Interacciones lípido-proteína de membrana en gliomael ácido 2-hidroxioleico como interruptor antiproliferativo

Laburpena

Glioblastoma multiform (GBM) is considered the most aggressive and lethal of primary tumours of the central nervous system (CNS). The standard treatment consists of maximum possible surgical resection, followed by radiotherapy and cycles of chemotherapy with temozolomide (TMZ), extending the median survival to 15 months (major, at best 2 additional months). In addition, TMZ contains undesirable side effects and induces the development of resistances and relapses. Due to the poor prognosis of patients, it is of great importance to develop new therapeutic strategies that improve the efficacy and safety of treatments with the aim of achieving complete remission of GBM. Biological membranes, in addition to a physiological barrier, host a multitude of proteins that act as signalling receptors or cell anchors and interact intermittently with peripheral proteins responsible for the signal transmission the signalling initiated by the receptors. The location, distribution and, consequently, activity of these proteins is regulated by the lipid composition and structure of the membranes, together with other factors, modulating the physiological state of the cell. Membrane Lipid Therapy (MLT) or Meliterapy is an innovative approach that proposes the use of new molecules designed to modify the composition and lipid structure of the membrane and reverse a pathological lipid state. This reversion would involve the modulation of a "lipid switch" which, in turn, would alter the expression of a disease-specific protein or modulate signalling cascades involved in the pathology. In this context, the compound 2OHOA (2-hydroxyoleic) has been developed, a bioactive lipid molecule and an analogue of oleic acid (OA) that has demonstrated an anti-tumour effect and high safety in cellular and animal models of GBM. The efficacy of 2OHOA in the treatment of patients with GBM is currently being evaluated in a phase IIb/III clinical study, having already confirmed the safety profile in previous clinical phases. This work focuses on the role the role of 2OHOA as a modulator of the lipid switch of cell proliferation, which is used by normal cells to induce or inhibit cell division and which is deregulated in cancer cells. The results of this work confirmed that 2OHOA is mostly incorporated in glioma cell membranes than in non-tumour cells, which would explain its specific effects in cancer treatment. After its incorporation, 2OHOA was metabolised to produce the compound C17:1n-9 by α-oxidation pathway, a key process for its anti-tumour effect in glioma cells. In addition, the C17:1n-9 metabolite showed an antiproliferative effect, independent of 2OHOA activity, and could be a useful biomarker to predict and trace 2OHOA treatment, based on pharmacokinetics observed in glioma patients treated with the drug in phase I/IIa and its accumulation in xenographic mouse tumours. In addition, 2OHOA produced general-level modulations in lipidoma of glioma cells, mainly it is incorporated, as its metabolite, in various lipid species. This is strongly correlated with changes in peripheral proteins location, producing a protein drain from the glioma cell membrane. These alterations in peripheral membrane proteins induced by the incorporation of 2OHOA into the membranes resulted in a cell proliferation switch.