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Coumarins possess a wide array of therapeutic capabilities, but often with unclear mechanism of action. We tested a small library of 18 coumarin derivatives against human invasive breast ductal carcinoma cells with the capacity of each compound to inhibit cell proliferation scored, and the most potent coumarin analogues selected for further studies. Interestingly, the presence of two prenyloxy groups (5,7-diprenyloxy-4-methyl-coumarin, 4g) or the presence of octyloxy substituent (coumarin 4d) was found to increase the potency of compounds in breast cancer cells, but not against healthy human fibroblasts. The activity of potent compounds on breast cancer cells cultured more similarly to the conditions of the tumour microenvironment was also investigated, and increased toxicity was observed. Results suggest that tested coumarin derivatives could potentially reduce the growth of tumour mass. Moreover, their use as (combination) therapy in cancer treatment might have the potential of causing limited side effects. Leonidas Gkionis and Eleni Kavetsou: Co-first authors.

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Angiopoietin ligands Ang1 and Ang2 and the Tie2 receptor tyrosine kinases form an endothelial signaling pathway regulating vascular homeostasis and controlling vessel permeability, inflammation and angiogenic responses. Whereas Ang1-mediated Tie2 activation reduces inflammation and endothelial permeability, its antagonist, Ang2 increases it. Increased plasma Ang2 levels are associated with poor outcomes in patients with acute lung injury (ALI), as well as in acute respiratory distress syndrome (ARDS). In the study presented here we tested the effect of a novel synthetic, nucleoside-modified mRNA-76 encoding for a hyperactive Ang1 derived fusion protein (COMP-Ang1) on attenuating post-inflammation vascular leakage. COMP-Ang1 mRNA was formulated into a cationic lipid nanoparticle (cLNP) using an optimized mixture of three different lipids and a microfluidic mixing technology. After intravenous injection, the respective mRNA-loaded LNPs were found to be delivered predominantly to the endothelial cells of the lung, while sparing other vascular beds. Also, the specific multimeric folding of the COMP-Ang1 protein complex appeared to be pivotal for its activity in preventing vascular leakage and in restoring the alveolar-endothelial barrier function in the inflamed and injured pulmonary vasculature. The mode of action of mRNA-76, such as its activation of the Tie2 signal transduction pathway, was tested by pharmacological studies in vitro and in vivo by systemic administration in respective mouse models. mRNA-76 was found to prevent lung vascular leakage/lung edema as well as neutrophil infiltration in an LPS-challenging model.