Omega-3 long chain polyunsaturated fatty acids as sensitizing 2 agents and multidrug resistance revertants in cancer therapy

The efficacy of chemotherapy depends on sensitivity and intrinsic or acquired drug 14 resistance of cancer cells. The n-3 long chain polyunsaturated fatty acids (n-3 LCPUFAs) are 15 considered chemosensitizing agents and revertants of multidrug resistance by pleiotropic 16 mechanisms. The specific mechanisms are not fully understood, but nowadays, it is widely accepted 17 that there are a complex network of mechanisms, including alteration in gene expression, 18 modulation of cellular proliferation and differentiation, induction of apoptosis, generation of 19 reactive oxygen species and lipid peroxidation. A crucial mechanism in the control of cell drug 20 uptake and efflux is related to n-3 LCPUFA influence on membrane lipid composition. The 21 incorporation of docosahexaenoic acid in the lipid rafts produces significant changes in their 22 physical-chemical properties affecting content and functions of transmembrane proteins, such as 23 growth factors, receptors and ATP-binding cassette transporters. Of note, n-3 LCPUFAs often 24 impact on the lipid compositions more in chemoresistant cells than in chemosensitive cells, 25 suggesting their adjuvant role in cancer treatment. 26