@article{MTMT:34568631, title = {ATP-Binding Cassette Subfamily G Member 2 in Acute Myeloid Leukemia: A New Molecular Target?}, url = {https://m2.mtmt.hu/api/publication/34568631}, author = {Damiani, Daniela and Tiribelli, Mario}, doi = {10.3390/biomedicines12010111}, journal-iso = {BIOMEDICINES}, journal = {BIOMEDICINES}, volume = {12}, unique-id = {34568631}, abstract = {Despite the progress in the knowledge of disease pathogenesis and the identification of many molecular markers as potential targets of new therapies, the cure of acute myeloid leukemia remains challenging. Disease recurrence after an initial response and the development of resistance to old and new therapies account for the poor survival rate and still make allogeneic stem cell transplantation the only curative option. Multidrug resistance (MDR) is a multifactorial phenomenon resulting from host-related characteristics and leukemia factors. Among these, the overexpression of membrane drug transporter proteins belonging to the ABC (ATP-Binding Cassette)-protein superfamily, which diverts drugs from their cellular targets, plays an important role. Moreover, a better understanding of leukemia biology has highlighted that, at least in cancer, ABC protein’s role goes beyond simple drug transport and affects many other cell functions. In this paper, we summarized the current knowledge of ABCG2 (formerly Breast Cancer Resistance Protein, BCRP) in acute myeloid leukemia and discuss the potential ways to overcome its efflux function and to revert its ability to confer stemness to leukemia cells, favoring the persistence of leukemia progenitors in the bone marrow niche and justifying relapse also after therapy intensification with allogeneic stem cell transplantation.}, keywords = {ABCG2; Multidrug resistance (MDR); acute myeloid leukemia (AML); Expression regulation; inhibitors}, year = {2024}, eissn = {2227-9059}, orcid-numbers = {Damiani, Daniela/0000-0002-1663-4468; Tiribelli, Mario/0000-0001-9449-2621} } @article{MTMT:34650501, title = {In Silico prediction of inhibitors for multiple transporters via machine learning methods}, url = {https://m2.mtmt.hu/api/publication/34650501}, author = {Duan, Hao and Lou, Chaofeng and Gu, Yaxin and Wang, Yimeng and Li, Weihua and Liu, Guixia and Tang, Yun}, doi = {10.1002/minf.202300270}, journal-iso = {MOL INFORM}, journal = {MOLECULAR INFORMATICS}, unique-id = {34650501}, issn = {1868-1743}, keywords = {INHIBITORS; TRANSPORTERS; machine learning; In silico prediction; meural networks}, year = {2024}, eissn = {1868-1751} } @article{MTMT:34780449, title = {High-throughput BCRP inhibitors screening system based on styrene maleic acid polymer membrane protein stabilization strategy and surface plasmon resonance biosensor}, url = {https://m2.mtmt.hu/api/publication/34780449}, author = {Fang, J. and Shen, S. and Wang, H. and He, Y. and Chao, L. and Cao, Y. and Chen, X. and Zhu, Z. and Hong, Z. and Chai, Y.}, doi = {10.1016/j.talanta.2024.125987}, journal-iso = {TALANTA}, journal = {TALANTA}, volume = {274}, unique-id = {34780449}, issn = {0039-9140}, year = {2024}, eissn = {1873-3573} } @article{MTMT:34540271, title = {Hyperuricemia and Gout Reduction by SGLT2 Inhibitors in Diabetes and Heart Failure: JACC Review Topic of the Week}, url = {https://m2.mtmt.hu/api/publication/34540271}, author = {Packer, M.}, doi = {10.1016/j.jacc.2023.10.030}, journal-iso = {J AM COLL CARDIOL}, journal = {JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY}, volume = {83}, unique-id = {34540271}, issn = {0735-1097}, abstract = {Gout is characterized by increased production of purines (through the pentose phosphate pathway), which is coupled with reduced renal or intestinal excretion of urate. Concurrent upregulation of nutrient surplus signaling (mammalian target of rapamycin and hypoxia-inducible factor-1a) and downregulation of nutrient deprivation signaling (sirtuin-1 and adenosine monophosphate–activated protein kinase) redirects glucose toward anabolic pathways (rather than adenosine triphosphate production), thus promoting heightened oxidative stress and cardiomyocyte and proximal tubular dysfunction, leading to cardiomyopathy and kidney disease. Hyperuricemia is a marker (rather than a driver) of these cellular stresses. By inducing a state of starvation mimicry in a state of nutrient surplus, sodium-glucose cotransporter-2 inhibitors decrease flux through the pentose phosphate pathway (thereby attenuating purine and urate synthesis) while promoting renal urate excretion. These convergent actions exert a meaningful effect to lower serum uric acid by ≈0.6 to 1.5 mg/dL and to reduce the risk of gout by 30% to 50% in large-scale clinical trials. © 2024 The Author}, keywords = {Humans; PHARMACOLOGY; PURINE; signal transduction; review; review; human; diabetes mellitus; diabetes mellitus; controlled study; CARDIOMYOPATHY; GLUCOSE; GLUCOSE; GLUCOSE; nonhuman; STARVATION; heart failure; heart failure; heart failure; urinary excretion; kidney disease; chronic kidney failure; chronic kidney disease; Adenosine Triphosphate; Adenosine Triphosphate; enzyme degradation; adenosine phosphate; hyperuricemia; hyperuricemia; hyperuricemia; gout; gout; gout; gout; protein kinase; upregulation; sirtuin 1; sirtuin 1; risk reduction; down regulation; cell stress; uric acid; uric acid; urate; hypoxia inducible factor 1alpha; hypoxia inducible factor 1alpha; kidney tubule absorption; uric acid blood level; mammalian target of rapamycin; mammalian target of rapamycin; pentose phosphate cycle; hexose monophosphate shunt; RENAL CLEARANCE; intestinal excretion; Sodium glucose cotransporter 2 inhibitor; Sodium glucose cotransporter 2 inhibitor; tubular dysfunction; uric acid urine level; purine synthesis; Sodium-glucose transporter 2 inhibitors; Oxidative stress; intestinal reabsorption}, year = {2024}, eissn = {1558-3597}, pages = {371-381} } @article{MTMT:34540272, title = {Ningalins, Pyrrole-Bearing Metabolites Isolated from Didemnum spp. Synthesis and MDR-Reversion Activity in Cancer Therapy}, url = {https://m2.mtmt.hu/api/publication/34540272}, author = {Segura-Quezada, L.A. and Hernández-Velázquez, E.D. and Corrales-Escobosa, A.R. and de, León-Solis C. and Solorio-Alvarado, C.R.}, doi = {10.1002/cbdv.202300883}, journal-iso = {CHEM BIODIVERS}, journal = {CHEMISTRY & BIODIVERSITY}, volume = {21}, unique-id = {34540272}, issn = {1612-1872}, abstract = {Multi-Drug Resistance (MDR) is one of the most frequent problems observed in the course of cancer chemotherapy. Cells under treatment, tend to develop survival mechanisms to drug-action thus generating drug-resistance. One of the most important mechanism to get it is the over expression of P-gp glycoprotein, which acts as an efflux-pump releasing the drug outside of the cancer cell. A strategy for a succesfull treatment consists in the co-administration of one compound that acts against P-gp and another which acts against the cell during chemotherapy. Ningalins are pyrrole-containing naturally occurring compounds isolated mainly from the marine tunicate Didemnum spp and also they are some of the top reversing agents in MDR treatment acting on P-gp. Considering the relevance displayed for some of these isolated alkaloids or their core as a drug for co-administration in cancer therapy, all the total synthesis described to date for the members of ningalins family are reviewed herein. © 2023 Wiley-VHCA AG, Zurich, Switzerland.}, keywords = {breast cancer; Total synthesis; Didemnum spp.; MDR-Reversion; Ningalin alcaloids}, year = {2024}, eissn = {1612-1880} } @article{MTMT:33842699, title = {ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives}, url = {https://m2.mtmt.hu/api/publication/33842699}, author = {Damiani, Daniela and Tiribelli, Mario}, doi = {10.3390/ijms24087147}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {33842699}, issn = {1661-6596}, abstract = {Despite recent advances, prognosis of acute myeloid leukemia (AML) remains unsatisfactory due to poor response to therapy or relapse. Among causes of resistance, over-expression of multidrug resistance (MDR) proteins represents a pivotal mechanism. ABCG2 is an efflux transporter responsible for inducing MDR in leukemic cells; through its ability to extrude many antineoplastic drugs, it leads to AML resistance and/or relapse, even if conflicting data have been reported to date. Moreover, ABCG2 may be co-expressed with other MDR-related proteins and is finely regulated by epigenetic mechanisms. Here, we review the main issues regarding ABCG2 activity and regulation in the AML clinical scenario, focusing on its expression and the role of polymorphisms, as well as on the potential ways to inhibit its function to counteract drug resistance to, eventually, improve outcomes in AML patients.