2. Academic Validation
  3. Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock

Pharmacological inhibition of Mint3 attenuates tumour growth, metastasis, and endotoxic shock

  • Commun Biol. 2021 Oct 7;4(1):1165. doi: 10.1038/s42003-021-02701-1.
Takeharu Sakamoto 1 2,  Yuya Fukui 3 4,  Yasumitsu Kondoh 5,  Kaori Honda 5,  Takeshi Shimizu 5,  Toshiro Hara 6,  Tetsuro Hayashi 7,  Yurika Saitoh 8,  Yoshinori Murakami 7,  Jun-Ichiro Inoue 4,  Shuichi Kaneko 3,  Hiroyuki Osada 5,  Motoharu Seiki 6
Affiliations

Affiliations

  • 1 Department of Cancer Biology, Institute of Biomedical Science, Kansai Medical University, Shin-machi, Hirakata, Osaka, Japan. sakamott@hirakata.kmu.ac.jp.
  • 2 Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takaramachi, Kanazawa, Ishikawa, Japan. sakamott@hirakata.kmu.ac.jp.
  • 3 Department of System Biology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takaramachi, Kanazawa, Ishikawa, Japan.
  • 4 Division of Cellular and Molecular Biology, The Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
  • 5 Chemical Biology Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
  • 6 Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
  • 7 Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
  • 8 Center for Medical Education, Teikyo University of Science, Senjusakuragi, Adachi-ku, Tokyo, Japan.
PMID: 34621018 DOI: 10.1038/s42003-021-02701-1
Abstract

Hypoxia-inducible factor-1 (HIF-1) plays essential roles in human diseases, though its central role in oxygen homoeostasis hinders the development of direct HIF-1-targeted pharmacological approaches. Here, we surveyed small-molecule compounds that efficiently inhibit the transcriptional activity of HIF-1 without affecting body homoeostasis. We focused on Mint3, which activates HIF-1 transcriptional activity in limited types of cells, such as Cancer cells and macrophages, by suppressing the factor inhibiting HIF-1 (FIH-1). We identified naphthofluorescein, which inhibited the Mint3-FIH-1 interaction in vitro and suppressed Mint3-dependent HIF-1 activity and glycolysis in Cancer cells and macrophages without evidence of cytotoxicity in vitro. In vivo naphthofluorescein administration suppressed tumour growth and metastasis without adverse effects, similar to the genetic depletion of Mint3. Naphthofluorescein attenuated inflammatory cytokine production and endotoxic shock in mice. Thus, Mint3 inhibitors may present a new targeted therapeutic option for Cancer and inflammatory diseases by avoiding severe adverse effects.

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