Molecular landscape of therapeutic deep eutectic systems selective toxicity towards colorectal cancer

Abstract

The foremost modern medicine challenges, such as cancer's high mortality rates, have emphasized the growing need for improved therapeutic agents. Following eutectic systems spotlight due to their remarkable physicochemical and biological properties, while mostly in compliance with the Green Chemistry Principles and sustainability metrics as the Sustainable Development Goals (SDG) from United Nations, we aimed to push forward their understanding as anticancer agents. Considering therapeutic deep eutectic systems (THEDES) promising reports of anticancer activity towards colorectal cancer (CRC) cells, we sought to fill the knowledge gap on these eutectics impact on these cancer cells molecular landscape. For that, an integrated approach was used to study how combining a terpene – as menthol (Me), thymol (Thy), perillyl alcohol (POH) and limonene (Lim) – with ibuprofen (Ibu) as a THEDES, affects permeability, cellular transport, cell viability, reactive oxygen species (ROS), cell metabolome and systemic toxicity. THEDES exposure resulted in increased Ibu cellular uptake, depletion of ROS, and cell dead induction via apoptosis. Moreover, CRC cells experienced alterations in their metabolite landscape with deleterious effects on essential metabolic pathways, such as lipid and anaerobic glycolysis energy production pathways. Furthermore, non-relevant systemic toxicity of these THEDES, within the range of concentrations tested, was observed. These findings underscore THEDES potential as selective anticancer agents, while offering a promising path for the development of therapeutics aligned with the sustainability metrics.