title: N-phenylmaleimides affect adipogenesis and present antitumor activity through reduction of FASN expression.
abstract: In light of the evidence that in contrast to most healthy tissues, several neoplasms overexpress fatty acid synthase (FASN) upon their dependence on increased lipogenesis; targeting of this protein is being considered as a valuable strategy in anticancer drug development. This can be particularly relevant for aggressive tumors such as melanoma in which FASN overexpression has been associated with increased depth of invasion and worse prognosis. We have previously shown that a sub-class of cyclic imides, the N-phenylmaleimides, presented antitumor activity against L1210 leukemia and B16F10 melanoma with evidences of interference in the energetic metabolism. Here, we aimed to investigate if some selected N-phenylmaleimides (M1 and M5) interfere with fatty acids metabolism and its relation with cancer. For that, a model of pre-adipocytes differentiation (3T3-L1 cells) and also human melanoma cells (SK-Mel-147) were used. As results, when 3T3-L1 cells were exposed to non-cytotoxic concentrations of M1 and M5 in the presence of an adipogenic cocktail, intracellular lipid content decreased by 26-36%, marking the inhibition of adipocyte differentiation. High selectivity indexes were obtained for both compounds for tumoral cells. Cell cycle phases analysis revealed a remarkable proportion of cells with DNA fragmentation after their exposure to M1 and M5. This was correlated to both apoptosis and necrosis, showed by Annexin-V/PI assay. Furthermore, M1 and M5 reduced FASN expression by 19-39%, respectively. In conclusion, M1 and M5 presented antiadipogenic and antitumoral activities. The antitumoral activity that was associated to apoptosis and necrosis is a possible consequence of the FASN reduction, which in turn, might result in a fuel decrease to cell proliferation. As it happens with antiangiogenic activity, reduction of fatty acid synthesis might be a potential target for cancer treatment in a strategy of hunger-strike, which valorizes these N-phenylmaleimides as candidates for drug development.
authors: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Daiane
authors: D
authors: Rosolen
authors: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Iara Fabrícia
authors: IF
authors: Kretzer
authors: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Evelyn
authors: E
authors: Winter
authors: Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Itajaí, SC, Brazil.
authors: Vânia Floriani
authors: VF
authors: Noldin
authors: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Ícaro Andrade
authors: ÍA
authors: Rodrigues do Carmo
authors: Departamento de Análises Clínicas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Fabíola Branco
authors: FB
authors: Filippin-Monteiro
authors: Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí (UNIVALI), Itajaí, SC, Brazil.
authors: Valdir
authors: V
authors: Cechinel-Filho
authors: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil. Electronic address: tania.pasa@ufsc.br.
authors: Tânia Beatriz
authors: TB
authors: Creczynski-Pasa
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D064429:Fatty Acid Synthases / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D008301:Maleimides / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice
chemical_list: D000970:Antineoplastic Agents; D008301:Maleimides; C028525:N-phenylmaleimide; D064429:Fatty Acid Synthases
keywords: Adipogenesis; Antitumoral activity; FASN; Melanoma; N-phenylmaleimides