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Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications

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Review

Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications

Yu Toyoda et al. Front Pharmacol.

Abstract

The ATP-binding cassette transporter G2 (ABCG2; also known as breast cancer resistance protein, BCRP) has been suggested to be involved in clinical multidrug resistance (MDR) in cancer like other ABC transporters such as ABCB1 (P-glycoprotein). As an efflux pump exhibiting a broad substrate specificity localized on cellular plasma membrane, ABCG2 excretes a variety of endogenous and exogenous substrates including chemotherapeutic agents, such as mitoxantrone and several tyrosine kinase inhibitors. Moreover, in the normal tissues, ABCG2 is expressed on the apical membranes and plays a pivotal role in tissue protection against various xenobiotics. For this reason, ABCG2 is recognized to be an important determinant of the pharmacokinetic characteristics of its substrate drugs. Although the clinical relevance of reversing the ABCG2-mediated MDR has been inconclusive, an appropriate modulation of ABCG2 function during chemotherapy should logically enhance the efficacy of anti-cancer agents by overcoming the MDR phenotype and/or improving their pharmacokinetics. To confirm this possibility, considerable efforts have been devoted to developing ABCG2 inhibitors, although there is no clinically available substance for this purpose. As a clue for addressing this issue, this mini-review provides integrated information covering the technical backgrounds necessary to evaluate the ABCG2 inhibitory effects on the target compounds and a current update on the ABCG2 inhibitors. This essentially includes our recent findings, as we serendipitously identified febuxostat, a well-used agent for hyperuricemia as a strong ABCG2 inhibitor, that possesses some promising potentials. We hope that an overview described here will add value to further studies involving in the multidrug transporters.

Keywords: BCRP; Ko143; cancer chemotherapy; drug repurposing; febuxostat; multidrug resistance; tumor lysis syndrome; vesicle transport.

Figures

FIGURE 1
FIGURE 1
Schematic illustrations of each in vitro assay. Generally used in vitro models which are classified into membrane-based systems and cell-based systems (Hegedus et al., 2009) are shown. In the former systems, investigators can use culture cell-derived plasma membrane vesicles or reconstituted proteoliposomes as described in the main text. In the latter systems, aside from a couple of exceptions using Xenopus laevis oocytes (Nakanishi et al., 2003; Woodward et al., 2009), mammalian cells expressing target ABC protein are generally used. (A,B) Plasma membrane vesicle- or proteoliposome-based methods: vesicle transport assay (A) and ATPase assay (B). Both plasma membrane vesicles and reconstituted proteoliposomes are applicable to the vesicle transport assay and the ATPase assay. Of note, the final step of the vesicle preparation—gentle homogenization of isolated membrane fraction—is empirically important for the formation of inside-out plasma membrane vesicles, whose outer faces are the cytoplasmic aspects of the parent membranes. Although the resulting plasma membrane vesicles are the mixture of inside-out and right-side-out components, without any separation of the right-side-out vesicles they are generally stored at –80°C and subjected to further assays. This is because that in these in vitro assays, only ABC proteins embedded in the inside-out vesicles have their ABCs outside of the vesicles and can use ATP in the reaction mixture for their transport function. In other words, the ABC proteins in the right-side-out vesicles cannot work due to an inaccessibility of the ABCs with ATP. Additionally, ABCG2-enriched plasma membrane vesicles are used for a biochemical analysis to study interactions of candidate chemicals with ABCG2 at the substrate-binding sites, known as the photoaffinity labeling of ABCG2 with [125I]-iodoarylazido-prazosin (Shukla et al., 2006). (C,D) Cell-based methods: drug resistance/accumulation test (C) and transcellular system (D). MDR, multidrug resistance.
FIGURE 2
FIGURE 2
Inhibitory effect of febuxostat against ABCG2 is stronger than that of Ko143 and elacridar, two well-used ABCG2 inhibitors. Febuxostat is known as an oral hypouricemic agent inhibiting xanthine oxidoreductase, a key enzyme for uric acid production. (Left) Effect of each compound on the transport activity of ABCG2 are shown. Data from our previous study under CC BY license (Miyata et al., 2016) are shown graphically, in which in the absence (vehicle control) or presence of 100 nM of each compound, the ATP-dependent urate transport activities of ABCG2 were measured using the vesicle transport assay. Data are expressed as the mean ± SD, n = 3. Of note, the half-maximal inhibitory concentration (IC50) of febuxostat against the urate transport activity of ABCG2 was 27 nM in the previous study. (Right) Chemical structures of each compound are depicted.

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