ω-3 Long Chain Polyunsaturated Fatty Acids as Sensitizing Agents and Multidrug Resistance Revertants in Cancer Therapy

Abstract

Chemotherapy efficacy is strictly limited by the resistance of cancer cells. The ω-3 long chain polyunsaturated fatty acids (ω-3 LCPUFAs) are considered chemosensitizing agents and revertants of multidrug resistance by pleiotropic, but not still well elucidated, mechanisms. Nowadays, it is accepted that alteration in gene expression, modulation of cellular proliferation and differentiation, induction of apoptosis, generation of reactive oxygen species, and lipid peroxidation are involved in ω-3 LCPUFA chemosensitizing effects. A crucial mechanism in the control of cell drug uptake and efflux is related to ω-3 LCPUFA influence on membrane lipid composition. The incorporation of docosahexaenoic acid in the lipid rafts produces significant changes in their physical-chemical properties affecting content and functions of transmembrane proteins, such as growth factors, receptors and ATP-binding cassette transporters. Of note, ω-3 LCPUFAs often alter the lipid compositions more in chemoresistant cells than in chemosensitive cells, suggesting a potential adjuvant role in the treatment of drug resistant cancers.

Keywords: DHA; EPA; PUFA; chemoresistance; membrane; ω-3.

Figure 1

Proposed mechanisms for ω-3 LCPUFA anticancer effects. LCPUFA—long chain polyunsaturated fatty acids; EPA—eicosapentaenoic acid; DHA—docosahexaenoic acid.

Figure 2

Overview of the key COX, LOX, and CYP-derived metabolites from EPA and DHA. COX—cyclooxygenases; LOX—lipoxygenases; CYP—cytochrome P450; PG—prostaglandin; Tx—thromboxane; HpETE—hydroperoxy eicosatetraenoic acid; HpEPE—hydroperoxy eicosapentaenoic acid; EpETE—epoxy eicosatetraenoic acid; DiHETE—dihydroxy eicosatetraenoic acid; HEPE—hydroxy eicosapentaenoic acid; HpDHA—hydroperoxy docosahexaenoic acid; HDHA—hydroxy docosahexaenoic acid; EpDPE—epoxy docosapentaenoic acid; DiHDPE—dihydroxy docosapentaenoic acid; Lx—lipoxin; LT—leukotriene; Mar—maresin, PD—protectin; RvD—D series resolvins; RvE—E series resolvins.

Figure 3

DHA impact on lipid raft structure. DHA incorporation in membrane affects lipid raft organization inducing a shift from cholesterol/saturated fatty acid-rich domains to ω-3 LCPUFA-rich/cholesterol-poor domains, which exhibit different height ranges.

Figure 4

ω-3 LCPUFAs reverse chemoresistance induced by P-glycoprotein by modulating cholesterol synthesis and altering membrane lipid microenvironment. (A) MDR cells have a high synthesis of cholesterol, owing to the constitutive over-expression of the enzyme 3-hydroxy-3-methlyglutaryl coenzyme A reductase (HMGCoAR). This is independent of the activation of the transcription factor sterol regulatory binding protein-2 (SREBP2) but is due to the lower activity of the E3-ubiquitin ligase Trc8. A high cholesterol content in the plasma membrane sustains the activity of P-glycoprotein (Pgp), which effluxes several chemotherapeutic drugs (d); (B) DHA and EPA are allosteric activators of Trc8 and increase the Trc8-mediated ubiquitination (Uq) of HMGCoAR, reducing cholesterol synthesis. Such cholesterol depletion, together with the incorporation of DHA/EPA in plasma membrane, alters the cholesterol rich/saturated fatty acids rich lipid micro-domains such as lipid rafts, reduces Pgp surface level and activity. As a result, ω-3 LCPUFAs increase the intracellular retention of Pgp substrates, chemosensitizing resistant cells.