TY - JOUR AU - Damiani, Daniela AU - Tiribelli, Mario TI - ATP-Binding Cassette Subfamily G Member 2 in Acute Myeloid Leukemia: A New Molecular Target? JF - BIOMEDICINES J2 - BIOMEDICINES VL - 12 PY - 2024 IS - 1 PG - 19 SN - 2227-9059 DO - 10.3390/biomedicines12010111 UR - https://m2.mtmt.hu/api/publication/34568631 ID - 34568631 N1 - This article belongs to the Special Issue Drug Resistance and Novel Targets for Cancer Therapy AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Duan, Hao AU - Lou, Chaofeng AU - Gu, Yaxin AU - Wang, Yimeng AU - Li, Weihua AU - Liu, Guixia AU - Tang, Yun TI - In Silico prediction of inhibitors for multiple transporters via machine learning methods JF - MOLECULAR INFORMATICS J2 - MOL INFORM PY - 2024 PG - 16 SN - 1868-1743 DO - 10.1002/minf.202300270 UR - https://m2.mtmt.hu/api/publication/34650501 ID - 34650501 LA - English DB - MTMT ER - TY - JOUR AU - Packer, M. TI - Hyperuricemia and Gout Reduction by SGLT2 Inhibitors in Diabetes and Heart Failure: JACC Review Topic of the Week JF - JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY J2 - J AM COLL CARDIOL VL - 83 PY - 2024 IS - 2 SP - 371 EP - 381 PG - 11 SN - 0735-1097 DO - 10.1016/j.jacc.2023.10.030 UR - https://m2.mtmt.hu/api/publication/34540271 ID - 34540271 N1 - Baylor Heart and Vascular Institute, Dallas, TX, United States Imperial College, London, United Kingdom Export Date: 29 January 2024 CODEN: JACCD Correspondence Address: Packer, M.; Baylor Heart and Vascular Institute, 621 North Hall Street, United States; email: milton.packer@baylorhealth.edu Chemicals/CAS: adenosine phosphate, 61-19-8, 8063-98-7; adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; glucose, 50-99-7, 84778-64-3, 8027-56-3; protein kinase, 9026-43-1; purine, 120-73-0; uric acid, 69-93-2; urate, 1198-77-2, 3106-08-9, 59216-10-3; Glucose; Sodium-Glucose Transporter 2 Inhibitors; Uric Acid AB - 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 LA - English DB - MTMT ER - TY - JOUR AU - Segura-Quezada, L.A. AU - Hernández-Velázquez, E.D. AU - Corrales-Escobosa, A.R. AU - de, León-Solis C. AU - Solorio-Alvarado, C.R. TI - Ningalins, Pyrrole-Bearing Metabolites Isolated from Didemnum spp. Synthesis and MDR-Reversion Activity in Cancer Therapy JF - CHEMISTRY & BIODIVERSITY J2 - CHEM BIODIVERS VL - 21 PY - 2024 IS - 1 SN - 1612-1872 DO - 10.1002/cbdv.202300883 UR - https://m2.mtmt.hu/api/publication/34540272 ID - 34540272 N1 - Universidad de Guanajuato, Departamento de Química, División de Ciencias Naturales y Exactas, Campus Guanajuato., Noria Alta S/N, Gto., Guanajuato, 36050, Mexico Instituto de Investigaciones Químicas, Biológicas, Biomédicas y Biofísicas., Universidad Mariano Gálvez, Guatemala, Guatemala Export Date: 29 January 2024 CODEN: CBHIA Correspondence Address: Solorio-Alvarado, C.R.; Universidad de Guanajuato, Noria Alta S/N, Gto., Mexico; email: csolorio@ugto.mx Correspondence Address: de León-Solis, C.; Instituto de Investigaciones Químicas, Guatemala; email: cdeleon@umg.edu.gt Funding details: Consejo Nacional de Ciencia y Tecnología, CONACYT, FORDECYT‐PRONACES/610286/2020 Funding details: Universidad de Guanajuato, UG Funding text 1: We are grateful to CONACyT (FORDECYT‐PRONACES/610286/2020) for financial support and for fellowships to L.A.S.Q and E.D.H.V. We acknowledge to the DCNE, the Chemistry Department, and the National Laboratory UG‐CONACyT (LACAPFEM) of the University of Guanajuato. We deeply thanks to Professor Euichi Hirose for allow the use of his pictures of morphotypes of . Didemnum molle Funding text 2: We are grateful to CONACyT (FORDECYT-PRONACES/610286/2020) for financial support and for fellowships to L.A.S.Q and E.D.H.V. We acknowledge to the DCNE, the Chemistry Department, and the National Laboratory UG-CONACyT (LACAPFEM) of the University of Guanajuato. We deeply thanks to Professor Euichi Hirose for allow the use of his pictures of morphotypes of Didemnum molle. