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

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.Squamous cell carcinoma of the head and neck (SCCHN) are aggressive tumours, which are still associated with poor prognosis despite improvements in surgical and radiotherapeutic techniques [1]. SCCHNs exhibit highly invasive growth, aggressive metastasis formation, and early recurrence [1]. In order to metastasise, tumour cells utilize a complex set of molecular mechanisms [2]. Migration through surrounding tissue is achieved upon the degradation of the extracellular matrix (ECM) by both, membrane-fixed and soluble proteases. In this respect, matrix metalloproteases (MMP) and the urokinase-type plasminogen-activator system (uPA), which is responsible for the conversion of plasminogen into plasmin, are of major importance. The activity of MMPs and uPA fosters cell migration, angiogenesis and metastasis [3,4]. Tumours greater than 1.5 mm3 in size are strictly dependent on intimate contacts to blood vessels or otherwise become necrotic [5]. Neo-angiogenesis is provided via the production of growth