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ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp, ABCB1) and ABCG2, are membrane proteins that couple the energy derived from ATP hydrolysis to efflux many chemically diverse compounds across the plasma membrane, thereby playing a critical and important physiological role in protecting cells from xenobiotics. These transporters are also implicated in the development of multidrug resistance (MDR) in cancer cells that have been treated with chemotherapeutics. One approach to blocking the efflux capability of an ABC transporter in a cell or tissue is inhibiting the activity of the transporters with a modulator. Since ABC transporter modulators can be used in combination with chemotherapeutics to increase the effective intracellular concentration of anticancer drugs, the possible impact of modulators of ABC drug transporters is of great clinical interest. Another possible clinical use of modulators that has recently attracted attention is their ability to increase oral bioavailability or increase tissue penetration of drugs transported by the transporters. Several preclinical and clinical studies have been performed to evaluate the feasibility and the safety of this approach. The primary focus of this review is to discuss progress made in recent years in the identification and applicability of compounds that may serve as ABC transporter modulators and the possible role of these compounds in altering the pharmacokinetics and pharmacodynamics of therapeutic drugs used in the clinic.

Improving Cancer Chemotherapy with Modulators of ABC Drug Transporters