Reversal of ABC Transporter-Dependent Multidrug Resistance in Cancer

Abstract

Multidrug resistance (MDR) remains the major cause of failure of chemotherapeutic treatment in cancer therapy. Thus, reversal of MDR in cancer is a desperately needed clinical requirement and a scientific challenge. The MDR phenotype can be mediated by adenosine triphosphate (ATP)-binding cassette (ABC) transporter molecules, which lower the intracellular accumulation of an entire panel of structurally and functionally unrelated anticancer drugs. Detailed knowledge of the transporter molecules, their sequence polymorphisms, their regulation at the transcriptional, translational, and post-translational levels, as well as their functional characteristics for substrate binding and transport, represent the basis for specific and, thus, successful intervention strategies for reversal of ABC transporter-dependent MDR in the clinic. Initial data obtained with third-generation inhibitors of ABC transporter-dependent MDR in clinical trials, and new developments with tools that interfere with expression of MDR genes, thereby leading to restored chemosensitization, are very promising attempts that provide grounds for cautious optimism. This article presents an overview of different strategies for overcoming ABC transporter-dependent MDR. Approaches targeting the function as well as the expression of MDR-related ABC transporters are summarized. Clinical trials evaluating the impact of compounds for reversal of ABC transporter-dependent MDR are discussed. The question remains, is reversal of MDR in cancer truly an achievable goal, given the different tumor entities and tumor heterogeneity, different tumor resistance profiles, and different therapeutic regimens? If so, MDR reversal will probably be successful only when tailored to an individual patient with an individual tumor, resistance profile and response prediction, i.e. individual prevention, circumvention, and reversal of MDR. Tailor-made MDR reversal strategies are the ultimate goal — and probably a realistic option.