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Effects of the fatty acid synthase inhibitor orlistat combined with 5-fluorouracil, cisplatin or paclitaxel on oral squamous carcinoma : study in a cell line and orthotopic model

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Author(s):
Luciana Yamamoto de Almeida
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Odontologia de Piracicaba
Defense date:
Examining board members:
Katiucia Batista da Silva Paiva; Fábio Dupart Nascimento; Débora Campanella Bastos; Ricardo Della Coletta
Advisor: Edgard Graner
Abstract

Squamous cell carcinoma (SCC) is the most frequent malignant epithelial tumor of the oral cavity, which presents variable degree of squamous differentiation and early regional lymph node metastases. It is most frequent in alcohol and tobacco users at the fifth and sixth decades of life. The prognosis of oral SCC depends on the size of the primary tumor, presence of positive lymph nodes and / or distant metastases at the moment of diagnosis. Surgery is the main treatment modality of choice for oral SCC, however, in advanced stages, patients are included in radiotherapy and chemoradiotherapy protocols. 5-fluorouracil (5-FU), cisplatin (CDDP) and paclitaxel (PTX) are used in chemotherapeutic regimens of several neoplasms, including OSCC. However, regardless the treatment modality, the overall 5-year survival rate is approximately 50%. Several studies demonstrate that the metabolic enzyme fatty acid synthase (FASN), responsible for the endogenous biosynthesis of long-chain fatty acids, is highly expressed in malignant neoplasms, including oral SCC, in which it seems to be associated with a worse prognosis. Orlistat (ORL) is an anti-obesity drug that also has antineoplastic properties by irreversibly inhibiting FASN. In our laboratory, we previously demonstrated that BALB/c nude mice orthotopically inoculated with SCC-9 ZsGreen LN1 cells and treated with ORL have smaller primary tumors as well as significant less cervical lymph node metastases (43%). To date, there are no studies investigating the effect of ORL as an adjuvant for chemotherapy of OSCC. In the present study, we describe the effects of ORL combined with 5-FU, CDDP and PTX at their respective IC50 on proliferation, death, migration and invasion on metastatic SCC-9 ZsGreen LN-1 cells. ORL + CDDP (OC) and ORL + PTX (OP) significantly increased apoptosis after 48 h, which was preceded by the accumulation of cells in the S and G2/M phases of the cell cycle, respectively. ORL + 5-FU therapy (OF) did not change cell cycle progression or cell death. OP decreased cyclin B1 production without significant changes in CDK1 and Cdc25C levels, which are responsible for G2/M transition. Although CDK1 were not changed by OC, this combination reduced the expression of cyclin B1 and Cdc25C. OC and OP increased FASN but not changed ERBB2, a cell surface receptor involved in the regulation of the former. The invasive phenotype was reduced by treatment with OC and OP, however, PTX was the main drug responsible for the inhibition of cell migration. Together, these findings suggest that OC and OP combinations show synergistic effects in the metastatic SCC-9 ZsGreen LN-1 cells and may have potential application for the oral SCC treatment (AU)