Membrane fatty acid remodeling along cytotoxic events induced by a novel copper-based antitumoral agent and tumor progression in mice models.

Altered fatty acid (FA) biosynthesis and metabolism have been related to enhanced cellular growth and proliferation of cancer cells. The membrane FA composition may influence its properties and membrane lipid-related signaling. The first part of this thesis aimed at the in vitro evaluation of the effects of a novel copper complex, [Cu(TPMA)(Phenanthroline)](ClO4)2, on cell viability and membrane fatty-acid lipidome. The complex was studied as a free compound or under an encapsulated form within polymeric nanoparticles in neuroblastoma (NB100) and breast carcinoma (MCF7) cell lines. In both cell lines, the Cu-complex induced oxidative stress and led to apoptosis and necroptosis. Membrane remodeling took place upon treatment with the complex at EC50 with an increase of saturated FA (SFA) and a decrease of monounsaturated FA (MUFA). Assessment of the stearoyl-CoA desaturase activity showed no enzymatic inhibition of MUFA biosynthesis. Cells pre-treatment with apoptosis inhibitors and ROS scavengers prevented both cytotoxicity and changes on FA composition. Finally, encapsulation of the complex in polymeric nanoparticles reduced its cytotoxicity and prevented membrane FA changes in treated cells. The second part involved the monitoring of FA composition of erythrocyte membrane at different stages of tumor occurrence and at early points of tumor occurrence after administration of iron nanoparticles (Fe-NPs) and bleomycin. The animal model studies consisted in SCID mice xenografted with human glioblastoma U87MG cells. Late stage tumor-bearing mice were characterized by statistically significant increase of SFA, accompanied by a decrease in total PUFA, unsaturation and peroxidation indices. Fe-NPs caused membrane remodeling in healthy Swiss mice, characterized by lower SFA and PUFA levels and higher MUFA content. In conclusion, fatty acid-based membrane lipidomics could be a valuable tool for evaluating the nutritional condition and metabolic status of an organism and contribute to the development of multi-targeted antitumoral approaches through customized cell membrane rearrangement.