Lipids as a target for drugs modulating multidrug resistance of cancer cells.
In this review we focus on the role of the membrane lipids in multidrug resistance and its modulation. Results of the research performed in recent years indicate the importance of lipid phase playing active role in many membrane processes. Along with the alterations of lipid membrane composition of cancer cells (with respect to the normal ones) the resulting changes of the biophysical membrane properties are discussed. Next we describe the general features of multidrug resistance phenomenon paying a special attention to the role of lipids and alterations of lipid membrane composition in MDR cells. Taking into account the phase separation properties of sphingolipids the importance of membrane heterogeneity (presence of caveole and lipid rafts) is emphasised. On the basis of vacuum cleaner hypothesis of drug transport proteins action we discuss the importance of lipid bilayer as medium in which diffusion of drugs takes place. Considering the membrane fluidity and its influence on the integral proteins activity, we underline the role of balance between the passive cellular influx and active efflux of the drug molecules. Finally the effects exerted on membranes by different kinds of multidrug resistance modulators (chemosensitizers) are described. In this part we discuss the influence of verapamil, phenothiazine derivatives, tamoxifen and chosen flavonoids on the biophysical properties of membrane lipids. Some further consequences of the alteration of membrane state are also considered.
Hendrich
A B
AB
Department of Biophysics, Wroclaw Medical University, Chalubinskiego 10, Wroclaw 50 368, Poland. hendrich@biofiz.am.wroc.pl
Michalak
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D008563:Membrane Lipids