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Damiani, Daniela AU - Tiribelli, Mario TI - ABCG2 in Acute Myeloid Leukemia: Old and New Perspectives JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 8 PG - 19 SN - 1661-6596 DO - 10.3390/ijms24087147 UR - https://m2.mtmt.hu/api/publication/33842699 ID - 33842699 N1 - Cited By :1 Export Date: 15 December 2023 Correspondence Address: Damiani, D.; Division of Hematology and Stem Cell Transplantation, P.le Santa Maria della Misericordia, 5, Italy; email: daniela.damiani@uniud.it AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Fu, Tingting AU - Zeng, Su AU - Zheng, Qingchuan AU - Zhu, Feng TI - The Important Role of Transporter Structures in Drug Disposition, Efficacy, and Toxicity JF - DRUG METABOLISM AND DISPOSITION J2 - DRUG METAB DISPOS VL - 51 PY - 2023 IS - 10 SP - 1316 EP - 1323 PG - 8 SN - 0090-9556 DO - 10.1124/dmd.123.001275 UR - https://m2.mtmt.hu/api/publication/34343675 ID - 34343675 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Kanoujia, Jovita AU - Das, Anjali AU - Raina, Neha AU - Kaur, Ginpreet AU - Singh, Sandeep K. AU - Tuli, Hardeep S. AU - Garg, Ashish AU - Gupta, Madhu TI - Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products JF - IUBMB LIFE J2 - IUBMB LIFE VL - n/a PY - 2023 IS - n/a SN - 1521-6543 DO - 10.1002/iub.2764 UR - https://m2.mtmt.hu/api/publication/34068112 ID - 34068112 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Liu, Jinfan AU - Fu, Lu AU - Yin, Fei AU - Yin, Li AU - Song, Xiaomei AU - Guo, Hong AU - Liu, Jianhui TI - Diosmetin Maintains Barrier Integrity by Reducing the Expression of ABCG2 in Colonic Epithelial Cells JF - JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY J2 - J AGR FOOD CHEM VL - 71 PY - 2023 IS - 23 SP - 8931 EP - 8940 PG - 10 SN - 0021-8561 DO - 10.1021/acs.jafc.3c00912 UR - https://m2.mtmt.hu/api/publication/34343676 ID - 34343676 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Mineiro, R. AU - Santos, C. AU - Gonçalves, I. AU - Lemos, M. AU - Cavaco, J.E.B. AU - Quintela, T. TI - Regulation of ABC transporters by sex steroids may explain differences in drug resistance between sexes JF - JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY J2 - J PHYSIOL BIOCHEM PY - 2023 SN - 1138-7548 DO - 10.1007/s13105-023-00957-1 UR - https://m2.mtmt.hu/api/publication/33773748 ID - 33773748 N1 - CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique. 6200-506, Covilhã, Portugal UDI-IPG-Unidade de Investigação Para o Desenvolvimento Do Interior, Instituto Politécnico da Guarda, Guarda, Portugal Export Date: 26 April 2023 CODEN: JPBIF Correspondence Address: Quintela, T.; CICS-UBI-Health Sciences Research Centre, Av. Infante D. Henrique. 6200-506, Portugal; email: tquintela@fcsaude.ubi.pt Funding text 1: Open access funding provided by FCT|FCCN (b-on). This work was developed within the scope of the CICS-UBI projects UIDB/00709/2020 and UIDP/00709/2020, financed by national funds through the Portuguese Foundation for Science and Technology/MCTES. AB - 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). LA - English DB - MTMT ER - TY - JOUR AU - Mózner, Orsolya AU - Zámbó, Boglárka AU - Bartos, Zsuzsa AU - Gergely, Anna AU - Szabó, Kata Sára AU - Jezsó, Bálint AU - Telbisz, Ágnes Mária AU - Várady, György AU - Homolya, László AU - Hegedűs, Tamás AU - Sarkadi, Balázs TI - Expression, Function and Trafficking of the Human ABCG2 Multidrug Transporter Containing Mutations in an Unstructured Cytoplasmic Loop JF - MEMBRANES (BASEL) J2 - MEMBRANES-BASEL VL - 13 PY - 2023 IS - 10 PG - 14 SN - 2077-0375 DO - 10.3390/membranes13100822 UR - https://m2.mtmt.hu/api/publication/34175360 ID - 34175360 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Nasyrova, R.F. AU - Shnayder, N.A. AU - Osipova, S.M. AU - Khasanova, A.K. AU - Efremov, I.S. AU - Al-Zamil, M. AU - Petrova, M.M. AU - Narodova, E.A. AU - Garganeeva, N.P. AU - Shipulin, G.A. TI - Genetic Predictors of Antipsychotic Efflux Impairment via Blood-Brain Barrier: Role of Transport Proteins JF - GENES J2 - GENES-BASEL VL - 14 PY - 2023 IS - 5 SN - 2073-4425 DO - 10.3390/genes14051085 UR - https://m2.mtmt.hu/api/publication/34059440 ID - 34059440 N1 - Institute of Personalized Psychiatry and Neurology, V.M. Bekhterev National Medical Research Centre for Psychiatry and Neurology, Saint-Petersburg, 192019, Russian Federation International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, Samara, 443016, Russian Federation Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, Krasnoyarsk, 660022, Russian Federation Department of Psychiatry, Russian Medical Academy for Continual Professional Education, Moscow, 125993, Russian Federation Department of Psychiatry and Addiction, Bashkir State Medical University, Ufa, 450008, Russian Federation Department of Physiotherapy, Faculty of Continuing Medical Education, Peoples’ Friendship University of Russia, Moscow, 117198, Russian Federation Department of General Medical Practice and Outpatient Therapy, Siberian State Medical University, Tomsk, 634050, Russian Federation Centre for Strategic Planning and Management of Biomedical Health Risks Management, Moscow, 119121, Russian Federation Export Date: 12 July 2023 Correspondence Address: Nasyrova, R.F.; Institute of Personalized Psychiatry and Neurology, Russian Federation; email: nreginaf77@gmail.com Correspondence Address: Shnayder, N.A.; Institute of Personalized Psychiatry and Neurology, Russian Federation; email: naschnaider@yandex.ru Chemicals/CAS: Antipsychotic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biomarkers; Multidrug Resistance-Associated Proteins; Neoplasm Proteins AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Nasyrova, R.F. AU - Vaiman, E.E. AU - Repkina, V.V. AU - Khasanova, A.K. AU - Asadullin, A.R. AU - Shipulin, G.A. AU - Altynbekov, K.S. AU - Al-Zamil, M. AU - Petrova, M.M. AU - Shnayder, N.A. TI - Single-Nucleotide Polymorphisms as Biomarkers of Antipsychotic-Induced Akathisia: Systematic Review JF - GENES J2 - GENES-BASEL VL - 14 PY - 2023 IS - 3 SN - 2073-4425 DO - 10.3390/genes14030616 UR - https://m2.mtmt.hu/api/publication/33773747 ID - 33773747 N1 - Institute of Personalized Psychiatry and Neurology, V.M. Bekhterev National Medical Research Center for Psychiatry and Neurology, Saint Petersburg, 192019, Russian Federation Department of Psychiatry, Russian Medical Academy for Continual Professional Education, Moscow, 125993, Russian Federation Department of Psychiatry and Addiction, Bashkir State Medical University, Ufa, 450008, Russian Federation Postgenome Technologies Center, Center for Strategic Planning of FMBA of Russia, Moscow, 119121, Russian Federation Republican Scientific and Practical Center of Mental Health, Almaty, 050022, Kazakhstan Department of Psychiatry and Narcology, S.D. Asfendiarov Kazakh National Medical University, Almaty, 050022, Kazakhstan Department of Physiotherapy, Peoples’ Friendship University of Russia, Moscow, 117198, Russian Federation Shared Core Facilities “Molecular and Cell Technologies”, V.F. Voino-Yasenetsky Krasnoyarsk State, Medical University, Krasnoyarsk, 660022, Russian Federation Export Date: 26 April 2023 Correspondence Address: Nasyrova, R.F.; Institute of Personalized Psychiatry and Neurology, V.M, Russian Federation; email: nreginaf77@gmail.com Correspondence Address: Shnayder, N.A.; Institute of Personalized Psychiatry and Neurology, Russian Federation; email: naschnaider@yandex.ru Chemicals/CAS: Antipsychotic Agents; Biomarkers AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Ohashi, Y. AU - Kuriyama, S. AU - Nakano, T. AU - Sekine, M. AU - Toyoda, Y. AU - Nakayama, A. AU - Takada, T. AU - Kawamura, Y. AU - Nakamura, T. AU - Matsuo, H. AU - Yokoo, T. AU - Ichida, K. TI - Urate Transporter ABCG2 Function and Asymptomatic Hyperuricemia: A Retrospective Cohort Study of CKD Progression JF - AMERICAN JOURNAL OF KIDNEY DISEASES J2 - AM J KIDNEY DIS VL - 81 PY - 2023 IS - 2 SP - 134 EP - 144e1 SN - 0272-6386 DO - 10.1053/j.ajkd.2022.05.010 UR - https://m2.mtmt.hu/api/publication/33250233 ID - 33250233 N1 - Department of Pathophysiology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan Jikei University School of Medicine, Tokyo, Japan Tokyo Regional Taxation Bureau Clinic, Tokyo, Japan Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama, Japan Third Division, Aeromedical Laboratory, Japan Air Self-Defense Force, Saitama, Japan Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Tokyo, Japan Laboratory for Mathematics, National Defense Medical College, Saitama, Japan Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Cited By :1 Export Date: 16 November 2022 CODEN: AJKDD Correspondence Address: Ichida, K.; Department of Pathophysiology, 1432-1 Horinouchi, Hachioji, Japan; email: ichida@toyaku.ac.jp Funding details: Japan Society for the Promotion of Science, KAKEN, 18K08224 Funding text 1: Yuki Ohashi, BPharm, Satoru Kuriyama, MD, PhD, Tomoko Nakano, MD, PhD, Mai Sekine, PhD, Yu Toyoda, PhD, Akiyoshi Nakayama, MD, PhD, Tappei Takada, PhD, Yusuke Kawamura, MD, Takahiro Nakamura, PhD, Hirotaka Matsuo, MD, PhD, Takashi Yokoo, MD, PhD, and Kimiyoshi Ichida, MD, PhD. Study design: YO, SK, TNakano, TT, HM, TY, KI; genetic analysis: YO, KI; sample analysis: SK, TNakano; statistical analysis: YO, TNakamura, KI; supervision/mentoring: SK, MS, AN, YT, TT, YK, HM, KI. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. This study was supported by grants from the Japan Society for the Promotion of Science including Grant-in-Aid for Scientific Research (C) (18K08224). The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication. The authors declare that they have no relevant financial interests. We express our gratitude to all of the participants involved in this study. We thank Tokyo Regional Taxation Bureau Clinic for the collection of samples from participants and their analysis. Received October 25, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor, an Associate Editor, and the Editor-in-Chief. Accepted in revised form May 8, 2022. Funding text 2: This study was supported by grants from the Japan Society for the Promotion of Science including Grant-in-Aid for Scientific Research (C) (18K08224). The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Paskas, S. AU - Stockmann, P. AU - Mijatović, S. AU - Kuhnert, L. AU - Honscha, W. AU - Hey-Hawkins, E. AU - Maksimović-Ivanić, D. TI - Carborane-Based ABCG2-Inhibitors Sensitize ABC-(Over)Expressing Cancer Cell Lines for Doxorubicin and Cisplatin JF - PHARMACEUTICALS J2 - PHARMACEUTICALS-BASE VL - 16 PY - 2023 IS - 11 SN - 1424-8247 DO - 10.3390/ph16111582 UR - https://m2.mtmt.hu/api/publication/34535346 ID - 34535346 N1 - Department of Immunology, Institute for Biological Research “Siniša Stanković”, National Institute of Republic of Serbia, Belgrade University, Belgrade, 11060, Serbia Institute of Inorganic Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Johannisallee 29, Leipzig, 04103, Germany Institute of Pharmacology, Pharmacy and Toxicology, Faculty of Veterinary Medicine, Universität Leipzig, An den Tierkliniken 15, Leipzig, 04103, Germany Export Date: 26 January 2024 Correspondence Address: Maksimović-Ivanić, D.; Department of Immunology, Serbia; email: nelamax@ibiss.bg.ac.rs Correspondence Address: Hey-Hawkins, E.; Institute of Inorganic Chemistry, Johannisallee 29, Germany; email: hey@uni-leipzig.de Chemicals/CAS: cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; doxorubicin, 23214-92-8, 25316-40-9; mitoxantrone, 65271-80-9, 70476-82-3 Tradenames: CyFlow Space, Partec, Germany; Nanodrop, Thermo, United States Manufacturers: NanoDrop; Partec, Germany; Thermo, United States Funding details: 451-03-47/2023-01/200007 Funding text 1: This project was funded by the Ministry of Science, Technological Development and Innovations, Republic of Serbia (451-03-47/2023-01/200007). Funding text 2: Financial support from the Graduate School Leipzig School of Natural Sciences—Building with Molecules and Nano-objects (BuildMoNa) is gratefully acknowledged. