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

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.

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

2006 ◽  
Vol 52 (2) ◽  
pp. 310-313 ◽  
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.

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

eFood ◽  
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.

scholarly journals ATP Binding Cassette Transporter A1 is Involved in Extracellular Secretion of Acetylated APE1/Ref-1

2019 ◽  
Vol 20 (13) ◽  
pp. 3178 ◽  
Author(s):  
Yu Ran Lee ◽  
Hee Kyoung Joo ◽  
Eun Ok Lee ◽  
Hyun Sil Cho ◽  
Sunga Choi ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Secretory Pathway ◽  
Trichostatin A ◽  
Atp Binding ◽  
Terminal Protein ◽  
Secretion Signal ◽  
Extracellular Secretion ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Acetylation of nuclear apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) is associated with its extracellular secretion, despite the lack of an N-terminal protein secretion signal. In this study, we investigated plasma membrane targeting and translocation of APE1/Ref-1 in HEK293T cells with enhanced acetylation. While APE1/Ref-1 targeting was not affected by inhibition of the endoplasmic reticulum/Golgi-dependent secretion, its secretion was reduced by inhibitors of ATP-binding cassette (ABC) transporters, and siRNA-mediated down-regulation of ABC transporter A1. The association between APE1/Ref-1 and ABCA1 transporter was confirmed by proximal ligation assay and immunoprecipitation experiments. An APE1/Ref-1 construct with mutated acetylation sites (K6/K7R) showed reduced co-localization with ABC transporter A1. Exposure of trichostatin A (TSA) induced the acetylation of APE1/Ref-1, which translocated into membrane fraction. Taken together, acetylation of APE1/Ref-1 is considered to be necessary for its extracellular targeting via non-classical secretory pathway using the ABCA1 transporter.

scholarly journals Structural and functional insights into the Diabrotica virgifera virgifera ATP-binding cassette transporter gene family

BMC Genomics ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Folukemi Adedipe ◽  
Nathaniel Grubbs ◽  
Brad Coates ◽  
Brian Wiegmman ◽  
Marcé Lorenzen
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Sequence Data ◽  
Transcriptome Assembly ◽  
Diabrotica Virgifera Virgifera ◽  
Atp Binding ◽  
Pest Species ◽  
Diabrotica Virgifera ◽  
Transporter Family ◽  
Atp Binding Cassette

Abstract Background The western corn rootworm, Diabrotica virgifera virgifera, is a pervasive pest of maize in North America and Europe, which has adapted to current pest management strategies. In advance of an assembled and annotated D. v. virgifera genome, we developed transcriptomic resources to use in identifying candidate genes likely to be involved in the evolution of resistance, starting with members of the ATP-binding cassette (ABC) transporter family. Results In this study, 65 putative D. v. virgifera ABC (DvvABC) transporters were identified within a combined transcriptome assembly generated from embryonic, larval, adult male, and adult female RNA-sequence libraries. Phylogenetic analysis placed the deduced amino-acid sequences of the DvvABC transporters into eight subfamilies (A to H). To supplement our sequence data with functional analysis, we identified orthologs of Tribolium castaneum ABC genes which had previously been shown to exhibit overt RNA interference (RNAi) phenotypes. We identified eight such D. v. virgifera genes, and found that they were functionally similar to their T. castaneum counterparts. Interestingly, depletion of DvvABCB_39715 and DvvABCG_3712 transcripts in adult females produced detrimental reproductive and developmental phenotypes, demonstrating the potential of these genes as targets for RNAi-mediated insect control tactics. Conclusions By combining sequence data from four libraries covering three distinct life stages, we have produced a relatively comprehensive de novo transcriptome assembly for D. v. virgifera. Moreover, we have identified 65 members of the ABC transporter family and provided the first insights into the developmental and physiological roles of ABC transporters in this pest species.

scholarly journals In Silico Genome-Wide Analysis of the ATP-Binding Cassette Transporter Gene Family in Soybean (Glycine max L.) and Their Expression Profiling

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Awdhesh Kumar Mishra ◽  
Jinhee Choi ◽  
Muhammad Fazle Rabbee ◽  
Kwang-Hyun Baek
Keyword(s):  
Gene Family ◽  
Abc Transporter ◽  
Abc Transporters ◽  
In Silico ◽  
Gene Families ◽  
Protein Domain ◽  
Atp Binding ◽  
Transporter Gene ◽  
Genome Wide ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) transporters constitute one of the largest gene families in all living organisms, most of which mediate transport across biological membranes by hydrolyzing ATP. However, detailed studies of ABC transporter genes in the important oil crop, soybean, are still lacking. In the present study, we carried out genome-wide identification and phylogenetic and transcriptional analyses of the ABC gene family in G. max. A total of 261 G. max ABC (GmABCs) genes were identified and unevenly localized onto 20 chromosomes. Referring to protein-domain orientation and phylogeny, the GmABC family could be classified into eight (ABCA-ABCG and ABCI) subfamilies and ABCG were the most abundantly present. Further, investigation of whole genome duplication (WGD) signifies the role of segmental duplication in the expansion of the ABC transporter gene family in soybean. The Ka/Ks ratio indicates that several duplicated genes are governed by intense purifying selection during evolution. In addition, in silico expression analysis based on RNA-sequence using publicly available database revealed that ABC transporters are differentially expressed in tissues and developmental stages and in dehydration. Overall, we provide an extensive overview of the GmABC transporter gene family and it promises the primary basis for the study in development and response to dehydration tolerance.

