The antimetastatic activity of orlistat is accompanied by an antitumoral immune response in mouse melanoma

Author(s):Show less -

de Almeida, Luciana Y. ^[1] ; Mariano, Flavia S. ^[1] ; Bastos, Debora C. ^[1] ; Cavassani, Karen A. ^[2] ; Raphelson, Janna ^[2] ; Mariano, Vania S. ^[3] ; Agostini, Michelle ^[4] ; Moreira, Fernanda S. ^[1] ; Coletta, Ricardo D. ^[1] ; Mattos-Graner, Renata O. ^[1] ; Graner, Edgard ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Sch Dent Piracicaba, Dept Oral Diag, Av Limeira 901, CP 52, BR-13414903 Piracicaba, SP - Brazil

^[2] Cedars Sinai Med Ctr, Samuel Oschin Comprehens Canc Inst, Urol Oncol Program, Urooncol Res Labs, Los Angeles, CA 90048 - USA

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Basic & Appl Immunol, Sao Paulo, SP - Brazil

^[4] Univ Fed Rio de Janeiro, Sch Dent, Dept Oral Diag & Pathol, Rio De Janeiro - Brazil

• Document type: Journal article
• Source: Cancer Chemotherapy and Pharmacology; v. 85, n. 2 DEC 2019.
• Web of Science Citations: 0

Abstract

Purpose Fatty acid synthase (FASN), the multifunctional enzyme responsible for endogenous fatty acid synthesis, is highly expressed and associated with poor prognosis in several human cancers, including melanoma. Our group has previously shown that pharmacological inhibition of FASN with orlistat decreases proliferation, promotes apoptosis, and reduces the metastatic spread of B16-F10 cells in experimental models of melanoma. While most of the orlistat antitumor properties seem to be closely related to direct effects on malignant cells, its impact on the host immune system is still unknown. Methods The effects of orlistat on the phenotype and activation status of infiltrating leukocytes in primary tumors and metastatic lymph nodes were assessed using a model of spontaneous melanoma metastasis (B16-F10 cells/C57BL/6 mice). Cells from the primary tumors and lymph nodes were mechanically dissociated and immune cells phenotyped by flow cytometry. The expression of IL-12p35, IL-12p40, and inducible nitric oxide synthase (iNOS) was analyzed by qRT-PCR and production of nitrite (NO2-) evaluated in serum samples with the Griess method. Results Orlistat-treated mice exhibited a 25% reduction in the number of mediastinal lymph node metastases (mean 3.96 +/- 0.78, 95% CI 3.63-4.28) compared to the controls (mean 5.7 +/- 1.72; 95% CI 5.01-6.43). The drug elicited an antitumor immune response against experimental melanomas by increasing maturation of intratumoral dendritic cells (DC), stimulating the expression of cytotoxicity markers in CD8 T lymphocytes and natural killer (NK) cells, as well as reducing regulatory T cells (Tregs). Moreover, the orlistat-treatment increased serum levels of nitric oxide (NO) concentrations. Conclusion Taken together, these findings suggest that orlistat supports an antitumor response against experimental melanomas by increasing CD80/CD81-positive and IL-12-positive DC populations, granzyme b/NKG2D-positive NK populations, and perforin/granzyme b-positive CD8 T lymphocytes as well as reducing Tregs counts within experimental melanomas. (AU)

• FAPESP's process: 08/57471-7 - The role of fatty acid synthase activity in apoptosis, metastasis and vasculogenesis in melanoma
• Grantee: Edgard Graner
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/25160-8 - Effects of the combined therapy orlistat/cisplatin/5-fluorouracil on the metastatic process of orthotopic tongue squamous cell carcinomas.
• Grantee: Luciana Yamamoto de Almeida
• Support Opportunities: Scholarships in Brazil - Doctorate