ATP-binding cassette (ABC) transporter proteins, multidrug resistance, and novel flavonoid dimers as potent, nontoxic, and selective inhibitors

Abstract

Multidrug resistance (MDR) is often a major impediment to successful chemotherapy in the treatment of cancer. A common mechanism for MDR is the overexpression of an active ATP-binding cassette (ABC) transporter protein, P-glycoprotein (P-gp/ABCB1, also known as MDR1), multidrug resistance protein 1 (MRP1/ABCC1), or breast cancer resistant protein (BCRP/ABCG2), on the plasma membrane of cancer cells. These transporters can pump many structurally diverse anticancer drugs out of the cancer cells and render these drugs ineffective at a therapeutic dosage, i.e., multidrug resistance. Coadministration of a potent ABC transporter inhibitor with an anticancer drug has been evaluated in several clinical trials to overcome MDR but has led to a disappointing outcome. By taking advantage of the pseudo-dimeric structure of ABC transporters, we demonstrated that some flavonoid dimers, using polyvalent interactions, can be potent inhibitors of ABC transporters. Selective inhibition of the three different transporters with flavonoid dimers can be achieved by placing the two flavonoid moieties at an optimal distance apart specific for each transporter. In addition to being potent and selective inhibitors of the transporters, flavonoid dimers are found to be nontoxic to normal cells at their corresponding effective concentrations. The in vivo efficacy of flavonoid dimers was demonstrated. Further investigation of these flavonoid dimers as clinical candidates to overcome MDR in cancer chemotherapy is warranted.