scholarly journals Identification and Characterization of a Brucella abortus ATP-Binding Cassette Transporter Homolog to Rhizobium meliloti ExsA and Its Role in Virulence and Protection in Mice

2002 ◽  
Vol 70 (9) ◽  
pp. 5036-5044 ◽  
Author(s):  
G. M. S. Rosinha ◽  
Daniela A. Freitas ◽  
Anderson Miyoshi ◽  
Vasco Azevedo ◽  
Eleonora Campos ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Brucella Abortus ◽  
Protective Immunity ◽  
Deletion Mutant ◽  
Rhizobium Meliloti ◽  
Host Cells ◽  
Atp Binding ◽  
Ortholog Group ◽  
Atp Binding Cassette

ABSTRACT Brucella abortus is a facultative intracellular bacterial pathogen that causes abortion in domestic animals and undulant fever in humans. The mechanism of virulence of Brucella spp. is not fully understood yet. Furthermore, genes that allow Brucella to reach the intracellular niche and to interact with host cells need to be identified. Using the genomic survey sequence (GSS) approach, we identified the gene encoding an ATP-binding cassette (ABC) transporter of B. abortus strain S2308. The deduced amino acid sequence encoded by this gene exhibited 69 and 67% identity with the sequences of the ABC transporters encoded by the exsA genes of Rhizobium meliloti and Mesorhizobium loti, respectively. Additionally, B. abortus ExsA, like R. meliloti and M. loti ExsA, possesses ATP-binding motifs and the ABC signature domain features of a typical ABC transporter. Furthermore, ortholog group analysis placed B. abortus ExsA in ortholog group 6 of ABC transporters more likely to be involved in bacterial pathogenesis. In R. meliloti, ExsA is an exopolysaccharide transporter essential for alfalfa root nodule invasion and establishment of infection. To test the role of ExsA in Brucella pathogenesis, an exsA deletion mutant was constructed. Replacement of the wild-type exsA by recombination was demonstrated by Southern blot analysis of Brucella genomic DNA. Decreased survival in mice of the Brucella ΔexsA mutant compared to the survival of parental strain S2308 demonstrated that ExsA is critical for full bacterial virulence. Additionally, the B. abortus exsA deletion mutant was used as a live vaccine. Challenge experiments revealed that the exsA mutant strain induced superior protective immunity in BALB/c mice compared to the protective immunity induced by strain S19 or RB51.

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

2012 ◽  
Vol 3 (4) ◽  
pp. 319-331 ◽  
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.

scholarly journals Contributions of Aspergillus fumigatus ATP-Binding Cassette Transporter Proteins to Drug Resistance and Virulence

2013 ◽  
Vol 12 (12) ◽  
pp. 1619-1628 ◽  
Author(s):  
Sanjoy Paul ◽  
Daniel Diekema ◽  
W. Scott Moye-Rowley
Keyword(s):  
Drug Resistance ◽  
Aspergillus Fumigatus ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Sequence Similarity ◽  
Atp Binding ◽  
Content Type ◽  
Transporter Proteins ◽  
Encoding Genes ◽  
Atp Binding Cassette

ABSTRACTIn yeast cells such as those ofSaccharomyces cerevisiae, expression of ATP-binding cassette (ABC) transporter proteins has been found to be increased and correlates with a concomitant elevation in azole drug resistance. In this study, we investigated the roles of twoAspergillus fumigatusproteins that share high sequence similarity withS. cerevisiaePdr5, an ABC transporter protein that is commonly overproduced in azole-resistant isolates in this yeast. The twoA. fumigatusgenes encoding the ABC transporters sharing the highest sequence similarity toS. cerevisiaePdr5 are calledabcAandabcBhere. We constructed deletion alleles of these two different ABC transporter-encoding genes in three different strains ofA. fumigatus. Loss ofabcBinvariably elicited increased azole susceptibility, whileabcAdisruption alleles had variable phenotypes. Specific antibodies were raised to both AbcA and AbcB proteins. These antisera allowed detection of AbcB in wild-type cells, while AbcA could be visualized only when overproduced from thehspApromoter inA. fumigatus. Overproduction of AbcA also yielded increased azole resistance. Green fluorescent protein fusions were used to provide evidence that both AbcA and AbcB are localized to the plasma membrane inA. fumigatus. Promoter fusions to firefly luciferase suggested that expression of both ABC transporter-encoding genes is inducible by azole challenge. Virulence assays implicated AbcB as a possible factor required for normal pathogenesis. This work provides important new insights into the physiological roles of ABC transporters in this major fungal pathogen.

