Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

• Published in: Drug metabolism and disposition Vol. 42; no. 4; pp. 623 - 631
• Main Authors: Callaghan, Richard, Luk, Frederick, Bebawy, Mary
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2014; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - genetics; Biological Transport; Drug Delivery Systems; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Humans; Neoplasms - drug therapy; Neoplasms - metabolism; Special Section on Transporters in Toxicity and Disease; Substrate Specificity; ABC; MP; PEG; P-gp; PKC; MDR; P450; CHO
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.113.056176

P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to “block” P-gp–mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application.