Dual antitumor and neuroprotective activities of lipid ether amide hybrids in glioma cells and metabolically damaged neurons.

BACKGROUND: Lipid metabolism and signaling via multiple receptors strongly influences the development of brain tumors and affects neuronal vulnerability and damage. Oleic and palmitic acids are endogenous ligands for the nuclear receptor TLX and the constitutively active G-Protein coupled receptors GPR3 and GPR6. TLX is overexpressed in glioma stem/progenitor cells and promotes tumor development, while GPR3 and GPR6 support neuronal survival and integrity. To exploit these pathways therapeutically, we designed and tested fatty acid lipid amide hybrids (LEAs) linking oleic or palmitic acid to a polar moiety of propranolol via a non-hydrolysable ether bond. METHODS: Oleic-LEA and palmitic-LEA hybrids were synthesized and validated by NMR and LC-MS/MS. Antitumor activity was assessed in patient-derived glioma cells grown as tumor spheres and adherent cultures. Neurotoxicity and neurorestorative effects were evaluated in primary neuronal cultures subjected to prolonged nutrient deprivation. Target engagement was assessed in silico using SwissDock Attractive Cavities 2.0 algorithm. RESULTS: LEA hybrids inhibited clonal growth and survival of human glioma stem/progenitor cells and adherent glioma layers low-micromolar IC50 values with no toxicity to normal cortical cultures. In contrast, LEAs significantly increased neuronal survival and restored neuronal architecture in metabolically stressed cerebellar neuron cultures. Docking analyses revealed nanomolar binding affinity to GPR3 and GPR6 and micromolar affinity to TLX, greatly exceeding that of parent fatty acids or propranolol alone. CONCLUSION: Oleic- and palmitic-LEA hybrids represent a novel class of bioactive lipids with dual antitumor and neuroprotective properties, acting through coordinated modulation of lipid-sensing GPCRs and the nuclear receptor TLX.