High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4)

Cheung, Leanna; Flemming, Claudia L.; Watt, Fujiko; Masada, Nanako; Yu, Denise; Huynh, Tony; Conseil, Gwenaëlle; Tivnan, Amanda; Polinsky, Alexander; Gudkov, Andrei V.; Munoz, Marcia A.; Vishvanath, Anasuya; Cooper, Dermot M.F.; Henderson, Michelle J.; Cole, Susan P.C.; Fletcher, Jamie I.; Haber, Michelle; Norris, Murray D.

doi:10.1016/j.bcp.2014.05.023

Cited by 54 publications

(54 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The tricyclic isoxazole LY475776 and ceefourin-2 have been identified as relatively selective inhibitors of MRP1 and MRP4, respectively (Dantzig et al, 2004;Cheung et al, 2014), but to our knowledge no MRP2 or MRP3 selective inhibitors have been reported. However, it seems evident that both existing and newly developed MRP inhibitors require extensive testing for activity against a broad range of both efflux and import transporters in a variety of intact cell and cell-free assay systems to substantiate all claims of MRP homolog selectivity.…”

Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

Csandl¹,

Conseil²,

Cole³

2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

Active efflux of both drugs and organic anion metabolites is mediated by the multidrug resistance proteins (MRPs). MRP1 (ABCC1), MRP2 (ABCC2), MRP3 (ABCC3), and MRP4 (ABCC4) have partially overlapping substrate specificities and all transport 17b-estradiol 17-(b-D-glucuronide) (E 2 17bG). The cysteinyl leukotriene receptor 1 (CysLT 1 R) antagonist MK-571 inhibits all four MRP homologs, but little is known about the modulatory effects of newer leukotriene modifiers (LTMs). Here we examined the effects of seven CysLT 1 R-and CysLT 2 R-selective LTMs on E 2 17bG uptake into MRP1-4-enriched inside-out membrane vesicles. Their effects on uptake of an additional physiologic solute were also measured for MRP1 [leukotriene C 4 (LTC 4 )] and MRP4 [prostaglandin E 2 (PGE 2 )]. The two CysLT 2 R-selective LTMs studied were generally more potent inhibitors than CysLT 1 R-selective LTMs, but neither class of antagonists showed any MRP selectivity. For E 2 17bG uptake, LTM IC 50 s ranged from 1.2 to 26.9 mM and were most comparable for MRP1 and MRP4. The LTM rank order inhibitory potencies for E 2 17bG versus LTC 4 uptake by MRP1, and E 2 17bG versus PGE 2 uptake by MRP4, were also similar. Three of four CysLT 1 R-selective LTMs also stimulated MRP2 (but not MRP3) transport and thus exerted a concentration-dependent biphasic effect on MRP2. The fourth CysLT 1 R antagonist, LY171883, only stimulated MRP2 (and MRP3) transport but none of the MRPs were stimulated by either CysLT 2 R-selective LTM. We conclude that, in contrast to their CysLTR selectivity, CysLTR antagonists show no MRP homolog selectivity, and data should be interpreted cautiously if obtained from LTMs in systems in which more than one MRP is present.

show abstract

Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

Csandl¹,

Conseil²,

Cole³

2016

Drug Metabolism and Disposition

View full text Add to dashboard Cite

show abstract

“…Early clinical trials using inhibitors of P-glycoprotein are in support of the need for selective inhibitors of target transporters (Szakács et al, 2006). In this regard, Cheung et al (2014) recently identified two chemically distinct small molecules (ceefourin 1 and 2), which inhibit the transport of a broad range of MRP4 substrates and yet are highly selective for MRP4 over the other ABC transporters. Based on the platform of a high-throughput bioluminescence screen, Cheung et al (2015) identified 36 compounds from a library of Food and Drug Administration-approved drugs that effectively inhibited MRP4.…”

Section: The Potential Of Mrp4 As a Drug Targetmentioning

confidence: 99%

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Wen

Luo

Huang

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Multidrug-resistant protein 4 (MRP4), a member of the C subfamily of ATP-binding cassette transporters, is distributed in a variety of tissues and a number of cancers. As a drug transporter, MRP4 is responsible for the pharmacokinetics and pharmacodynamics of numerous drugs, especially antiviral drugs, antitumor drugs, and diuretics. In this regard, the functional role of MRP4 is affected by a number of factors, such as genetic mutations; tissue-specific transcriptional regulations; post-transcriptional regulations, including miRNAs and membrane internalization; and substrate competition. Unlike other C family members, MRP4 is in a pivotal position to transport cellular signaling molecules, through which it is tightly connected to the living activity and physiologic processes of cells and bodies. In the context of several cancers in which MRP4 is overexpressed, MRP4 inhibition shows striking effects against cancer progression and drug resistance. In this review, we describe the role of MRP4 more specifically in both healthy conditions and disease states, with an emphasis on its potential as a drug target.

show abstract

“…PGE 2 , dehydroepiandrostenedione sulfate) (65,75) despite their relatively distinct structures, and it will be of interest to determine whether S1P and LPI are also transported by MRP4. In this regard, pharmacological inhibitors that can distinguish between MRP1 and MRP4 may be useful (4,91).…”

Section: Lipid-derived Signaling Molecules As Substrates Of Mrp1mentioning

confidence: 99%

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Cole

2014

Journal of Biological Chemistry

Self Cite

292

245

View full text Add to dashboard Cite

The multidrug resistance protein 1 (MRP1) encoded by ABCC1 was originally discovered as a cause of multidrug resistance in tumor cells. However, it is now clear that MRP1 serves a broader role than simply mediating the ATP-dependent efflux of drugs from cells. The antioxidant GSH and the pro-inflammatory cysteinyl leukotriene C 4 have been identified as key physiological organic anions effluxed by MRP1, and an ever growing body of evidence indicates that additional lipid-derived mediators are also substrates of this transporter. As such, MRP1 is a multitasking transporter that likely influences the etiology and progression of a host of human diseases.

show abstract

High-throughput screening identifies Ceefourin 1 and Ceefourin 2 as highly selective inhibitors of multidrug resistance protein 4 (MRP4)

Cited by 54 publications

References 46 publications

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

Cysteinyl Leukotriene Receptor 1/2 Antagonists Nonselectively Modulate Organic Anion Transport by Multidrug Resistance Proteins (MRP1-4)

The Pharmacological and Physiological Role of Multidrug-Resistant Protein 4

Multidrug Resistance Protein 1 (MRP1, ABCC1), a “Multitasking” ATP-binding Cassette (ABC) Transporter

Contact Info

Product

Resources

About