ω-3 PUFA reduce cholesterol biosynthesis and doxorubicin resistance in colon cancer cells

Multidrug resistance (MDR) indicates a decrease in sensitivity of cancer to a wide variety of cytotoxic compounds, as doxorubicin. In fact the most frequent drawback of doxorubicin treatment is the onset of drug resistance, due to its active efflux from cancer cells through P-glycoprotein (Pgp). Altough a central role has been ascribed to Pgp in MRD, lipid membrane transporter and is mainly localized in lipid rafts. In particular, membrane cholesterol is essential to maintain a high Pgp activity (1), consequently tumors with a MDR phenotype have higher concentrations of plasma membrane cholesterol than chemosensitive ones. Several studies have demonstrated that ω-3 polynsaturated fatty acids (ω-3 PUFA) intake is correlated to low incidence of colorectal cancer (2). The mechanism(s) by which ω-3 PUFA might exhibit a protective effect remains unclear but one of the hypotheses indicates that they may also change the fluidity of cell membrane and thus influence signalling pathways. We treated human doxorubicin-sensitive (HT29) and doxorubicin-resistant (HT29-dx) colon cancer cells with EPA and DHA (50 µmol/L). Preliminary results indicate that DHA and EPA are incorporated in plasma membrane with a reduction of cholesterol content, in particular in HT29-dx cells. The cholesterol biosynthesis is higher in drug-resistant cells compared to drug-sensitive ones, and is decreased dose-dependently by PUFA treatment in both cell lines. Moreover, ω-3 PUFA, especially DHA, determine a reduction of HMGCoAR activity and expression. Only in HT29 dx cells, we have verified a slightly reduction of SREBP-2 nuclear content. Finally, DHA induces doxorubicin accumulation in drug resistant HT29-dx cells and reduces the Pgp activity, measured as the ability to extrude rhodamine. The evaluation of lipid raft Pgp localization and lipid composition will give the indication of a direct effect of ω-3 PUFA on raft structure and function. 1 Kopecka J, Journal of Controlled Release 2011. 2 Giros A, Cancer Prevention Research 2009.