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

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.

Drug–Membrane Interactions: Molecular Mechanisms Underlying Therapeutic and Toxic Effects of Drugs

“…According to this, a drug that is able to induce alterations of bilayer properties, especially altering fluidity and permeability, should play an essential role in the processes of MDR modulation. Hence, most of the MDR reversing agents are preferentially soluble in lipids and they may also exert an influence on the physical properties of lipid bilayers [94][95][96]. For example, phenothiazines, considered as MDR reversing agents affect the properties of the lipid bilayer causing phase separation in membranes containing lipid microdomains of sphingolipids and cholesterol [95].…”

The Role of the Membrane Actions of Phenothiazines and Flavonoids as Functional Modulators

“…The substrates and the modulators of P-gp were found in the highest concentrations within the membrane interface region. The role of drug-lipid membrane interactions in MDR and its reversal was reviewed in detail elsewhere [53,187].…”

“…Especially high affinity was detected for flavanolignan dehydrosilybin (DHS) (53). DHS (53) strongly inhibited leukotriene C4 transport by membrane vesicles from MRP1-transfected cells and chemosensitized the cells to vincristine.…”

“…The authors of these studies suggested that the DHS (53) binding site overlapped the ATP-binding site in the NBD of MRP1. Binding affinities toward NBD1 were further increased for prenylated and geranylated derivatives of DHS (53). Although the relationship between ATPase activity of ABC transporters and transport of their substrates is not fully understood, it is assumed that compounds that stimulate the ATPase activity of MDR transporter interact with the protein.…”

“…Recently the dependencies between drug-membrane interactions and phenothiazine MDR-modulatory properties were reviewed by Tsakovska and Pajeva [52]. The role of phenothiazine-lipid interaction in MDR reversal was also reviewed by Michalak et al [53]. Passive transport of anticancer drugs is one of the crucial factors governing their accumulation inside the cells.…”