Interactions of Phenothiazines with Lipid Bilayer and their Role in Multidrug Resistance Reversal

K.      Michalak; O.      Wesolowska; N.      Motohashi; J.      Molnar; A.   B.   Hendrich

Abstract

The mechanism of multidrug resistance (MDR) reversal is not fully understood yet. Interaction of MDR modifiers with lipid bilayer of cell membranes and alterations of fluidity or other biophysical properties of plasma membrane might be an important factor in mechanism of MDR modulation and reversal. In this review we focus on phenothiazines which belong to the group of drugs known to modify MDR in different types of cells, from cancer cells up to various kinds of microorganisms. First, the aggregation properties of phenothiazines and their interactions with lipid bilayers are described. The localization of phenothazine derivative molecules in bilayers and alteration of membrane properties are discussed. Apart from the influence on model bilayers also the interactions of phenothiazines with cellular membranes (especially of erythrocytes) are reviewed. In subsequent sections the anti-MDR activity of phenothiazine derivatives observed in microorganisms and in cancer cells is described. The possible molecular mechanisms involved in MDR reversal by these compounds are presented. The direct interactions of phenothiazines with multidrug transporters and other effects of these modulators on plasma membranes are discussed. Finally, the structural features of phenothiazine derivatives essential for their optimal MDR reversal activity are described.

Keywords: Phenothiazines, multidrug resistance (MDR), P-glycoprotein, drug-membrane interactions, lipid bilayers, chlorpromazine, trifluoperazine, thioridazine