A promising therapeutic strategy for the development of new drugs blocking lymphangiogenesis

A promising therapeutic strategy for the development of new drugs blocking lymphangiogenesis

Researchers from the University of Liège (Agnès Noel’s Laboratory, GIGA-R) have recently provided evidence that toluquinol abrogates lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signalling pathway.

Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphedema and other inflammatory disorders.

In the present study, ULg’s researchers evaluated the potential of toluquinol (a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004) to inhibit lymphangiogenesis.

To address this issue, 2D and 3D in vitro culture of human lymphatic endothelial cells (LEC), the ex vivo mouse lymphatic ring assay and in vivo experimental models (the transgenic Fli1:eGFPy1 zebrafish, the mouse ear sponges and cornea models ) were used.

For the first time, researchers demonstrated that toluquinol inhibits LEC proliferation, migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced LEC apoptosis after 14 h of treatment in vitro, blocked the thoracic duct development in zebrafish, and reduced the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, researchers provide evidence that this drug abrogates the VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependent manner, and represses Akt and ERK1/2 phosphorylations.

Altogether, by showing that toluquinol inhibits several crucial steps in the lymphangiogenic process, our data open novel pharmacological perspectives for the treatment of lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies.

This article was published in the « British Journal of Pharmacology ».

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