Multimodal therapy for synergic inhibition of tumour cell invasion and tumour-induced angiogenesis.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
A combined approach targeting different families of proteases and cyclooxygenases represents a promising adjuvant therapy.
Zengel
Pamela
P
Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig-Maximilians-University of Munich, Marchioninistr 15, 81377 Munich, Germany. pamela.zengel@med.uni-muenchen.de
Ramp
Diana
D
Mack
Brigitte
B
Zahler
Stefan
S
Berghaus
Alexander
A
Muehlenweg
Bernd
B
Gires
Olivier
O
Schmitz
Suna
S
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000473:pathology* / Q000628:therapy; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D003131:Combined Modality Therapy / Q000379:methods; D006367:HeLa Cells; D006258:Head and Neck Neoplasms / Q000473:pathology* / Q000628:therapy; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D009389:Neovascularization, Pathologic; D010447:Peptide Hydrolases / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D010447:Peptide Hydrolases; D014568:Urokinase-Type Plasminogen Activator