Drug resistance remains a major obstacle in the treatment of cancer. Multidrug resistance (MDR) in cancer is the phenomenon when a tumor exhibits resistance to a number of structurally and mechanistically diverse chemotherapeutic agents. Although resistance may be multifactorial, a primary mechanism is the involvement of efflux membrane transporters such as P-glycoprotein, MRP1, and BCRP, part of the ATP Binding Cassette (ABC) transporter family. For example, the over-expression of P-glycoprotein in tumor cells results in MDR by preventing the intracellular accumulation of a variety of chemotherapeutic agents, including anthracyclines, taxanes, vinca alkyloids, and epipodophyllotoxins. Inhibition of P-glycoprotein and other ABC transporters, on the other hand, may reverse MDR by increasing intracellular drug accumulation in tumor cells, thus fostering their destruction.
Inhibitors of ABC transporters—termed MDR modulators—started with the calcium channel antagonist verapamil and the immunosuppressant cyclosporine A, followed by extensive investigations with 1,4-dihydropyridines. Third generation MDR drugs with high affinity for P-glycoprotein and other ABC transporters including LY335979 (zosuquidar), GF120918 (elacridar) and TR9576 (tariquidar) have more recently been developed. While many in vitro studies have demonstrated the potential of these MDR modulators to reverse MDR, this research, to date, has not translated into clinical successes. Clinical trials generally report toxicities, either due to those associated with the MDR modulator, the effects of higher intracellular concentrations of the chemotherapeutic agent due to transporter inhibition, or other effects of the modulator on chemotherapeutic drug disposition, such as through inhibition of metabolizing enzymes such as CYP3A4. While these toxicities have limited the dose and possibly the efficacy of clinical trials reported so far, it should be noted that some of the third generation MDR drugs have been associated with less toxicity in patients. For example, tariquidar (XR9576) has been proven to inhibit P-glycoprotein in humans with minimal toxicity alone or in combination with chemotherapy. However, despite these findings, few clinical trials have been able to demonstrate improved chemotherapeutic efficacy for most of these third generation modulators. As stated by Zarrin et al., (Chem Biol Drug Design 76:369, 2010) “After more than four decades of efforts, we are still far from an established treatment for MDR.”
What are the reasons for this in vitro-in vivo disconnect? While the hypothesis is that inhibition of ABC transporters results in increased accumulation in tumor cells, we do not know if this indeed occurs clinically with the doses used of the MDR modulators. Also, in clinical trials, the study patients must be adequately characterized with regards to transporter expression, including the presence of transporter polymorphisms and the potential up- or down-regulation of other transporters, as well as changes in metabolizing enzymes that could impact chemotherapeutic drug disposition, since these factors will greatly influence outcomes. Additionally, we hypothesize that inhibition of an ABC transporter, such as P-glycoprotein that is over-expressed in tumors, will result in reversal of MDR when the chemotherapeutic agent is a substrate for that transporter. But, is MDR in cancer so multifactorial and complex that we cannot expect successful translation using ABC transporter inhibitors, even if multiple transporters are targeted?
We are left with many questions but few answers: Is the targeting of P-glycoprotein or another ABC transporter a therapeutic strategy that may be successful in reversing MDR in any type of cancer? Is there a need for personalized medicine to identify appropriate patients that might benefit? Might other selective targeting approaches be more successful? Answers to these questions will determine whether targeting efflux transporters would remain as a useful clinical strategy in cancer therapy.