}, keywords = {SURVIVAL; Prognosis; ABCG2; multidrug resistance; Acute myeloid leukemia; Counteraction}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Tiribelli, Mario/0000-0001-9449-2621} } @article{MTMT:34343675, title = {The Important Role of Transporter Structures in Drug Disposition, Efficacy, and Toxicity}, url = {https://m2.mtmt.hu/api/publication/34343675}, author = {Fu, Tingting and Zeng, Su and Zheng, Qingchuan and Zhu, Feng}, doi = {10.1124/dmd.123.001275}, journal-iso = {DRUG METAB DISPOS}, journal = {DRUG METABOLISM AND DISPOSITION}, volume = {51}, unique-id = {34343675}, issn = {0090-9556}, abstract = {The ATP-binding cassette (ABC) and solute carrier (SLC) transport-ers are critical determinants of drug disposition, clinical efficacy, and toxicity as they specifically mediate the influx and efflux of var-ious substrates and drugs. ABC transporters can modulate the pharmacokinetics of many drugs via mediating the translocation of drugs across biologic membranes. SLC transporters are important drug targets involved in the uptake of a broad range of compounds across the membrane. However, high-resolution experimental structures have been reported for a very limited number of trans-porters, which limits the study of their physiologic functions. In this review, we collected structural information on ABC and SLC transporters and described the application of computational meth-ods in structure prediction. Taking P-glycoprotein (ABCB1) and se-rotonin transporter (SLC6A4) as examples, we assessed the pivotal role of structure in transport mechanisms, details of ligand-receptor interactions, drug selectivity, the molecular mechanisms of drug-drug interactions, and differences caused by genetic poly-morphisms. The data collected contributes toward safer and more effective pharmacological treatments. SIGNIFICANCE STATEMENT The experimental structure of ATP-binding cassette and solute carrier transporters was collected, and the application of computational methods in structure prediction was described. P-glycoprotein and serotonin transporter were used as examples to reveal the pivotal role of structure in transport mechanisms, drug selectivity, the molec-ular mechanisms of drug-drug interactions, and differences caused by genetic polymorphisms.}, year = {2023}, eissn = {1521-009X}, pages = {1316-1323} } @article{MTMT:34068112, title = {Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products}, url = {https://m2.mtmt.hu/api/publication/34068112}, author = {Kanoujia, Jovita and Das, Anjali and Raina, Neha and Kaur, Ginpreet and Singh, Sandeep K. and Tuli, Hardeep S. and Garg, Ashish and Gupta, Madhu}, doi = {10.1002/iub.2764}, journal-iso = {IUBMB LIFE}, journal = {IUBMB LIFE}, volume = {n/a}, unique-id = {34068112}, issn = {1521-6543}, abstract = {Abstract Breast cancer is the prominent cause of cancer-related death in women globally in terms of incidence and mortality. Despite, recent advances in the management of breast cancer, there are still a lot of cases of resistance to medicines, which is currently one of the biggest problems faced by researchers across the globe. Out of several mechanisms, breast cancer resistance protein (BCRP) arbitrated drug resistance is a major concern. Hormonal, cytotoxic and immunotherapeutic drugs are used in the systemic therapy of breast cancer. It is vital to choose drugs based on the clinical and molecular attributes of the tumor to provide better treatment with greater efficacy and minimal harm. Given the aforementioned necessity, the use of marine flora in treating breast cancer cannot be neglected. The scientists also stressed the value of marine-derived goods in avoiding breast cancer resistance. Future research into the identification of anticancer drugs will heavily draw upon the marine environment's ample supply of marine-derived natural products (MNPs), which have a wide range of biological functions. Cell cycle arrest, induction of apoptosis and anti-angiogenic, anti-proliferative and anti-metastasis actions are all part of their processes. The overview of breast cancer, the mechanisms underlying its resistance, recent clinical trials based on marine-derived products in breast cancer and the use of marine products in the treatment of breast cancer are highlighted in this paper. Moreover, the authors also emphasised the importance of marine-derived products in preventing breast cancer resistance.}, keywords = {breast cancer resistance protein; breast cancer; Breast cancer resistance; marine-based products}, year = {2023}, eissn = {1521-6551} } @article{MTMT:34343676, title = {Diosmetin Maintains Barrier Integrity by Reducing the Expression of ABCG2 in Colonic Epithelial Cells}, url = {https://m2.mtmt.hu/api/publication/34343676}, author = {Liu, Jinfan and Fu, Lu and Yin, Fei and Yin, Li and Song, Xiaomei and Guo, Hong and Liu, Jianhui}, doi = {10.1021/acs.jafc.3c00912}, journal-iso = {J AGR FOOD CHEM}, journal = {JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY}, volume = {71}, unique-id = {34343676}, issn = {0021-8561}, abstract = {Crohn's disease (CD) is arelapsing and chronic inflammatorybowel disease. Recent advances have highlighted that dysfunction ofthe barrier function formed by a polarized monolayer of columnar epithelialcells plays a crucial role in the pathophysiology of CD. At present,we reported that diosmetin increased cell viability by reducing thelevels of TNF alpha and IL-6 in lipopolysaccharide (LPS)-treatedcolonic epithelial Caco-2 cells. Meanwhile, diosmetin conferred adirect effect on maintaining barrier integrity by reducing epithelialpermeability and increasing the expression of proteins associatedwith tight junctions, including zonula occludens-l (ZO-1), occludin,and claudin-1, in LPS-treated Caco-2 cells and in 2,4,6-trinitrobenzenesulfonic acid-induced CD mice. Additionally, diosmetin decreased theprotein content of adenosine triphosphate-binding cassette effluxtransporter G2 (ABCG2) in vitro and in vivo. Over-expression of ABCG2 had an important impact on the epithelialpermeability and barrier-related protein levels induced by LPS inCaco-2 cells. At the same time, Ko143, a specific ABCG2 inhibitor,dramatically enhanced the role of diosmetin in ZO-1 and occludin proteinsin LPS-treated Caco-2 cells. Mechanically, diosmetin significantlyattenuated the role of LPS in the phosphorylation of adenosine 5 '-monophosphate(AMP)-activated protein kinase (AMPK), phosphatidylinositol-3-kinase(PI3K)/protein kinase B (PKB/AKT), and cAMP-response element bindingprotein (CREB) in Caco-2 cells. The AMPK inhibitor Compound C obviouslyprevented the effect of diosmetin on ZO-1 and occludin expressionin LPS-treated Caco-2 cells. Taken together, the results of this studysuggest that AMPK/AKT/CREB-mediated ABCG2 expression plays a crucialrole in diosmetin, improving the barrier dysfunction in CD.}, keywords = {Inflammation; BARRIER FUNCTION; Diosmetin; adenosinetriphosphate (ATP)-binding cassette efflux transporterG2 (ABCG2); Crohn's disease(CD)}, year = {2023}, eissn = {1520-5118}, pages = {8931-8940} } @article{MTMT:33773748, title = {Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes}, url = {https://m2.mtmt.hu/api/publication/33773748}, author = {Mineiro, R. and Santos, C. and Gonçalves, I. and Lemos, M. and Cavaco, J.E.B. and Quintela, T.}, doi = {10.1007/s13105-023-00957-1}, journal-iso = {J PHYSIOL BIOCHEM}, journal = {JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY}, unique-id = {33773748}, issn = {1138-7548}, abstract = {Drug efficacy is dependent on the pharmacokinetics and pharmacodynamics of therapeutic agents. Tight junctions, detoxification enzymes, and drug transporters, due to their localization on epithelial barriers, modulate the absorption, distribution, and the elimination of a drug. The epithelial barriers which control the pharmacokinetic processes are sex steroid hormone targets, and in this way, sex hormones may also control the drug transport across these barriers. Thus, sex steroids contribute to sex differences in drug resistance and have a relevant impact on the sex-related efficacy of many therapeutic drugs. As a consequence, for the further development and optimization of therapeutic strategies, the sex of the individuals must be taken into consideration. Here, we gather and discuss the evidence about the regulation of ATP-binding cassette transporters by sex steroids, and we also describe the signaling pathways by which sex steroids modulate ATP-binding cassette transporters expression, with a focus in the most important ATP-binding cassette transporters involved in multidrug resistance. © 2023, The Author(s).