u-104 and Squamous-Cell-Carcinoma-of-Head-and-Neck

The effects of cisplatin, CA IX/XII specific inhibitor SLC-0111, and the combinatorial treatment were tested on proliferation, migration, invasion of HNSCC cells grown in 2D and 3D models. Main signal pathways and the expression of stemness, mesenchymal and apoptotic markers were analyzed by western blotting. Molecular imaging using NIR-Annexin V and NIR-Prosense was performed in HNSCC xenografts to detect tumor growth and metastatic spread.. HNSCC cells grown in 2D and 3D models under hypoxic conditions showed increased levels of CA IX/XII and greater resistance to cisplatin than cells grown under normoxic conditions. The addition of CA IX/XII inhibitor SLC-0111 to cisplatin sensitized HNSCC cells to the chemotherapeutic agent and caused a reduction of proliferation, migration and invasiveness. Furthermore, the combination therapy hampered activation of STAT3, AKT, ERK, and EMT program, whereas it induced apoptosis. In HNSCC xenografts the treatment with cisplatin plus SLC-0111 caused an inhibition of tumor growth and an induction of apoptosis as well as a reduction of metastatic spread at a higher extent than single agents.. Our results highlight the ability of SLC-0111 to sensitize HNSCC to cisplatin by hindering hypoxia-induced signaling network that are shared among mechanisms involved in therapy resistance and metastasis.

Topics: Animals; Carbonic Anhydrases; Cell Proliferation; Cisplatin; Head and Neck Neoplasms; Humans; Mice; Phenylurea Compounds; Squamous Cell Carcinoma of Head and Neck; Sulfonamides; Tumor Microenvironment