Phenothiazines and structurally related compounds as modulators of cancer multidrug resistance

Phenothiazines and structurally related compounds alongside their other biological activities are able to modulate multidrug resistance (MDR) in tumor cells. The extensive investigations on their MDR modulation effects consist part of the efforts to overcome MDR - the major obstacle in cancer chemotherapy. In this article we try to systematize the results collected in the last two decades in two main aspects. The first one comprises the mechanism of modulation by phenothiazine-type MDR modulators. Two main possible mechanisms of MDR reversal are reviewed: (i) direct interaction with Pgp; (ii) interactions with membrane phospholipids. The second aspect relates to the structural properties of phenothiazines and related compounds responsible for their MDR reversing effect. The structural alerts and physicochemical properties influencing anti-MDR activity are considered as identified by structure--activity (SAR) or quantitative structure--activity relationship (QSAR) studies. Results discussed in the article point to MDR modulation by phenothiazines and related compounds as a complex process in which more than one mechanism are certainly involved. Further investigations in this direction should contribute to elucidation of the possible mechanisms of MDR modulation by these compounds. On the basis of the studies discussed the potential use of phenothiazine-type MDR modulators as a model system in the further investigations of the MDR phenomenon is outlined.