}, keywords = {ABC TRANSPORTERS; sex differences; SEX STEROIDS; epithelial barriers}, year = {2023}, eissn = {1877-8755} } @article{MTMT:34175360, title = {Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop}, url = {https://m2.mtmt.hu/api/publication/34175360}, author = {Mózner, Orsolya and Zámbó, Boglárka and Bartos, Zsuzsa and Gergely, Anna and Szabó, Kata Sára and Jezsó, Bálint and Telbisz, Ágnes Mária and Várady, György and Homolya, László and Hegedűs, Tamás and Sarkadi, Balázs}, doi = {10.3390/membranes13100822}, journal-iso = {MEMBRANES-BASEL}, journal = {MEMBRANES (BASEL)}, volume = {13}, unique-id = {34175360}, abstract = {The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics, contributes to cancer drug resistance and the development of gout. In this work, we have analyzed the effects of selected variants, residing in a structurally unresolved cytoplasmic region (a.a. 354–367) of ABCG2 on the function and trafficking of this protein. A cluster of four lysines (K357–360) and the phosphorylation of a threonine (T362) residue in this region have been previously suggested to significantly affect the cellular fate of ABCG2. Here, we report that the naturally occurring K360del variant in human cells increased ABCG2 plasma membrane expression and accelerated cellular trafficking. The variable alanine replacements of the neighboring lysines had no significant effect on transport function, and the apical localization of ABCG2 in polarized cells has not been altered by any of these mutations. Moreover, in contrast to previous reports, we found that the phosphorylation-incompetent T362A, or the phosphorylation-mimicking T362E variants in this loop had no measurable effects on the function or expression of ABCG2. Molecular dynamics simulations indicated an increased mobility of the mutant variants with no major effects on the core structure of the protein. These results may help to decipher the potential role of this unstructured region within this transporter.}, year = {2023}, eissn = {2077-0375}, orcid-numbers = {Mózner, Orsolya/0000-0001-5784-7702; Bartos, Zsuzsa/0000-0001-9695-1422; Jezsó, Bálint/0000-0002-1306-4797; Telbisz, Ágnes Mária/0000-0003-0972-4606; Várady, György/0000-0003-2012-9680; Homolya, László/0000-0003-1639-8140; Hegedűs, Tamás/0000-0002-0331-9629; Sarkadi, Balázs/0000-0003-0592-4539} } @article{MTMT:34059440, title = {Genetic Predictors of Antipsychotic Efflux Impairment via Blood-Brain Barrier: Role of Transport Proteins}, url = {https://m2.mtmt.hu/api/publication/34059440}, author = {Nasyrova, R.F. and Shnayder, N.A. and Osipova, S.M. and Khasanova, A.K. and Efremov, I.S. and Al-Zamil, M. and Petrova, M.M. and Narodova, E.A. and Garganeeva, N.P. and Shipulin, G.A.}, doi = {10.3390/genes14051085}, journal-iso = {GENES-BASEL}, journal = {GENES}, volume = {14}, unique-id = {34059440}, issn = {2073-4425}, abstract = {Antipsychotic (AP)—induced adverse drug reactions (ADRs) are a current problem of biological and clinical psychiatry. Despite the development of new generations of APs, the problem of AP-induced ADRs has not been solved and continues to be actively studied. One of the important mechanisms for the development of AP-induced ADRs is a genetically-determined impairment of AP efflux across the blood-brain barrier (BBB). We present a narrative review of publications in databases (PubMed, Springer, Scopus, Web of Science E-Library) and online resources: The Human Protein Atlas; GeneCards: The Human Gene Database; US National Library of Medicine; SNPedia; OMIM Online Mendelian Inheritance in Man; The PharmGKB. The role of 15 transport proteins involved in the efflux of drugs and other xenobiotics across cell membranes (P-gp, TAP1, TAP2, MDR3, BSEP, MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, MRP8, MRP9, BCRP) was analyzed. The important role of three transporter proteins (P-gp, BCRP, MRP1) in the efflux of APs through the BBB was shown, as well as the association of the functional activity and expression of these transport proteins with low-functional and non-functional single nucleotide variants (SNVs)/polymorphisms of the ABCB1, ABCG2, ABCC1 genes, encoding these transport proteins, respectively, in patients with schizophrenia spectrum disorders (SSDs). The authors propose a new pharmacogenetic panel “Transporter protein (PT)—Antipsychotic (AP) Pharmacogenetic test (PGx)” (PTAP-PGx), which allows the evaluation of the cumulative contribution of the studied genetic biomarkers of the impairment of AP efflux through the BBB. The authors also propose a riskometer for PTAP-PGx and a decision-making algorithm for psychiatrists. Conclusions: Understanding the role of the transportation of impaired APs across the BBB and the use of genetic biomarkers for its disruption may make it possible to reduce the frequency and severity of AP-induced ADRs, since this risk can be partially modified by the personalized selection of APs and their dosing rates, taking into account the genetic predisposition of the patient with SSD. © 2023 by the authors.}, keywords = {Humans; metabolism; GENETICS; human; Biomarkers; Neoplasm Proteins; ATP-Binding Cassette Transporters; breast cancer resistance protein; ABCG2; biological marker; Antipsychotic Agents; United States; United States; Blood-Brain Barrier; Pharmacogenetics; blood brain barrier; ABC transporter; Multidrug Resistance-Associated Proteins; adverse drug reaction; neuroleptic agent; EFFLUX; tumor protein; Antipsychotic; P-gp; BCRP; ABCB1; pharmacogenetic testing; Transport protein; ABCC1; MRP1; multidrug resistance associated protein; personalized psychiatry; ATP Binding Cassette Transporter, Subfamily G, Member 2; single nucleotide variant}, year = {2023}, eissn = {2073-4425} } @article{MTMT:33773747, title = {Single-Nucleotide Polymorphisms as Biomarkers of Antipsychotic-Induced Akathisia: Systematic Review}, url = {https://m2.mtmt.hu/api/publication/33773747}, author = {Nasyrova, R.F. and Vaiman, E.E. and Repkina, V.V. and Khasanova, A.K. and Asadullin, A.R. and Shipulin, G.A. and Altynbekov, K.S. and Al-Zamil, M. and Petrova, M.M. and Shnayder, N.A.}, doi = {10.3390/genes14030616}, journal-iso = {GENES-BASEL}, journal = {GENES}, volume = {14}, unique-id = {33773747}, issn = {2073-4425}, abstract = {Antipsychotic-induced akathisia (AIA) is a movement disorder characterized by a subjective feeling of inner restlessness or nervousness with an irresistible urge to move, resulting in repetitive movements of the limbs and torso, while taking antipsychotics (APs). In recent years, there have been some associative genetic studies of the predisposition to the development of AIA. Objective: The goal of our study was to review the results of associative genetic and genome-wide studies and to systematize and update the knowledge on the genetic predictors of AIA in patients with schizophrenia (Sch). Methods: We searched full-text publications in PubMed, Web of Science, Springer, Google Scholar, and e-Library databases from 1977 to 2022. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) quality scale was used for the critical selection of the studies. Results: We identified 37 articles, of which 3 were included in the review. Thus, the C allele of rs1800498 (59414 C>T) and the A allele of rs1800497 (17316 G>A) (TaqIA) from the DRD2 gene as well as the TT genotype rs13212041 (77461407 C>T) from the HTR1B gene were found to be associated with AIA. Conclusions: Uncovering the genetic biomarkers of AIA may provide a key to developing a strategy for the personalized prevention and treatment of this adverse neurological drug reaction of APs in patients with Sch in real clinical practice. © 2023 by the authors.}, keywords = {Humans; SCHIZOPHRENIA; SCHIZOPHRENIA; GENE; ASSOCIATION; GENETICS; Polymorphism, Single Nucleotide; single nucleotide polymorphism; human; Biomarkers; biological marker; Antipsychotic Agents; Pharmacogenetics; adverse drug reaction; neuroleptic agent; Antipsychotics; Psychomotor Agitation; restlessness; Variation; genetic biomarker; Extrapyramidal disorder; single nucleotide variant; antipsychotic-induced akathisia}, year = {2023}, eissn = {2073-4425} } @article{MTMT:33250233, title = {Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression}, url = {https://m2.mtmt.hu/api/publication/33250233}, author = {Ohashi, Y. and Kuriyama, S. and Nakano, T. and Sekine, M. and Toyoda, Y. and Nakayama, A. and Takada, T. and Kawamura, Y. and Nakamura, T. and Matsuo, H. and Yokoo, T. and Ichida, K.