Olmutinib (HM61713) reversed multidrug resistance by inhibiting the activity of ATP-binding cassette subfamily G member 2 in vitro and in vivo

Multidrug Resistance Proteins (MRPs), together with the cystic fibrosis conductance regulator (CFTR/ABCC7) and the sulfonylurea receptors (SUR1/ABCC8 and SUR2/ABCC9) comprise the 13 members of the human “C” branch of the ATP binding cassette (ABC) superfamily. All C branch proteins share conserved structural features in their nucleotide binding domains (NBDs) that distinguish them from other ABC proteins. The MRPs can be further divided into two subfamilies “long” (MRP1, -2, -3, -6, and -7) and “short” (MRP4, -5, -8, -9, and -10). The short MRPs have a typical ABC transporter structure with two polytropic membrane spanning domains (MSDs) and two NBDs, while the long MRPs have an additional NH2-terminal MSD. In vitro, the MRPs can collectively confer resistance to natural product drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, arsenical and antimonial oxyanions, peptide-based agents, and, under certain circumstances, alkylating agents. The MRPs are also primary active transporters of other structurally diverse compounds, including glutathione, glucuronide, and sulfate conjugates of a large number of xeno- and endobiotics. In vivo, several MRPs are major contributors to the distribution and elimination of a wide range of both anticancer and non-anticancer drugs and metabolites. In this review, we describe what is known of the structure of the MRPs and the mechanisms by which they recognize and transport their diverse substrates. We also summarize knowledge of their possible physiological functions and evidence that they may be involved in the clinical drug resistance of various forms of cancer.

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A Selective ATP-Binding Cassette Subfamily G Member 2 Efflux Inhibitor Revealed via High-Throughput Flow Cytometry

CrossRef Listing of Deleted DOIs ◽

10.1177/1087057112456875 ◽

2012 ◽

Vol 18 (1) ◽

pp. 26-38 ◽

Cited By ~ 15

Author(s):

J. Jacob Strouse ◽

Irena Ivnitski-Steele ◽

Hadya M. Khawaja ◽

Dominique Perez ◽

Jerec Ricci ◽

...

Keyword(s):

Molecular Probes ◽

Atp Binding ◽

Specific Substrate ◽

Tumor Resistance ◽

Drug Concentrations ◽

Efflux Inhibition ◽

Substrate Inhibitor ◽

Atp Binding Cassette

Chemotherapeutics tumor resistance is a principal reason for treatment failure, and clinical and experimental data indicate that multidrug transporters such as ATP-binding cassette (ABC) B1 and ABCG2 play a leading role by preventing cytotoxic intracellular drug concentrations. Functional efflux inhibition of existing chemotherapeutics by these pumps continues to present a promising approach for treatment. A contributing factor to the failure of existing inhibitors in clinical applications is limited understanding of specific substrate/inhibitor/pump interactions. We have identified selective efflux inhibitors by profiling multiple ABC transporters against a library of small molecules to find molecular probes to further explore such interactions. In our primary screening protocol using JC-1 as a dual-pump fluorescent reporter substrate, we identified a piperazine-substituted pyrazolo[1,5-a]pyrimidine substructure with promise for selective efflux inhibition. As a result of a focused structure-activity relationship (SAR)–driven chemistry effort, we describe compound 1 (CID44640177), an efflux inhibitor with selectivity toward ABCG2 over ABCB1. Compound 1 is also shown to potentiate the activity of mitoxantrone in vitro as well as preliminarily in vivo in an ABCG2-overexpressing tumor model. At least two analogues significantly reduce tumor size in combination with the chemotherapeutic topotecan. To our knowledge, low nanomolar chemoreversal activity coupled with direct evidence of efflux inhibition for ABCG2 is unprecedented.

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The role of dietary flavonoids for modulation of ATP binding cassette transporter mediated multidrug resistance

eFood ◽

10.53365/efood.k/144604 ◽

2021 ◽

Author(s):

Hui Teng ◽

Hongting Deng ◽

Yuanju He ◽

Qiyan Lv ◽

Lei Chen

Keyword(s):

