 Dachau, Germanyauthor email corresponding author email
BMC Cancer 2010, 10:92 doi:10.1186/1471−2407−10−92
Published: 11 March 2010
Squamous cell carcinoma of the head and neck (SCCHN) are highly invasive tumours with frequent local and distant recurrence. Metastasis formation requires degradation of the extracellular matrix, which is fulfilled by membrane−associated proteases such as the urokinase plasminogen activator (uPA). WX−UK1 is a competitive active site inhibitor of the protease function of uPA that impairs on the capacity of tumour cells to invade in vitro.
In the present study, effects of combinations of WX−UK1 with matrix metalloprotease inhibitors (MMP, galardin®) and cyclooxygenase−2 (COX−2, celecoxib®) inhibitors on tumour cell proliferation, invasion, and angiogenesis induction were evaluated. Matrigel invasion chambers and a spheroid co−cultivation model with human fibroblast served to determine the invasive potential of both FaDu (SCCHN) and HeLa (cervical carcinoma) cells, each treated with combinations of Celecoxib®, Galardin®, and WX−UK1.
Blocking of single protease systems resulted in a significant 50% reduction of tumour cell invasion using WX−UK1, while the triple combination was even more effective with 80% reduction of invasion. Additionally, a sprouting assay with HUVEC was used to test the anti−angiogenetic potential of the triple combination, resulting in a 40% decrease in the sprouting rate.
A combined approach targeting different families of proteases and cyclooxygenases represents a promising adjuvant therapy.
