The fatty acid synthase inhibitor orlistat reduces experimental metastases and angiogenesis in B16-F10 melanomas.
BACKGROUND
Fatty acid synthase (FASN) is overexpressed and associated with poor prognosis in several human cancers. Here, we investigate the effect of FASN inhibitors on the metastatic spread and angiogenesis in experimental melanomas and cultured melanoma cells.


METHODS
The lung colonisation assay and cutaneous melanomas were performed by the inoculation of mouse melanoma B16-F10 cells in C57BL6 mice. Blood vessel endothelial cells (RAEC and HUVEC) were applied to determine cell proliferation, apoptosis, and the formation of capillary-like structures. Vascular endothelial growth factor A (VEGFA) expression was evaluated by quantitative RT-PCR and ELISA in B16-F10, human melanoma (SK-MEL-25), and human oral squamous carcinoma (SCC-9) cells. Conditioned media from these cancer cell lines were used to study the effects of FASN inhibitors on endothelial cells.


RESULTS
B16-F10 melanoma-induced metastases and angiogenesis were significantly reduced in orlistat-treated mice. Fatty acid synthase inhibitors reduced the viability, proliferation, and the formation of capillary-like structures by RAEC cells, as well as the tumour cell-mediated formation of HUVEC capillary-like structures. Cerulenin and orlistat stimulated the production of total VEGFA in B16-F10, SK-MEL-25, and SCC-9 cells. Both drugs also enhanced VEGFA(121), (165), (189,) and (165b) in SK-MEL-25 and SCC-9 cells.


CONCLUSIONS
FASN inhibitors reduce metastasis and tumour-induced angiogenesis in experimental melanomas, and differentially modulate VEGFA expression in B16-F10 cells.
Department of Oral Diagnosis, School of Dentistry of Piracicaba, University of Campinas, Avenida Limeira 901, CP 52, Areão, Piracicaba, CEP 13414-018, SP, Brazil.
F
F
Seguin
M A
MA
Carvalho
D C
DC
Bastos
M
M
Agostini
K G
KG
Zecchin
M P
MP
Alvarez-Flores
A M
AM
Chudzinski-Tavassi
R D
RD
Coletta
E
E
Graner
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000517:prevention & control* / Q000556:secondary; D008545:Melanoma / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009062:Mouth Neoplasms / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D000077403:Orlistat; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007783:Lactones; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077403:Orlistat; D064429:Fatty Acid Synthases