Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells: evaluation of current strategies

Abstract

Overexpression of ATP-binding cassette (ABC) drug transporters that actively efflux a variety of amphipathic compounds can cause multidrug resistance (MDR) in cancer cells, which is a major obstacle in the success of cancer chemotherapy. The development of synthetic small molecule compounds or the identification of natural products that block ABC transporter-mediated efflux has been the conventional approach used to combat MDR. The strategy of using chemosensitizers, however, has not been successful in clinical cancer chemotherapy. Therefore, alternative approaches to identify or to synthesize compounds that can induce selective toxicity in cancer cells overexpressing one or more ABC transporters have been undertaken. This review summarizes the recent advances in identifying strategies to restore sensitivity to chemotherapeutics in multidrug resistant cancer cells.

Keywords: ATP-binding cassette transporters; Chemosensitizers; Collateral sensitivity; Modulators; Multidrug resistance.

Fig. 1. Schematic of the various methods used to circumvent MDR mediated by ABC transporters

Gene silencing of ABC transporters can be performed using synthetic siRNA(1), shRNA in a vector (2), and hammerhead ribozyme (3). Numerous negative modulators/transcriptional regulators (4) can inhibit transcription of these transporters in the nucleus. MDR can also be modulated by plasma membrane alterations (5). In addition, monoclonal antibodies (6), non-substrate drugs (7), and drug encapsulation (8) have also been used to evade MDR in cancer cells.