}, doi = {10.1053/j.ajkd.2022.05.010}, journal-iso = {AM J KIDNEY DIS}, journal = {AMERICAN JOURNAL OF KIDNEY DISEASES}, volume = {81}, unique-id = {33250233}, issn = {0272-6386}, abstract = {Rationale & Objective: Treatment of asymptomatic hyperuricemia is not commonly implemented. However, it is unclear whether urate deposition that begins during asymptomatic hyperuricemia can induce nephropathy. Dysfunction of ATP-binding cassette subfamily G member 2 (ABCG2), a urate efflux transporter, leads to elevated serum uric acid concentration (SUA). We investigated the association between asymptomatic hyperuricemia and decreased estimated glomerular filtration rate (eGFR), and the impact of ABCG2 on this relationship. Study Design: Retrospective cohort study. Setting & Participants: 1,885 Japanese adults undergoing routine health care follow-up between 2007 and 2017 who had eGFR ≥60 mL/min/1.73 m2, of which 311 had asymptomatic hyperuricemia (SUA >7.0 mg/dL). Study participants were classified into 3 categories of estimated ABCG2 function (full, 75%, and ≤50% function). Predictors: Baseline SUA and estimated ABCG2 function. Outcome: Change in eGFR over time. Analytical Approach: Linear mixed-effect models were used to analyze the relationship between asymptomatic hyperuricemia, ABCG2 function, and eGFR decline. Results: Asymptomatic hyperuricemia was negligibly associated with eGFR decline overall. However, among those with eGFR 60-89 mL/min/1.73 m2 and ≤50% ABCG2 function, eGFR decline was associated with asymptomatic hyperuricemia (P = 0.03). ABCG2 was not associated with eGFR reductions when the SUA was <6.0 mg/dL. Among participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, ≤50% ABCG2 function was associated with approximately 1.2-fold faster eGFR decline compared with fully functional ABCG2 (P = 0.02). Among the participants with SUA ≥6.0 mg/dL and eGFR 60-89 mL/min/1.73 m2, the adjusted eGFR slopes (given as mean ± standard error of the mean, in mL/min/1.73 m2 per year) were −0.946 ± 0.049, −1.040 ± 0.046, and −1.148 ± 0.069 for full, 75%, and ≤50% ABCG2 function, respectively. Limitations: Lack of measurement of urinary urate and uremic toxins that are known to be transported by ABCG2, and no independent validation cohort. Conclusions: Asymptomatic hyperuricemia was not associated with eGFR decline, except when in the presence of ≤50% ABCG2 function. Plain-Language Summary: The urate transporter ABCG2 is a protein that regulates serum urate concentrations; when dysfunctional, it can lead to elevated serum concentrations of this compound (ie, hyperuricemia). Although persistent hyperuricemia induces gout and kidney injury, the effects on organs during the asymptomatic phase have yet to be established. Therefore, to clarify the relationship between ABCG2, asymptomatic hyperuricemia, and kidney function, we conducted a retrospective cohort study of 1,885 healthy participants, including 311 participants with asymptomatic hyperuricemia. We found that the coexistence of asymptomatic hyperuricemia and severe ABCG2 dysfunction was associated with the age-dependent decline in kidney function. We concluded that asymptomatic hyperuricemia represents a risk factor for chronic kidney disease, at least in individuals with highly dysfunctional ABCG2. This new finding highlights the potential importance of ABCG2 in the pathogenesis of hyperuricemia-induced kidney injury. © 2022 National Kidney Foundation, Inc.}, keywords = {ABCG2; hyperuricemia; kidney function; urate; genetic risk factor; Risk allele; kidney disease progression; estimated glomerular filtration rate (eGFR); Null mutation; Serum uric acid (SUA); eGFR slope; ABCG2 function}, year = {2023}, eissn = {1523-6838}, pages = {134-144e1} } @article{MTMT:34535346, title = {Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin}, url = {https://m2.mtmt.hu/api/publication/34535346}, author = {Paskas, S. and Stockmann, P. and Mijatović, S. and Kuhnert, L. and Honscha, W. and Hey-Hawkins, E. and Maksimović-Ivanić, D.}, doi = {10.3390/ph16111582}, journal-iso = {PHARMACEUTICALS-BASE}, journal = {PHARMACEUTICALS}, volume = {16}, unique-id = {34535346}, abstract = {The ABCG2 transporter protein, as part of several known mechanisms involved in multidrug resistance, has the ability to transport a broad spectrum of substrates out of the cell and is, therefore, considered as a potential target to improve cancer therapies or as an approach to combat drug resistance in cancer. We have previously reported carborane-functionalized quinazoline derivatives as potent inhibitors of human ABCG2 which effectively reversed breast cancer resistance protein (BCRP)-mediated mitoxantrone resistance. In this work, we present the evaluation of our most promising carboranyl BCRP inhibitors regarding their toxicity towards ABCG2-expressing cancer cell lines (MCF-7, doxorubicin-resistant MCF-7 or MCF-7 Doxo, HT29, and SW480) and, consequently, with the co-administration of an inhibitor and therapeutic agent, their ability to increase the efficacy of therapeutics with the successful inhibition of ABCG2. The results obtained revealed synergistic effects of several inhibitors in combination with doxorubicin or cisplatin. Compounds DMQCa, DMQCc, and DMQCd showed a decrease in IC50 value in ABCB1- and ABCG2-expressing SW480 cells, suggesting a possible targeting of both transporters. In an HT29 cell line, with the highest expression of ABCG2 among the tested cell lines, using co-treatment of doxorubicin and DMQCd, the effective inhibitory concentration of the antineoplastic agent could be reduced by half. Interestingly, co-treatment of compound QCe with cisplatin, which is not an ABCG2 substrate, showed synergistic effects in MCF-7 Doxo and HT29 cells (IC50 values halved or reduced by 20%, respectively). However, a literature-known upregulation of cisplatin-effluxing ABC transporters and their effective inhibition by the carborane derivatives emerges as a possible reason. © 2023 by the authors.}, keywords = {ARTICLE; human; reverse transcription polymerase chain reaction; breast cancer resistance protein; breast cancer resistance protein; ABCG2; controlled study; TOXICITY; Flow Cytometry; Gene Expression; human cell; drug combination; unclassified drug; antineoplastic agent; doxorubicin; multidrug resistance; multidrug resistance; cancer therapy; breast cancer; cisplatin; mitoxantrone; MITOCHONDRIAL RESPIRATION; ANTINEOPLASTIC ACTIVITY; Cell viability; drug interaction; ABC transporter; quinazoline derivative; RNA isolation; MTT assay; Molecular docking; Synergistic effect; IC50; SW480 cell line; MCF-7 cell line; HT-29 cell line; SW620 cell line; carborane; antagonistic effect; carborane derivative; dmqcc compound; dmqcd compound; qcc compound; qce compound}, year = {2023}, eissn = {1424-8247} } @article{MTMT:34091916, title = {ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer—In Silico and Wet Analysis}, url = {https://m2.mtmt.hu/api/publication/34091916}, author = {Sałagacka-Kubiak, A. and Zawada, D. and Saed, L. and Kordek, R. and Jeleń, A. and Balcerczak, E.}, doi = {10.3390/ijms241310539}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34091916}, issn = {1661-6596}, abstract = {ABCG2 (ATP-binding cassette superfamily G member 2) is a cell membrane pump encoded by the ABCG2 gene. ABCG2 can protect cells against compounds initiating and/or intensifying neoplasia and is considered a marker of stem cells responsible for cancer growth, drug resistance and recurrence. Expression of the ABCG2 gene or its protein has been shown to be a negative prognostic factor in various malignancies. However, its prognostic significance in colorectal cancer remains unclear. Using publicly available data, ABCG2 was shown to be underexpressed in colon and rectum adenocarcinomas, with lower expression compared to both the adjacent nonmalignant lung tissues and non-tumour lung tissues of healthy individuals. This downregulation could result from the methylation level of some sites of the ABCG2 gene. This was connected with microsatellite instability, weight and age among patients with colon adenocarcinoma, and with tumour localization, population type and age of patients for rectum adenocarcinoma. No association was found between ABCG2 expression level and survival of colorectal cancer patients. In wet analysis of colorectal cancer samples, neither ABCG2 gene expression, analysed by RT-PCR, nor ABCG2 protein level, assessed by immunohistochemistry, was associated with any clinicopathological factors or overall survival. An ABCG2-centered protein–protein interaction network build by STRING showed proteins were found to be involved in leukotriene, organic anion and xenobiotic transport, endodermal cell fate specification, and histone methylation and ubiquitination. Hence, ABCG2 underexpression could be an indicator of the activity of certain signalling pathways or protein interactors essential for colorectal carcinogenesis. © 2023 by the authors.