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

Area of Science:

• Biochemistry
• Molecular Biology
• Pharmacology

Background:

• Hypoxia-inducible factor-1 (HIF-1) is crucial in human diseases but challenging to target pharmacologically due to its role in oxygen homeostasis.
• Mint3 activates HIF-1 in specific cells like cancer and macrophages by inhibiting the factor inhibiting HIF-1 (FIH-1).

Purpose of the Study:

• To identify small molecules that inhibit HIF-1 transcriptional activity without disrupting body homeostasis.
• To investigate Mint3 as a specific target for modulating HIF-1 activity in disease contexts.

Main Methods:

• Screening for compounds inhibiting the Mint3-FIH-1 interaction.
• Assessing naphthofluorescein's effects on HIF-1 activity, glycolysis, and cell viability in cancer cells and macrophages in vitro.
• Evaluating naphthofluorescein's efficacy in vivo for tumor growth, metastasis, and inflammatory responses in mouse models.

Main Results:

• Naphthofluorescein inhibited the Mint3-FIH-1 interaction in vitro.
• The compound suppressed Mint3-dependent HIF-1 activity and glycolysis in cancer cells and macrophages without cytotoxicity.
• In vivo, naphthofluorescein reduced tumor growth, metastasis, and inflammatory cytokine production, similar to Mint3 genetic depletion, without adverse effects.

Conclusions:

• Naphthofluorescein is a novel inhibitor of Mint3-dependent HIF-1 activation.
• Mint3 inhibitors represent a potential therapeutic strategy for cancer and inflammatory diseases, offering targeted treatment with a favorable safety profile.