The Omega-3 Fatty Acids Eicosapentaenoic Acid and Docosahexaenoic Acid Enhance the Effects of Temozolomide Chemotherapy in Glioblastoma Cells

Overcoming resistance to temozolomide (TMZ) chemotherapy is a major challenge in glioma treatment. Polyunsaturated fatty acids (PUFAs) can interfere with drug resistance in glioma but their mechanism of action is poorly understood. Eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) effects were assessed using proliferation and clonogenic assays, adhesion and migration assays, glucose and lactate metabolism, detection of lipid droplets, acidic vesicles, reactive oxygen species, and phosphokinase proteome analysis. EPA or DHA caused significant reductions in cell number, colony formation, adhesion, and migration in comparison with TMZ alone, increasing lipid droplet accumulation, reactive oxygen species formation, acidic vesicle number and apoptosis, while also altering glucose and lactate metabolism. TMZ increased phosphorylation of ERK 1/2, GSK3α/β, AMPKα1, Akt 1/2/3, PRAS40, CREB, HSP27, WNK1, and c-Jun in U87MG TMZR cells. EPA in the presence of TMZ reduced the phosphorylation of GSK3α/β, Akt 1/2/3, HSP27, and WNK1, while DHA reduced the phosphorylation of ERK 1/2, GSK3α/β, AMPKα1, Akt 1/2/3, and WNK1, thereby leading to additive or synergistic effects of EPA or DHA in combination with TMZ. Overall, the present study highlights the alterations seen in TMZ-resistant glioma cells when exposed to EPA or DHA and demonstrates the therapeutic potential that modulation of lipid metabolism can exert upon important aspects of glioma cell biology.