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Identification of a selective inhibitor of human monocarboxylate transporter 4

Futagi, Yuya ; Kobayashi, Masaki ; Narumi, Katsuya ; Furugen, Ayako ; Iseki, Ken

Biochemical and biophysical research communications, 2018-01, Vol.495 (1), p.427-432 [Periódico revisado por pares]

United States: Elsevier Inc

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  • Título:
    Identification of a selective inhibitor of human monocarboxylate transporter 4
  • Autor: Futagi, Yuya ; Kobayashi, Masaki ; Narumi, Katsuya ; Furugen, Ayako ; Iseki, Ken
  • Assuntos: 60 APPLIED LIFE SCIENCES ; ANIMAL TISSUES ; hMCT1 ; hMCT4 ; LACTATES ; LACTIC ACID ; Monocarboxylate transporter ; NEOPLASMS ; Oocyte ; OOCYTES
  • É parte de: Biochemical and biophysical research communications, 2018-01, Vol.495 (1), p.427-432
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: The human monocarboxylate transporters (hMCTs/SLC16As) mediate the uptake of various monocarboxylates. Several isoforms of hMCTs are expressed in cancerous tissue as well as in normal tissue. In cancerous tissue, hypoxia induces the expression of hMCT4, which transports the energetic metabolite l-lactate across the plasma membrane. Since hMCT4 is involved in pH regulation and the transport of l-lactate in cancer cells, an hMCT4 inhibitor could function as an anticancer agent. Although several non specific hMCT inhibitors have been developed, a selective hMCT4 inhibitor has not yet been identified. The aim of this study was therefore to identify a selective hMCT4 inhibitor for use as a pharmacological tool for studying hMCT4. The heterologous expression system of the Xenopus oocyte was used to assess the effects of test compounds on hMCT4, whereupon isobutyrate derivatives, fibrates, and bindarit (2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid) were demonstrated to exhibit selective inhibitory effects against this transporter. It is suggested that the structure formed from the joining of an isobutyrate moiety and two aromatic rings by appropriate linkers is important for acquiring the selective hMCT4-inhibiting activity. These findings provide novel insights into the ligand recognition of hMCT4, and contribute to the development of novel anticancer agents. •hMCT4 transporter mediates the transport of metabolites such as l-lactate and pyruvate.•5-ETZ, a bioisostere of propionate, is recognized by hMCT1 and hMCT4.•Fibrates, a group of isobutyrate derivatives, selectively inhibit hMCT4.•Bindarit might be the first-identified potent and selective inhibitor of hMCT4.
  • Editor: United States: Elsevier Inc
  • Idioma: Inglês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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