Multidrug Resistance ◽

Abc Transporters ◽

Systemic Circulation ◽

Atp Binding ◽

Cancer Resistance ◽

Associated Proteins ◽

Food Toxin ◽

Atp Binding Cassette

Flavonoids are widely existing compounds with enormous pharmacological effects from food and medicine. However, the low bioavailability in intestinal absorption and metabolism limits their clinical application. Intestinal efflux ABC (ATP binding cassette) transporters, including P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), act as "pumping doors" to regulate the efflux of flavonoids from intestinal epithelial cells into the intestinal cavity or the systemic circulation. The present review describes the critical effect of ABC transporters involved in the efflux of flavonoids which depend on its efflux direction. And the role of flavonoids for modulation of intestinal ABC transporters was emphasized and several examples were given. We summarized that the resistance effect of flavonoid-mediated multidrug on ABC transporters may influence the bioavailability of drugs, bioactive ingredients and/or toxic compounds upon dietary uptake. Meanwhile, flavonoids functionalized as reversing agents of the ABC transporter may be an important mechanism for unexpected food-drug, food-toxin or food-food interactions. The overview also indicates that elucidation of the action and mechanism of the intestinal metabolic enzymes-efflux transporters coupling will lay a foundation for improving the bioavailability of flavonoids <i>in vivo</i> and increasing their clinical efficacy.

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Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/− (triple-knockout) and wild-type mice

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-07-2250 ◽

2008 ◽

Vol 7 (8) ◽

pp. 2280-2287 ◽

Cited By ~ 131

Author(s):

Serena Marchetti ◽

Nienke A. de Vries ◽

Tessa Buckle ◽

Maria J. Bolijn ◽

Maria A.J. van Eijndhoven ◽

...

Keyword(s):

Drug Transporters ◽

Atp Binding ◽

Pharmacokinetic Studies ◽

Wild Type ◽

Atp Binding Cassette

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In vitro and in vivo downregulation of the ATP binding cassette transporter B1 by the HMG-CoA reductase inhibitor simvastatin

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-015-1169-3 ◽

2015 ◽

Vol 389 (1) ◽

pp. 17-32 ◽

Cited By ~ 12

Author(s):

Bihter Atil ◽

Evelyn Berger-Sieczkowski ◽

Johanna Bardy ◽

Martin Werner ◽

Martin Hohenegger

Keyword(s):

Reductase Inhibitor ◽

Atp Binding ◽

Hmg Coa Reductase ◽

Atp Binding Cassette Transporter ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase ◽

Atp Binding Cassette

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Neratinib Reverses ATP-Binding Cassette B1-Mediated Chemotherapeutic Drug Resistance In Vitro, In Vivo, and Ex Vivo

Molecular Pharmacology ◽

10.1124/mol.111.076299 ◽

2012 ◽

Vol 82 (1) ◽

pp. 47-58 ◽

Cited By ~ 65

Author(s):

Xiao-qin Zhao ◽

Jing-dun Xie ◽

Xing-gui Chen ◽

Hong May Sim ◽

Xu Zhang ◽

...

Keyword(s):

Drug Resistance ◽

Ex Vivo ◽

Atp Binding ◽

Chemotherapeutic Drug ◽

Atp Binding Cassette

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ATP-Binding Cassette (ABC) Transporter Proteins, Multidrug Resistance and Novel Flavonoid Dimers as Potent, Nontoxic and Selective Inhibitors

Canadian Journal of Chemistry ◽

10.1139/cjc-2021-0108 ◽

2021 ◽

Author(s):

Larry M. C. Chow ◽

Tak Hang Chan

Keyword(s):

Multidrug Resistance ◽

Cancer Cells ◽

Abc Transporter ◽

Abc Transporters ◽

Selective Inhibition ◽

Common Mechanism ◽

Atp Binding ◽

Selective Inhibitors ◽

Atp Binding Cassette

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: either the P-glycoprotein (P-gp/ABCB1, also known as MDR1), the multidrug resistance protein 1 (MRP1/ABCC1) or the 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 inhibitor of ABC transporter with an anticancer drug has been evaluated in several clinical trials to overcome MDR but led to a disappointing outcome. By taking advantage of the pseudo-dimeric structure (Figure 1) of ABC transporters, we demonstrated that some flavonoid dimers, using polyvalent interactions, can be potent inhibitors of the ABC transporters. Selective inhibition of the three different transporters with the flavonoid dimers can be achieved by placing the two flavonoid moieties at an optimal distance apart specific for each of the transporters. In addition to being potent and selective inhibitors of the transporters, the flavonoid dimers are found to be nontoxic to normal cells at their corresponding effective concentrations. The in vivo efficacy of the flavonoid dimers has been demonstrated. Further investigation of these flavonoid dimers as clinical candidates to overcome multidrug resistance in cancer chemotherapy is warranted.

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