BACKGROUND AND PURPOSE
Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic
dissemination, graft rejection, lymphoedema and other inflammatory disorders. The development of new drugs that block
lymphangiogenesis has become a promising therapeutic strategy. In this study, we investigated the ability of toluquinol,
a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibit
lymphangiogenesis in vitro, ex vivo and in vivo.
EXPERIMENTAL APPROACH
We used human lymphatic endothelial cells (LECs) to analyse the effect of toluquinol in 2D and 3D in vitro cultures and in the
ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, mouse ear sponges and cornea
models were used. Western blotting and apoptosis analyses were carried out to search for drug targets.
KEY RESULTS
Toluquinol inhibited LEC proliferation,migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol
induced apoptosis of LECs after 14 h of treatment in vitro, blocked the development of the thoracic duct in zebrafish and reduced
the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we demonstrated that
this drug attenuates VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependentmanner and suppresses the phosphorylation
of Akt and ERK1/2.
CONCLUSIONS AND IMPLICATIONS
Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of
lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications
in vascular ocular pathologies.