scholarly journals ATP-Binding Cassette (ABC) Transporter Genes Involved in Pyrethroid Resistance in the Malaria Vector Anopheles sinensis: Genome-Wide Identification, Characteristics, Phylogenetics, and Expression Profile

2019 ◽  
Vol 20 (6) ◽  
pp. 1409 ◽  
Author(s):  
Qiyi He ◽  
Zhentian Yan ◽  
Fengling Si ◽  
Yong Zhou ◽  
Wenbo Fu ◽  
...  
Keyword(s):  
Abc Transporter ◽  
Abc Transporters ◽  
Pyrethroid Resistance ◽  
Expression Profiles ◽  
Anopheles Sinensis ◽  
Atp Binding ◽  
Rna Seq ◽  
Transporter Family ◽  
Abc Transporter Genes ◽  
Atp Binding Cassette

background: The ATP-binding cassette (ABC) transporters family is one of the largest families of membrane proteins existing in all living organisms. Pyrethroid resistance has become the largest unique obstacle for mosquito control worldwide. ABC transporters are thought to be associated with pyrethroid resistance in some agricultural pests, but little information is known for mosquitoes. Herein, we investigated the diversity, location, characteristics, phylogenetics, and evolution of ABC transporter family of genes in the Anopheles sinensis genome, and identified the ABC transporter genes associated with pyrethroid resistance through expression profiles using RNA-seq and qPCR. Results: 61 ABC transporter genes are identified and divided into eight subfamilies (ABCA-H), located on 22 different scaffolds. Phylogenetic and evolution analyses with ABC transporters of A. gambiae, Drosophila melanogaster, and Homo sapiens suggest that the ABCD, ABCG, and ABCH subfamilies are monophyly, and that the ABCC and ABCG subfamilies have experienced a gene duplication event. Both RNA-seq and qPCR analyses show that the AsABCG28 gene is uniquely significantly upregulated gene in all three field pyrethroid-resistant populations (Anhui, Chongqing, and Yunnan provinces) in comparison with a laboratory-susceptible strain from Jiangsu province. The AsABCG28 is significantly upregulated at 12-h and 24-h after deltamethrin exposure in three-day-old female adults. Conclusion: This study provides the information frame for ABC transporter subfamily of genes, and lays an important basis for the better understanding and further research of ABC transporter function in insecticide toxification. The AsABCG28 gene is associated with pyrethroid detoxification, and it functions at later period in the detoxification process for xenobiotics transportation.

Expression of the Human ATP-Binding Cassette Transporter Superfamily in Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1179-1179
Author(s):  
Maria Ho ◽  
Donna E. Hogge ◽  
Victor Ling
Keyword(s):  
Acute Myeloid Leukemia ◽  
Abc Transporter ◽  
Abc Transporters ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Normal Blood ◽  
Atp Binding ◽  
Normal Peripheral Blood ◽  
Acute Myeloid ◽  
Atp Binding Cassette

Abstract Members of the ATP-Binding-Cassette (ABC) transporter superfamily of proteins are involved in resistance to multiple chemotherapeutic drugs ( Multidrug Resistance or MDR) in a variety of malignant cells including leukemic blasts. Overexpression of some ABC transporters has been demonstrated in acute myeloid leukemia (AML) and is associated with clinical MDR and failure of conventional chemotherapy, which occurs frequently in this leukemia. Recent studies have also demonstrated ABC transporter expression in primitive normal hematopoietic cells, including progenitors which may give rise to AML after malignant transformation. In this study we used quantitative Real-Time PCR to assess and compare the expression level of all 47 known human ABC transporters in AML blasts and normal peripheral blood. Peripheral blood blasts from 17 patients with newly-diagnosed AML who subsequently received conventional remission induction therapy with cytosine arabinoside and daunorubicin were studied; 11 of these subsequently achieved complete remission of their leukemia while the remaining 6 had chemotherapy refractory disease. Contrary to expectations, no consistent difference in mRNA levels was found between the chemotherapy responsive and refractory groups of patient samples for any ABC transporter, including known MDR-related members such as MDR-1 and BCRP. Profiling of the 47 ABC transporters in 12 normal peripheral blood samples (6 mobilized with G-CSF, 6 non-mobilized) showed that TAP1 and MRP3 were 3.3-fold (P = 0.032) and 24-fold (P = 0.012), respectively, higher in normal donors as compared to AML patients. ABCA7, ABCB8, MRP3, MRP7, ALDP, PMP70 and PMP69 were greater than 3-fold higher (P &lt; 0.05) in G-CSF-mobilized as compared to steady state normal blood. These results suggest that levels of ABC transporter mRNA expression in AML blasts prior to chemotherapy are not predictive of treatment response. This raises questions regarding the role of ABC transporters in intrinsic as opposed to induced or acquired chemotherapy drug resistance, which in turn has important implications in clinical usage of ABC-reversal agents. In addition, we identified expression of a variety of ABC transporters in both AML blasts and normal blood cells suggesting that this class of transporter proteins may have importance in both normal and malignant hematopoiesis.

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