}, keywords = {immunohistochemistry; SURVIVAL; Prognosis; ABCG2; QPCR; Protein-protein interaction network}, year = {2023}, eissn = {1422-0067} } @article{MTMT:34059441, title = {Method for Testing of Drugs Belonging to Substrates and Inhibitors of the Transporter Protein BCRP on Caco-2 Cells}, url = {https://m2.mtmt.hu/api/publication/34059441}, author = {Tranova, Y.S. and Slepnev, A.A. and Chernykh, I.V. and Shchulkin, A.V. and Mylnikov, P.Yu. and Popova, N.M. and Povetko, M.I. and Yakusheva, E.N.}, doi = {10.33380/2305-2066-2023-12-2-87-94}, journal-iso = {RAZRABOTKA I REGISTRATSIYA LEKARSTVENNYKH SREDSTV}, journal = {RAZRABOTKA I REGISTRATSIYA LEKARSTVENNYKH SREDSTV}, volume = {12}, unique-id = {34059441}, issn = {2305-2066}, abstract = {Introduction. Breast cancer resistance protein (BCRP) is an efflux membrane transporter that controls the pharmacokinetics of a large number of drugs. Its activity may change when taking some endo-and exogenous substances, thus making it a link in drug interactions. Aim. The aim of the study was to develop a method for testing of drugs for belonging to BCRP substrates and inhibitors in vitro. Materials and methods. The work was performed on Caco-2 cells overexpressing BCRP, the cultivation was performed in a transwell-system consisting of the apical and basolateral chambers. Cells were seeded at the bottom of the apical chamber, which is a semipermeable membrane. Primarily, the transport of BCRP substrates: methotrexate, mitoxantrone and quercetin was evaluated in the concentration range of 1, 5, 10, and 50 μM in the direction from the basal chamber to the apical one (Papp b-a) and in the opposite direction (Papp a-b). The ratio Papp b-a / Papp a-b more than «2» characterizes the participation of transporter proteins in the transcellular transport of substances. To confirm the participation of BCRP in their transport the experiment was carried out with the addition of a transporter inhibitor, reserpine, to the transport medium at a concentration of 50 μM. The concentration of substrates in the chambers was analyzed by HPLC-MS/MS. Results and their discussion. The addition of methotrexate (1 μM), mitoxantrone (1 μM), and quercetin (1–10 μM) to both the apical or basolateral chambers of the transwell-system, their content in the recipient chamber was not detected. When methotrexate concentration became 5 μM the Papp b-a / Papp a-b ratio was 3.38 ± 0.08, which indicates the involvement of transporters in its transfer. The addition of methotrexate to the donor chamber at concentrations of 10 and 50 μM, Papp b-a / Papp a-b decreased to values below «2». At mitoxantrone concentration of 5 μM Papp b-a / Papp a-b was 2.72 ± 0.16. An increase in the concentration to 10 μM led to an increase in Papp b-a / Papp a-b to 6.18 ± 0.08. With a substance content of 50 μM the indicator decreased but remained above the value «2». In the quercetin concentration of 50 microns, Papp b-a / Papp was below "2". Reserpine reduced Papp b-a / Papp a-b of methotrexate by 3.31 times (p = 0.0002), which indicates the elimination of asymmetry in the transport of the substance. At a mitoxantrone concentration of 10 microns, reserpine reduced its Papp b-a / Papp a-b by 3.36 times (p < 0.0001). The results indicate the participation of BCRP in the control of the transfer of both substances through the cellular monolayer. Conclusion. A method of testing drugs belonging to BCRP substrates and inhibitors using methotrexate (5 μM) and mitoxantrone (10 μM) as marker substrates and reserpine (50 μM) as inhibitor was developed and tested on Caco-2 cells. © Tranova Yu. S., Slepnev A. A., Chernykh I. V., Shchulkin A. V., Mylnikov P. Yu., Popova N. M., Povetko M. I., Yakusheva E. N., 2023.}, keywords = {INHIBITORS; Quercetin; METHOTREXATE; RESERPINE; mitoxantrone; Substrates; EFFLUX; BCRP; Caco-2 cell culture}, year = {2023}, pages = {87-94} } @article{MTMT:33248278, title = {The Good, the Bad and the New about Uric Acid in Cancer}, url = {https://m2.mtmt.hu/api/publication/33248278}, author = {Allegrini, Simone and Garcia-Gil, Mercedes and Pesi, Rossana and Camici, Marcella and Tozzi, Maria Grazia}, doi = {10.3390/cancers14194959}, journal-iso = {CANCERS}, journal = {CANCERS}, volume = {14}, unique-id = {33248278}, abstract = {Simple Summary The concentration of uric acid in blood is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant and is a scavenger of singlet oxygen and radicals. At high intracellular concentration, uric acid has been demonstrated to act as a pro-oxidant molecule. Recently, uric acid has been reported to affect the properties of several proteins involved in metabolic regulation and signaling, and the relationship between uric acid and cancer has been extensively investigated. In this review, we present the most recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in the pathogenesis of several diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. Uric acid is the final product of purine catabolism in man and apes. The serum concentration of uric acid is sex-, age- and diet-dependent and is maintained close to its maximal solubility, indicating that it plays some important role. Indeed, it has been demonstrated that, at physiological concentrations, uric acid is a powerful antioxidant, while at high intracellular concentrations, it is a pro-oxidant molecule. In this review, we describe the possible causes of uric acid accumulation or depletion and some of the metabolic and regulatory pathways it may impact. Particular attention has been given to fructose, which, because of the complex correlation between carbohydrate and nucleotide metabolism, causes uric acid accumulation. We also present recent results on the positive and negative effects played by uric acid in cancer and some new findings and hypotheses about the implication of this metabolite in a variety of signaling pathways, which can play a role in the pathogenesis of diseases such as metabolic syndrome, diabetes, and inflammation, thus favoring the development of cancer. The loss of uricase in Homo sapiens and great apes, although exposing these species to the potentially adverse effects of uric acid, appears to be associated with evolutionary advantages.}, keywords = {CANCER; fructose; AKT; hyperuricemia; Xanthine oxidoreductase; uric acid; mTor; AMPK; Oxidative stress; Uricase}, year = {2022}, eissn = {2072-6694}, orcid-numbers = {Pesi, Rossana/0000-0003-4785-7282} } @article{MTMT:33084731, title = {Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery}, url = {https://m2.mtmt.hu/api/publication/33084731}, author = {Feyzizadeh, M. and Barfar, A. and Nouri, Z. and Sarfraz, M. and Zakeri-Milani, P. and Valizadeh, H.}, doi = {10.1080/17460441.2022.2112666}, journal-iso = {EXPERT OPIN DRUG DIS}, journal = {EXPERT OPINION ON DRUG DISCOVERY}, volume = {17}, unique-id = {33084731}, issn = {1746-0441}, abstract = {Introduction: The argument around cancer therapy is an old one. Using chemotherapeutic drugs, as one of the most effective strategies in treatment of malignancies, is restricted by various issues that progress during therapy and avoid achieving clinical endpoints. Multidrug resistance (MDR), frequently mediated by ATP-binding cassette (ABC) transporters, is one of the most recognized obstacles in the success of pharmacological anticancer approaches. These transporters efflux diverse drugs to extracellular environment, causing MDR and responsiveness of tumor cells to chemotherapy diminishes. Areas covered: Several strategies have been used to overcome MDR phenomenon. Succession in this field requires complete knowledge about features and mechanism of ABC transporters. In this review, conventional synthetic and natural inhibitors are discussed first and then novel approaches including RNA, monoclonal antibodies, nanobiotechnology, and structural modification techniques are represented. Expert opinion: With increasing frequency of MDR in cancer cells, it is essential to develop new drugs to inhibit MDR. Using knowledge acquired about ABC transporter’s structure, rational design of inhibitors is possible. Also, some herbal products have shown to be potential lead compounds in drug discovery for reversal of MDR. © 2022 Informa UK Limited, trading as Taylor & Francis Group.