Biomedical scientists use chemistry-driven processes found in nature as an inspiration to design biomaterials as promising diagnostic tools, therapeutic solutions, or tissue substitutes.

P-glycoprotein (P-gp) appears to be associated within specialized raftlike membrane microdomains. The activity of P-gp is sensitive to its lipid environment, and a functional association in raft microdomains will require that P-gp retains activity in the microenvironment. Purified hamster P-gp was reconstituted in liposomes comprising sphingomyelin and cholesterol, both highly enriched in membrane microdomains and known to impart a liquid-ordered phase to bilayers. The activity of P-gp was compared with that of proteoliposomes composed of crude egg phosphatidylcholine (unsaturated) or dipalmitoyl phosphatidylcholine (saturated) in the presence or absence of cholesterol. The maximal rate of ATP hydrolysis was not significantly altered by the nature of the lipid species. However, the potencies of nicardipine and XR9576 to modulate the ATPase activity of P-gp were increased in the sphingolipid-based proteoliposomes. The drug-P-gp interaction was investigated by measurement of the rates of The phenomenon of resistance to chemotherapy displayed by cancer cells is a significant clinical problem, and the underlying mechanisms are numerous. Resistance pathways are either inherent to the three-dimensional arrangement of the tissue or acquired after exposure to anticancer drugs. The plasma membrane plays a major role in resistance to chemotherapy by preventing the accumulation of drugs at efficacious concentrations. The principal mechanism is via active extrusion of anticancer drugs by transporters belonging to the ATP binding cassette (ABC) superfamily. The best-described and most widely observed ABC transporter in cancer tissues is P-glycoprotein (P-gp), whose expression is associated with a reduced rate of remission and poor prognosis. P-gp is an unusual transporter in that it recognizes an extremely broad range of drug substrates that are neither chemically nor functionally related. As a consequence, it is classified as a "multidrug" transporter, and the ability to recognize a range of drugs is attributable to the presence of multiple allosterically linked binding sites (1).The only common characteristic of drugs transported by P-gp is hydrophobicity, and several lines of evidence have demonstrated that the binding sites on the protein are in the intrabilayer region (2-5). Over the last 20 years, a consistent, if unexplained, observation has been that P-gp and its membrane environment display a complex and interwoven relationship [for review, see ref. (6)]. For example, the incorporation of P-gp into bilayers is known to alter lipid-packing properties (7), to produce ultrastructural changes in the membrane (8, 9), and has even been suggested to mediate the transbilayer translocation of specific phospholipids (7,10,11). More recent observations have proposed that P-gp is localized to detergentresistant low density membrane microdomains (12) and caveolae (13,14). In addition, the major lipid species (e.g., sphingolipids and cholesterol) found in caveolae and rafts display increased levels in several P-gp-contai...