P-Glycoprotein: One Mechanism, Many Tasks and the Consequences for Pharmacotherapy of Cancers

P-glycoprotein or multidrug resistance protein (MDR1) is an adenosine triphosphate (ATP)binding cassette transporter (ABCB1) intensely investigated because it is an obstacle tosuccessful pharmacotherapy of cancers. P-glycoprotein prevents cellular uptake of alarge number of structurally and functionally diverse compounds, including most cancertherapeutics and in this way causes multidrug resistance (MDR). To overcome MDR,and thus improve cancer treatment, an understanding of P-glycoprotein inhibition at themolecular level is required. With this goal in mind, we propose rules that predict whether acompound is a modulator, substrate, inhibitor, or inducer of P-glycoprotein. This new setof rules is derived from a quantitative analysis of the drug binding and transport propertiesof P-glycoprotein. We further discuss the role of P-glycoprotein in immune surveillanceand cell metabolism. Finally, the predictive power of the proposed rules is demonstratedwith a set of FDA approved drugs which have been repurposed for cancer therapy.