}, keywords = {CANCER; CHEMOTHERAPY; multidrug resistance; ABC transporter; ATP-binding cassette}, year = {2022}, eissn = {1746-045X}, pages = {1013-1027} } @article{MTMT:32612583, title = {Ins and outs of AlphaFold2 transmembrane protein structure predictions}, url = {https://m2.mtmt.hu/api/publication/32612583}, author = {Hegedűs, Tamás and Geisler, Markus and Lukács, Gergely László and Farkas, Bianka Vivien}, doi = {10.1007/s00018-021-04112-1}, journal-iso = {CELL MOL LIFE SCI}, journal = {CELLULAR AND MOLECULAR LIFE SCIENCES}, volume = {79}, unique-id = {32612583}, issn = {1420-682X}, year = {2022}, eissn = {1420-9071}, orcid-numbers = {Hegedűs, Tamás/0000-0002-0331-9629; Geisler, Markus/0000-0002-6641-5810; Lukács, Gergely László/0000-0003-0900-0675; Farkas, Bianka Vivien/0000-0002-0258-6864} } @article{MTMT:32811162, title = {Membrane Transporters and Carriers in Human Seminal Vesicles}, url = {https://m2.mtmt.hu/api/publication/32811162}, author = {Malinowski, D. and Grzegółkowski, P. and Piotrowska, K. and Słojewski, M. and Droździk, M.}, doi = {10.3390/jcm11082213}, journal-iso = {J CLIN MED}, journal = {JOURNAL OF CLINICAL MEDICINE}, volume = {11}, unique-id = {32811162}, abstract = {Seminal vesicles play an important role in the male reproductive system, producing seminal fluid and thus adequate environment for sperm. However, mechanisms underlying secretory functions of the seminal vesicles’ epithelium have not been defined yet. The aim of the present study was to characterize expression and immunolocalization of selected membrane transporters and carriers in the seminal vesicles. The study included biopsy specimens collected from nonaffected parts of seminal vesicles from 53 patients of Caucasian origin subjected for prostatectomy. RT-PCR was used to define expression of 15 genes coding for ABC-family and 37 genes encoding 37 SLC-family transporters/carriers. Immunohistochemistry was used to define localization of 6 transporters. In the seminal vesicles, the following membrane transporters and carriers were defined: ABCA1, ABCB1, ABCB5, ABCB6, ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCG2, SLC01C1, SLC02B1, SLC04A1, SLC04C1, SLC10A1, SLC15A1, SLC15A2, SLC16A1, SLC16A3, SLC19A1, SLC22A1, SLC22A3, SLC22A11, SLC22A18, SLC22A4, SLC22A5, SLC28A1, SLC2A9, SLC33A1, SLC47A1, SLC47A2, SLC51A, SLC51B, SLC7A5, SLC7A6. Age-dependent expression was evidenced for ABCB1, ABCG2, SLC04C1, SLC15A1, SLC16A1, SLC22A11, SLC22A18, SLC47A1 and SLC47A2. ABCG2, P-gp, MRP1, MRP3, MCT1 and LAT1 were localized in the apical membrane and P-gp in the basolateral membrane of the seminal vesicle epithelium. The expression of the membrane transporters and carriers in the seminal vesicle epithelium confirms its secretory and barrier functions. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.}, keywords = {ABC TRANSPORTERS; DRUG TRANSPORTERS; Seminal vesicles; solute-linked carrier}, year = {2022}, eissn = {2077-0383} } @article{MTMT:33084278, title = {Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology}, url = {https://m2.mtmt.hu/api/publication/33084278}, author = {Tordai, Hedvig and Suhajda, Erzébet and Sillitoe, Ian and Nair, Sreenath and Varadi, Mihaly and Hegedűs, Tamás}, doi = {10.3390/ijms23168877}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {23}, unique-id = {33084278}, issn = {1661-6596}, abstract = {The number of unique transmembrane (TM) protein structures doubled in the last four years, which can be attributed to the revolution of cryo-electron microscopy. In addition, AlphaFold2 (AF2) also provided a large number of predicted structures with high quality. However, if a specific protein family is the subject of a study, collecting the structures of the family members is highly challenging in spite of existing general and protein domain-specific databases. Here, we demonstrate this and assess the applicability and usability of automatic collection and presentation of protein structures via the ABC protein superfamily. Our pipeline identifies and classifies transmembrane ABC protein structures using the PFAM search and also aims to determine their conformational states based on special geometric measures, conftors. Since the AlphaFold database contains structure predictions only for single polypeptide chains, we performed AF2-Multimer predictions for human ABC half transporters functioning as dimers. Our AF2 predictions warn of possibly ambiguous interpretation of some biochemical data regarding interaction partners and call for further experiments and experimental structure determination. We made our predicted ABC protein structures available through a web application, and we joined the 3D-Beacons Network to reach the broader scientific community through platforms such as PDBe-KB.}, keywords = {MECHANISM; CLASSIFICATION; MUTATIONS; CHANNEL; P-GLYCOPROTEIN; TRANSPORTERS; protein structure; inventory; ABC TRANSPORTERS; PROTEIN COMPLEX; Biochemistry & Molecular Biology; Structure database; AlphaFold2; AF-multimer}, year = {2022}, eissn = {1422-0067}, orcid-numbers = {Tordai, Hedvig/0000-0002-0875-5569; Varadi, Mihaly/0000-0002-3687-0839; Hegedűs, Tamás/0000-0002-0331-9629} } @article{MTMT:32920302, title = {Targeting breast cancer resistance protein (BCRP/ABCG2): Functional inhibitors and expression modulators}, url = {https://m2.mtmt.hu/api/publication/32920302}, author = {Zattoni, I.F. and Delabio, L.C. and Dutra, J.D.P. and Kita, D.H. and Scheiffer, G. and Hembecker, M. and Pereira, G.D.S. and Moure, V.R. and Valdameri, G.}, doi = {10.1016/j.ejmech.2022.114346}, journal-iso = {EUR J MED CHEM}, journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, volume = {237}, unique-id = {32920302}, issn = {0223-5234}, abstract = {The primary source of failure of cancer therapies is multidrug resistance (MDR), which can be caused by different mechanisms, including the overexpression of ABC transporters in cancer cells. Among the 48 human ABC proteins, the breast cancer resistance protein (BCRP/ABCG2) has been described as a pivotal player in cancer resistance. The use of functional inhibitors and expression modulators is a promising strategy to overcome the MDR caused by ABCG2. Despite the lack of clinical trials using ABCG2 inhibitors, many compounds have already been discovered. This review presents an overview about various ABCG2 inhibitors that have been identified, discussing some chemical aspects and the main experimental methods used to identify and characterize the mechanisms of new inhibitors. In addition, some biological requirements to pursue preclinical tests are described. Finally, we discuss the potential use of ABCG2 inhibitors in cancer stem cells (CSC) for improving the objective response rate and the mechanism of ABCG2 modulators at transcriptional and protein expression levels. © 2022 Elsevier Masson SAS}, keywords = {Female; Female; Humans; INHIBITOR; metabolism; human; Chemistry; Neoplasm Proteins; Drug Resistance; Breast Neoplasms; antineoplastic agent; multidrug resistance; multidrug resistance; breast tumor; Antineoplastic Agents; MODULATOR; Drug Resistance, Multiple; Drug Resistance, Neoplasm; tumor protein; Cancer stem cells; Abcg2 transporter; ABCG2 protein, human; ATP Binding Cassette Transporter, Subfamily G, Member 2}, year = {2022}, eissn = {1768-3254} } @article{MTMT:32118446, title = {Bisphenol a inhibits the transporter function of the blood-brain barrier by directly interacting with the abc transporter breast cancer resistance protein (Bcrp)}, url = {https://m2.mtmt.hu/api/publication/32118446}, author = {Engdahl, E. and van, Schijndel M.D.M. and Voulgaris, D. and Di, Criscio M. and Ramsbottom, K.A. and Rigden, D.J. and Herland, A. and Rüegg, J.