Title: The proteasome inhibitor Bortezomib induces head and neck cancer cells death in vitro and interferes with tumor growth of transplanted salivary gland cancer cells in mice

Abstract

Background: Head and neck cancer, the seventh most common cancer worldwide, has often an aggressive course with an emerging resistance to conventional chemotherapy. Therefore, the use of new therapeutic agents is being evaluated. Bortezomib is a proteasome inhibitor with potent in vitro and in vivo anticancer activities. Methods: in vitro antitumoral activity of Bortezomib was evaluated using human pharynx (FaDu), tongue (SCC-15, CAL-27), salivary gland (A-253) cancer cell lines and a murine cell line (SALTO-5) derived from an adenocarcinoma of the salivary gland from BALB-neuT male mice transgenic for the oncogene neu. We also analyzed the in vivo effects of Bortezomib in mice transplanted with murine SALTO-5 cells. Results: Bortezomib inhibited cells proliferation, induced apoptosis, modulated the expression and activation of molecules involved in pro-survival signal transduction pathways mediated by ErbB receptors (MAPK) and AKT, and inhibited proteasome activity in vitro. Furthermore, intraperitoneal administration of Bortezomib interfered with tumor growth of SALTO-5 cells transplanted in BALB-neuT mice, prolonged their survival, modulated tumor microenvironment by increasing tumor-infiltrating immune cells (CD4+ and CD8+ T cells, B lymphocytes, macrophages, and Natural Killer cells) and by decreasing vessels density. Conclusions: Our findings suggest a potential use of Bortezomib for the treatment of head and neck carcinomas alone or in combination with conventional therapies or other biological drugs.