Lipids: A key role in multidrug resistance? (Review)

Among tumoral resistances, multidrug resistance (MDR) is characterized as c ross-resistance to a variety of structurally and functionally unrelated dru gs such as vinca alkaloids, colchicine, and anthracyclines. Decreased drug cellular influx and increased cellular ability for drug extrusion are the m ain mechanisms involved in MDR. Two plasma membrane proteins, p-glycoprotei n (p-gp) and the multidrug resistance-associated protein (MRP), act as ATP- dependent cellular efflux 'pumps'. Furthermore, protein kinase C (PKC) is a lso central to MDR. The present study reviews the role of cholesterol and o ther lipids in the reduction of drug influx and drug binding to cellular me mbranes. The study also examines the effect of lipid composition on p-gp 't ransporter' activity. Concerning the role of PKC in MDR, two phospholipases involved in diacylglycerol (DG) production increase in MDR cells. These ar e phosphatidylinositol-4,5-bis-phosphate-specific phospholipase C and phosp hatidylethanolamine-specific phospholipase D. A positive feedback mechanism for DG production which includes these phospholipases, a phosphatidylcholi ne-specific phospholipase C and a phosphatidylcholine-specific phospholipas e A(2) has also been suggested. The hypothesis of exocytic involvement in M DR is reviewed, and some lipid changes found in MDR cells are interpreted a ccording to those fusogenic properties normally involved in exocytic transp ort. Also, the possible role of lipid mediators, such as phosphatidic acid and platelet-activating factor, is examined.