}, doi = {10.3390/ijms22115534}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {32118446}, issn = {1661-6596}, abstract = {The breast cancer resistance protein (BCRP) is an important efflux transporter in the blood-brain barrier (BBB), protecting the brain from a wide range of substances. In this study, we investigated if BCRP function is affected by bisphenol A (BPA), a high production volume chemical used in common consumer products, as well as by bisphenol F (BPF) and bisphenol S (BPS), which are used to substitute BPA. We employed a transwell-based in vitro cell model of iPSC-derived brain microvascular endothelial cells, where BCRP function was assessed by measuring the intracellular accumulation of its substrate Hoechst 33342. Additionally, we used in silico modelling to predict if the bisphenols could directly interact with BCRP. Our results showed that BPA significantly inhibits the transport function of BCRP. Additionally, BPA was predicted to bind to the cavity that is targeted by known BCRP inhibitors. Taken together, our findings demonstrate that BPA inhibits BCRP function in vitro, probably by direct interaction with the transporter. This effect might contribute to BPA’s known impact on neurodevelopment. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.}, keywords = {Humans; metabolism; GENETICS; human; PHENOLS; Chemistry; Neoplasm Proteins; breast cancer resistance protein; ABCG2; drug effect; Cells, Cultured; Protein Binding; Protein Binding; in vitro study; Sulfones; Gene Expression; Gene Expression; Blood-Brain Barrier; Blood-Brain Barrier; cell culture; Cell Culture Techniques; endothelium cell; endothelial cells; blood brain barrier; Benzimidazoles; phenol derivative; benzhydryl derivative; Benzhydryl Compounds; tumor protein; Molecular docking; BCRP; induced pluripotent stem cell; Induced pluripotent stem cells; benzimidazole derivative; 4,4' isopropylidenediphenol; Molecular Docking Simulation; In Vitro Techniques; cell culture technique; BBB; sulfone; BPA; fused heterocyclic rings; Diketopiperazines; Bisphenol F; BPS; Bisphenols; Heterocyclic Compounds, 4 or More Rings; ABCG2 protein, human; ATP Binding Cassette Transporter, Subfamily G, Member 2; Piperazinedione; bisbenzimide ethoxide trihydrochloride; BPF; 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino(1',2'-1,6)pyrido(3,4-b)indol-3-yl)propionic acid tert-butyl ester; bis(4-hydroxyphenyl)sulfone}, year = {2021}, eissn = {1422-0067} } @article{MTMT:31953886, title = {The incredible diversity of structures and functions of ABC transporters}, url = {https://m2.mtmt.hu/api/publication/31953886}, author = {Hamdoun, A. and Hellmich, U.A. and Szakács, Gergely and Kuchler, K.}, doi = {10.1002/1873-3468.14061}, journal-iso = {FEBS LETT}, journal = {FEBS LETTERS}, volume = {595}, unique-id = {31953886}, issn = {0014-5793}, keywords = {CLASSIFICATION; human; editorial; priority journal; nonhuman; Cryoelectron Microscopy; Homeostasis; PROTEIN FUNCTION; Environment; protein structure; ABC transporter}, year = {2021}, eissn = {1873-3468}, pages = {671-674} } @article{MTMT:33084733, title = {Research progress on the traditional Chinese medicine-pharmaceutical drug interaction mediated by the ABC transporter family}, url = {https://m2.mtmt.hu/api/publication/33084733}, author = {He, Y.-Z. and Wang, H. and Fang, J.-H. and Cao, Y.-H. and Hong, Z.-Y. and Chai, Y.-F.}, doi = {10.16438/j.0513-4870.2021-0605}, journal-iso = {ACTA PHARMACEUTICA SINICA}, journal = {ACTA PHARMACEUTICA SINICA}, volume = {56}, unique-id = {33084733}, issn = {0513-4870}, abstract = {ABC transporters on the intestinal barrier, blood-brain barrier and on tumor cells will affect drug bioavailability, transport across the blood-brain barrier and multidrug resistance. The active ingredients of traditional Chinese medicines can affect the function and expression of ABC transporters. When combined with pharmaceuticals the potential interaction between the two can change the efficacy of the medicines. We review the ABC transporter superfamily and their distribution with regard to their relationship and interactions with traditional Chinese medicine on the intestinal barrier and the blood-brain barrier, as well as their role in tumor multidrug resistance mediated by ABC transporters. We summarize the research progress over the past five years. © 2021, Chinese Pharmaceutical Association. All rights reserved.}, keywords = {ARTICLE; Blood-Brain Barrier; multidrug resistance; intestine mucosa permeability; blood brain barrier; cancer resistance; drug interaction; ABC transporter; protein family; Chinese medicine; Multi-drug resistance; Intestinal barrier; ATP binding cassette-transporter; traditional Chinese medicine-chemical medicine interaction}, year = {2021}, pages = {1778-1788} } @article{MTMT:31960289, title = {Medically important alterations in transport function and trafficking of abcg2}, url = {https://m2.mtmt.hu/api/publication/31960289}, author = {Homolya, László}, doi = {10.3390/ijms22062786}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {31960289}, issn = {1661-6596}, abstract = {Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo-and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed. © 2021 by the author. Licensee MDPI, Basel, Switzerland.}, keywords = {MUTATIONS; POLYMORPHISMS; TRANSPORT; TRAFFICKING; multidrug resistance; urate; ABC (ATP-binding cassette) transporters}, year = {2021}, eissn = {1422-0067}, orcid-numbers = {Homolya, László/0000-0003-1639-8140} } @article{MTMT:32613108, title = {ATP-binding cassette transporters and neurodegenerative diseases}, url = {https://m2.mtmt.hu/api/publication/32613108}, author = {Katzeff, Jared S and Kim, Woojin Scott}, doi = {10.1042/EBC20210012}, journal-iso = {ESSAYS BIOCHEM}, journal = {ESSAYS IN BIOCHEMISTRY}, volume = {65}, unique-id = {32613108}, issn = {0071-1365}, year = {2021}, eissn = {1744-1358}, pages = {1013-1024} } @article{MTMT:32058564, title = {Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms}, url = {https://m2.mtmt.hu/api/publication/32058564}, author = {Khunweeraphong, Narakorn and Kuchler, Karl}, doi = {10.3390/ijms22094806}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {32058564}, issn = {1661-6596}, year = {2021}, eissn = {1422-0067}, orcid-numbers = {Khunweeraphong, Narakorn/0000-0001-8457-2230; Kuchler, Karl/0000-0003-2719-5955} } @article{MTMT:31960379, title = {Cancer stem cells in colorectal cancer and the association with chemotherapy resistance}, url = {https://m2.mtmt.hu/api/publication/31960379}, author = {Lei, X. and He, Q. and Li, Z. and Zou, Q. and Xu, P. and Yu, H. and Ding, Y. and Zhu, W.}, doi = {10.1007/s12032-021-01488-9}, journal-iso = {MED ONCOL}, journal = {MEDICAL ONCOLOGY}, volume = {38}, unique-id = {31960379}, issn = {1357-0560}, abstract = {The incidence and mortality of colorectal cancer (CRC) have always been among the highest in the world, although the diagnosis and treatment are becoming more and more advanced. At present, the main reason is that patients have acquired drug resistance after long-term conventional drug treatment. An increasing number of evidences confirm the existence of cancer stem cells (CSCs), which are a group of special cells in cancer, only a small part of cancer cells. These special cell populations are not eliminated by chemotherapeutic drugs and result in tumor recurrence and metastasis after drug treatment. CSCs have the ability of self-renewal and multidirectional differentiation, which is associated with the occurrence and development of cancer. CSCs can be screened and identified by related surface markers. In this paper, the characteristic surface markers of CSCs in CRC and the related mechanism of drug resistance will be discussed in detail. A better understanding of the mechanism of CSCs resistance to chemotherapy may lead to better targeted therapy. © 2021, Springer Science+Business Media, LLC, part of Springer Nature.}, keywords = {colorectal cancer; Cancer stem cells; Chemotherapeutic resistance; surface markers}, year = {2021}, eissn = {1559-131X} } @article{MTMT:32118445, title = {Ganciclovir and its hemocompatible more lipophilic derivative can enhance the apoptotic effects of methotrexate by inhibiting breast cancer resistance protein (Bcrp)}, url = {https://m2.mtmt.hu/api/publication/32118445}, author = {Markowicz-Piasecka, M. and Huttunen, J. and Montaser, A. and Adla, S.K. and Auriola, S. and Lehtonen, M. and Huttunen, K.M.