Mechanisms and therapeutic potential of inhibiting drug efflux transporters.

Introduction: The ATP-binding cassette transporters are among the largest transmembrane protein families in humans and are expressed in a wide variety of tissues. By promoting outward transport, they protect cells from the accumulation of undesirable substrates. This protection might lead to suboptimal concentration of chemotherapeutics in the tumor cells, resulting in therapy resistance and poor disease prognosis. In the past decades, a considerable effort was made to reverse multidrug resistance (MDR).

Areas Covered: We briefly summarize the present knowledge on the clinical efficacy of MDR reversing agents in various types of cancer and discuss their availability in a non-cancerous disease (rheumatoid arthritis). The classical and novel pharmacological approaches directly inhibiting the transporters' function and their extensive investigations in human clinical studies are also mentioned. Furthermore, the article highlights the methodological concerns raised by these investigations.

Expert Opinion: The development of chemotherapeutics lacking transporter-inducing effects, gene therapy approaches, nanomedicinal formulations and the identification of natural compounds to modulate transporter function are intriguing but face serious delivery challenges. Understanding and mapping molecular mechanisms of drug resistance will make it easier to design clinical treatment regimes that avoid escalation of MDR, by utilizing collateral sensitivity.