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

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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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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ATP-binding cassette transporters and neurodegenerative diseases

Essays in Biochemistry ◽

10.1042/ebc20210012 ◽

2021 ◽

Author(s):

Jared S. Katzeff ◽

Woojin Scott Kim

Keyword(s):

Neurodegenerative Diseases ◽

Abc Transporters ◽

Brain Diseases ◽

Atp Binding ◽

Future Directions ◽

Diverse Range ◽

The Brain ◽

Lateral Sclerosis ◽

Atp Binding Cassette

Abstract ATP-binding cassette (ABC) transporters are one of the largest groups of transporter families in humans. ABC transporters mediate the translocation of a diverse range of substrates across cellular membranes, including amino acids, nucleosides, lipids, sugars and xenobiotics. Neurodegenerative diseases are a group of brain diseases that detrimentally affect neurons and other brain cells and are usually associated with deposits of pathogenic proteins in the brain. Major neurodegenerative diseases include Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. ABC transporters are highly expressed in the brain and have been implicated in a number of pathological processes underlying neurodegenerative diseases. This review outlines the current understanding of the role of ABC transporters in neurodegenerative diseases, focusing on some of the most important pathways, and also suggests future directions for research in this field.

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Human ATP-Binding Cassette Transporter TaqMan Low-Density Array: Analysis of Macrophage Differentiation and Foam Cell Formation

Clinical Chemistry ◽

10.1373/clinchem.2005.059774 ◽

2006 ◽

Vol 52 (2) ◽

pp. 310-313 ◽

Cited By ~ 39

Author(s):

Thomas Langmann ◽

Richard Mauerer ◽

Gerd Schmitz

Keyword(s):

Multidrug Resistance ◽

Abc Transporter ◽

Abc Transporters ◽

Metabolic Regulation ◽

Foam Cell ◽

Expression Patterns ◽

Foam Cell Formation ◽

Atp Binding ◽

Low Density ◽

Atp Binding Cassette

Abstract Background: ATP-binding cassette (ABC) transporters cause various diseases and regulate many physiologic processes, such as lipid homeostasis, iron transport, and immune mechanisms. Several ABC transporters are involved in bile acid, phospholipid, and sterol transport, and their expression is itself controlled by lipids. In addition, ABC proteins mediate drug export in tumor cells and promote the development of multidrug resistance. Methods: We created an ABC Transporter TaqMan Low-Density Array based on an Applied Biosystems 7900HT Micro Fluidic Card. We used a 2-μL reaction well with 2 ng of sample. To evaluate this method for lipidomic research and to characterize expression patterns of ABC transporters in cells relevant for atherosclerosis research, we monitored mRNA expression in human primary monocytes, in vitro–differentiated macrophages, and cells stimulated with the liver-X-receptor and retinoid-X-receptor agonists T0901317 and 9-cis retinoic acid, mimicking sterol loading. Results: The method enabled simultaneous analysis of 47 human ABC transporters and the reference gene 18S rRNA in 2 replicates of 4 samples per run. Conclusions: The new system uses only 2 ng of sample and small volumes of reagent, and the precaptured primers and probes avoided labor-intensive pipetting steps. The ABC Transporter TaqMan Low-Density Array may be a useful tool to monitor dysregulated ABC transporter mRNA profiles in human lipid disorders and cancer-related multidrug resistance and to analyze the pharmacologic and metabolic regulation of ABC transporter expression important for drug development in large-scale screening approaches.

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Genome-wide characterization and expression analysis of ATP-binding cassette (ABC) transporters in strawberry reveal the role of FvABCC11 in cadmium tolerance

Scientia Horticulturae ◽

10.1016/j.scienta.2020.109464 ◽

2020 ◽

Vol 271 ◽

pp. 109464 ◽

Cited By ~ 1

Author(s):

Mengyun Shi ◽

Shuaishuai Wang ◽

Yang Zhang ◽

Shen Wang ◽

Jing Zhao ◽

...

