Effects of the combined therapy orlistat/cisplatin/5-fluorouracil on the metastatic process of orthotopic tongue squamous cell carcinomas.

Abstract

Fatty acid synthase (FASN) is the enzyme responsible for the de novo biosynthesis of fatty acids (FA). Its expression is high in several malignancies, including oral squamous cell carcinoma (OSCC). FASN overexpression has been associated with high recurrence rates, increased risk of metastasis, lower survival rates and consequently poor prognosis in several human cancers. Orlistat (Xenical ®) is an anti-obesity drug with anti-neoplastic properties by irreversibly inhibiting FASN. Previous studies conducted in our laboratory demonstrated that BALB/c nude mice treated with orlistat have smaller orthotopic squamous cell carcinomas of the tongue as well as significant less cervical lymph node metastases (43%), in comparison with the controls. Surgery is widely used for the treatment for OSCC, however, in advanced stages patients are included in chemoradiotherapy protocols. Cisplatin (CDDP) and 5-fluorouracil (5-FU) are drugs commonly used in the chemotherapy for several human carcinomas, including OSCC. To date, there are no studies investigating the potential use of orlistat as an adjuvant for the chemotherapy of OSCC. Therefore, in the present study, we aim to investigate whether the blockage of FASN activity with orlistat associated to CDDP and 5-FU has a synergistic effect on the rates of apoptosis and proliferation of cultured OSCC cells, as well as in the metastatic spread of orthotopic tongue SCC.