}, doi = {10.3390/ijms22147727}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {32118445}, issn = {1661-6596}, abstract = {Efflux transporters, namely ATP-binding cassette (ABC), are one of the primary reasons for cancer chemoresistance and the clinical failure of chemotherapy. Ganciclovir (GCV) is an antiviral agent used in herpes simplex virus thymidine kinase (HSV-TK) gene therapy. In this therapy, HSV-TK gene is delivered together with GCV into cancer cells to activate the phosphorylation process of GCV to active GCV-triphosphate, a DNA polymerase inhibitor. However, GCV interacts with efflux transporters that are responsible for the resistance of HSV-TK/GCV therapy. In the present study, it was explored whether GCV and its more lipophilic derivative (1) could inhibit effluxing of another chemotherapeutic, methotrexate (MTX), out of the human breast cancer cells. Firstly, it was found that the combination of GCV and MTX was more hemocompatible than the corresponding combination with compound 1. Secondly, both GCV and compound 1 enhanced the cellular accumulation of MTX in MCF-7 cells, the MTX exposure being 13–21 times greater compared to the MTX uptake alone. Subsequently, this also reduced the number of viable cells (41–56%) and increased the number of late apoptotic cells (46–55%). Moreover, both GCV and compound 1 were found to interact with breast cancer resistant protein (BCRP) more effectively than multidrug-resistant proteins (MRPs) in these cells. Since the expression of BCRP was higher in MCF-7 cells than in MDA-MB-231 cells, and the cellular uptake of GCV and compound 1 was smaller but increased in the presence of BCRP-selective inhibitor (Fumitremorgin C) in MCF-7 cells, we concluded that the improved apoptotic effects of higher MTX exposure were raised mainly from the inhibition of BCRP-mediated efflux of MTX. However, the effects of GCV and its derivatives on MTX metabolism and the quantitative expression of MTX metabolizing enzymes in various cancer cells need to be studied more thoroughly in the future. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).}, keywords = {Multidrug resistance (MDR); Breast cancer resistant protein (BCRP); Methotrexate (MTX); Ganciclovir (GCV); MCF-7/MDA-MB-231 human breast cancer cells}, year = {2021}, eissn = {1422-0067} } @article{MTMT:32281343, title = {Anticancer Natural Products with Collateral Sensitivity: A Review}, url = {https://m2.mtmt.hu/api/publication/32281343}, author = {Qian, Jiajun and Cui, Jiahua and Li, Shaoshun and Chen, Jun and Jia, Jinping}, doi = {10.2174/1389557521666210112141455}, journal-iso = {MINI REV MED CHEM}, journal = {MINI-REVIEWS IN MEDICINAL CHEMISTRY}, volume = {21}, unique-id = {32281343}, issn = {1389-5575}, abstract = {Background: Multidrug resistance (MDR) is the resistance of cancer cells against a variety of currently used antineoplastic agents with diverse structural scaffolds and different anticancer mechanisms. It has been recognized as one of the major impediments to the successful treatment of cancer, leading to the metastasis and relapse of malignant diseases.Introduction: Collateral sensitivity (CS) is the characteristic of certain chemicals to kill the drugresistant sublines selectively over the parental cell lines from which the resistant cells were generated. The research and development of new drug candidates with collateral sensitivity will be an efficient approach to conquer multidrug resistance in cancer. We aim to provide an update on the discovery of natural products with collateral sensitivity.Results and Conclusion: The review focused on the characterized anticancer natural products and their derivatives with collateral sensitivity, their working mechanisms, and related structure-activity relationships, emphasizing recently identified CS compounds. According to their structural features, these MDR-targeting compounds were mainly classified into the following categories: flavonoids, terpenoids, stilbenes, alkaloids and quinones. The exploration of molecular mechanisms of collateral sensitivity and structural features of anticancer agents with collateral sensitivity provided an effective approach for the clinic treatment of MDR in cancer.}, keywords = {MOLECULAR MECHANISM; Structure-activity relationships; multidrug resistance; Anticancer; COLLATERAL SENSITIVITY}, year = {2021}, eissn = {1875-5607}, pages = {1465-1486}, orcid-numbers = {Cui, Jiahua/0000-0001-7164-6851} } @article{MTMT:32522070, title = {Potential role of the ABCG2-Q141K polymorphism in type 2 diabetes}, url = {https://m2.mtmt.hu/api/publication/32522070}, author = {Szabó, Edit Zsuzsanna and Kulin, Anna and Mózner, Orsolya and Korányi, László and Literáti-Nagy, Botond and Vitai, Márta and Cserepes, Judit and Sarkadi, Balázs and Várady, György}, doi = {10.1371/journal.pone.0260957}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {16}, unique-id = {32522070}, issn = {1932-6203}, year = {2021}, eissn = {1932-6203}, orcid-numbers = {Kulin, Anna/0000-0002-2877-5831; Mózner, Orsolya/0000-0001-5784-7702; Literáti-Nagy, Botond/0000-0002-1319-6474; Sarkadi, Balázs/0000-0003-0592-4539; Várady, György/0000-0003-2012-9680} } @article{MTMT:31906470, title = {Identification of two dysfunctional variants in the abcg2 urate transporter associated with pediatric-onset of familial hyperuricemia and early-onset gout}, url = {https://m2.mtmt.hu/api/publication/31906470}, author = {Toyoda, Y. and Pavelcová, K. and Bohatá, J. and Ješina, P. and Kubota, Y. and Suzuki, H. and Takada, T. and Stiburkova, B.}, doi = {10.3390/ijms22041935}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {22}, unique-id = {31906470}, issn = {1661-6596}, abstract = {The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K—a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type—has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 µmol/L for men or 360 µmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397–405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations—c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.}, keywords = {Roma; Precision Medicine; Genetic variations; serum uric acid; rare variant; urate transporter; ABCG2 genotype; Clinico-genetic analysis; Ethnic specificity; SUA-lowering therapy}, year = {2021}, eissn = {1422-0067} } @article{MTMT:31960380, title = {A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival}, url = {https://m2.mtmt.hu/api/publication/31960380}, author = {Wang, L. and Sun, C. and Li, X. and Mao, C. and Qian, J. and Wang, J. and Wu, J. and Li, Q. and Bai, C. and Han, B. and Gao, Z. and Xu, J. and Yin, J. and Liu, Z. and Lu, D. and Jin, L. and Wang, H.}, doi = {10.7150/JCA.51621}, journal-iso = {J CANCER}, journal = {JOURNAL OF CANCER}, volume = {12}, unique-id = {31960380}, issn = {1837-9664}, abstract = {Objective: The expression and function of platinum transporters affect drug tissue concentration and therapeutic effects. We had previously characterized functional variant of platinum intake transporter SLC31A1 gene. We aimed to investigate the association of platinum efflux transporter gene ABCG2 polymorphism and combined ABCG2 and SLC31A1 polymorphisms with clinical outcomes of NSCLC patients receiving platinum-based chemotherapy. Methods: We genotyped thirteen tagging and functional SNPs of ABCG2 in 1004 patients, and assessed their association with response, toxicity and survival using unconditional logistic regression and Cox proportional hazards regression analyses respectively. Results: Nonsynonymous rs2231142 (odds ratio [OR] 2.07; 95 % confidence interval [CI] 1.26-3.63), rs1871744 (OR 0.60; 95 % CI 0.42-0.87) and their haplotype and diplotype were associated with objective response. Rs4148157 was associated with shorter overall survival (Log-rank P = 0.002; hazard ratio [HR] 1.22; 95 % CI 1.05-1.42). Furthermore, the combined SLC31A1 rs2233914 and ABCG2 rs1871744 genotype was significantly associated with poor response (OR 0.31; 95 % CI 0.17-0.56; Pinteraction = 0.003). And the combined genotypes of the functional rs10759637 of SLC31A1 and the nonsynonymous rs2231142 (Log-rank P = 5.20×10-5; HR 1.47; 95 % CI 1.19-1.81; Pinteraction = 0.007) or linked rs4148157 of ABCG2 were significantly associated with poor survival. Conclusion: This study reveals divergent association of ABCG2 polymorphism with response and survival of NSCLC patients receiving platinum-based chemotherapy, demonstrates the combined effects of functional variants of ABCG2 and SLC31A1 on clinical outcomes, and highlights pharmacogenetic relevance of platinum transporter genes interaction. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.}, keywords = {ABCG2; SNP; Pharmacogenetics; NSCLC; platinum transporter; SLC31A1}, year = {2021}, eissn = {1837-9664}, pages = {1270-1283} }