Keyword(s):

Expression Analysis ◽

Abc Transporters ◽

Atp Binding ◽

Cadmium Tolerance ◽

Genome Wide ◽

Atp Binding Cassette

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Multidrug resistance-associated ABC transporters – too much of one thing, good for nothing

BioMolecular Concepts ◽

10.1515/bmc-2012-0006 ◽

2012 ◽

Vol 3 (4) ◽

pp. 319-331 ◽

Cited By ~ 3

Author(s):

Jirina Prochazkova ◽

Martina Lanova ◽

Jiri Pachernik

Keyword(s):

Multidrug Resistance ◽

Cancer Cells ◽

Abc Transporters ◽

Family Members ◽

Atp Binding ◽

Detailed Mechanism ◽

P Glycoprotein ◽

The Future ◽

Good For

AbstractOverexpression of ATP-binding cassette (ABC) transporters in cancer cells results in multidrug resistance (MDR) which leads to unsuccessful chemotherapy. The most important MDR-associated members of ABC superfamily are ABC B1/P-glycoprotein/MDR1, ABC C1/multidrug resistance associated protein 1 (MRP1), and ABC G2/BCRP. This study is not only focused on function, substrates, and localization of these popular proteins but also on other ABC C family members such as ABC C2–6/MRP2-6 and ABC C7/CFTR. Current research is mainly oriented on the cancer-promoting role of these proteins, but important lessons could also be learned from the physiological roles of these proteins or from polymorphisms affecting their function. Thorough knowledge of structure and detailed mechanism of efflux can aid in the discovery of new chemotherapy targets in the future. Although the best way on how to deal with MDR would be to prevent its development, we describe some new promising strategies on how to conquer both inherited and induced MDRs.

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Two novel multidrug resistance associated protein (MRP/ABCC) from the Mediterranean mussel (Mytilus galloprovincialis): characterization and expression patterns in detoxifying tissues

Canadian Journal of Zoology ◽

10.1139/cjz-2015-0011 ◽

2015 ◽

Vol 93 (7) ◽

pp. 567-578 ◽

Cited By ~ 4

Author(s):

V. Lozano ◽

R. Martínez-Escauriaza ◽

M.L. Pérez-Parallé ◽

A.J. Pazos ◽

J.L. Sánchez

Keyword(s):

Multidrug Resistance ◽

Digestive Gland ◽

Okadaic Acid ◽

Abc Transporters ◽

Mytilus Galloprovincialis ◽

Expression Patterns ◽

Cancer Resistance ◽

Mediterranean Mussel ◽

The Mediterranean

Multidrug resistance associated proteins (MRP) belong to the ABCC branch of the ABC transporters. The MRP together with P-gp (P-glycoprotein; MDR1; ABCB1) and BCRP (breast cancer resistance protein; ABCG2) confer multixenobiotic resistance (MXR) in marine vertebrates. In aquatic invertebrates, little is known about the presence and role of these ABC transporters. The ABC transporters play an important role in the absorption, distribution, and excretion of drugs, xenobiotics, and endogenous compounds and are predominantly expressed in excretory organs. In the present study, we identified and characterized two MRP/ABCC transporters (mrp1 and mrp2) from the Mediterranean mussel (Mytilus galloprovincialis Lamarck, 1819). The two cDNAs finally obtained were 4648 bp for mrp1 and 5065 bp for mrp2 with open reading frames of 1500 and 1524 residues, respectively. Analysis of the amino acid sequences revealed the structural organization of ABC transporters with the typical and highly conserved motifs. The expression levels of these genes revealed that the highest expression of mrp1 and mrp2 genes was found in the digestive gland followed by gills, and the lowest expression of the three tissues was detected in the mantle. The expression of these genes was also studied in mussels naturally contaminated with okadaic acid (from a bloom of Dinophysis acuminata Claparède and Lachmann, 1859). The overexpression of mrp2 in the digestive gland suggests that this gene is involved in the process of detoxification of okadaic acid in M. galloprovincilais. These expression patterns agree with the suggested role of these genes in the protection against endogenous or exogenous compounds in aquatic organisms.

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