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Sałagacka-Kubiak, A. AU - Zawada, D. AU - Saed, L. AU - Kordek, R. AU - Jeleń, A. AU - Balcerczak, E. TI - ABCG2 Gene and ABCG2 Protein Expression in Colorectal Cancer—In Silico and Wet Analysis JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 13 SN - 1661-6596 DO - 10.3390/ijms241310539 UR - https://m2.mtmt.hu/api/publication/34091916 ID - 34091916 N1 - Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Medical University of Lodz, Lodz, 92-213, Poland Department of Pathology, Medical University of Lodz, Lodz, 92-213, Poland Export Date: 9 August 2023 Correspondence Address: Sałagacka-Kubiak, A.; Department of Pharmaceutical Biochemistry and Molecular Diagnostics, Poland; email: aleksandra.salagacka@umed.lodz.pl AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Tranova, Y.S. AU - Slepnev, A.A. AU - Chernykh, I.V. AU - Shchulkin, A.V. AU - Mylnikov, P.Yu. AU - Popova, N.M. AU - Povetko, M.I. AU - Yakusheva, E.N. TI - Method for Testing of Drugs Belonging to Substrates and Inhibitors of the Transporter Protein BCRP on Caco-2 Cells JF - RAZRABOTKA I REGISTRATSIYA LEKARSTVENNYKH SREDSTV J2 - RAZRABOTKA I REGISTRATSIYA LEKARSTVENNYKH SREDSTV VL - 12 PY - 2023 IS - 2 SP - 87 EP - 94 PG - 8 SN - 2305-2066 DO - 10.33380/2305-2066-2023-12-2-87-94 UR - https://m2.mtmt.hu/api/publication/34059441 ID - 34059441 N1 - Export Date: 12 July 2023 Correspondence Address: Chernykh, I.V.; Ryazan State Medical University named after academician I. P. Pavlov, 9, Vysokovoltnaya str, Russian Federation; email: Ivchernykh88@mail.ru AB - 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. LA - Russian DB - MTMT ER - TY - JOUR AU - Allegrini, Simone AU - Garcia-Gil, Mercedes AU - Pesi, Rossana AU - Camici, Marcella AU - Tozzi, Maria Grazia TI - The Good, the Bad and the New about Uric Acid in Cancer JF - CANCERS J2 - CANCERS VL - 14 PY - 2022 IS - 19 PG - 22 SN - 2072-6694 DO - 10.3390/cancers14194959 UR - https://m2.mtmt.hu/api/publication/33248278 ID - 33248278 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Feyzizadeh, M. AU - Barfar, A. AU - Nouri, Z. AU - Sarfraz, M. AU - Zakeri-Milani, P. AU - Valizadeh, H. TI - Overcoming multidrug resistance through targeting ABC transporters: lessons for drug discovery JF - EXPERT OPINION ON DRUG DISCOVERY J2 - EXPERT OPIN DRUG DIS VL - 17 PY - 2022 IS - 9 SP - 1013 EP - 1027 PG - 15 SN - 1746-0441 DO - 10.1080/17460441.2022.2112666 UR - https://m2.mtmt.hu/api/publication/33084731 ID - 33084731 N1 - Student Research Committee and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran College of Pharmacy, Al Ain University, Al Ain, United Arab Emirates Liver and Gastrointestinal Diseases Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran Drug Applied Research Center and Faculty of Pharmacy, Tabriz University of Medical Science, Tabriz, Iran Export Date: 8 September 2022 Correspondence Address: Valizadeh, H.; Faculty of Pharmacy, Iran; email: valizadeh@tbzmed.ac.ir AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Hegedűs, Tamás AU - Geisler, Markus AU - Lukács, Gergely László AU - Farkas, Bianka Vivien TI - Ins and outs of AlphaFold2 transmembrane protein structure predictions JF - CELLULAR AND MOLECULAR LIFE SCIENCES J2 - CELL MOL LIFE SCI VL - 79 PY - 2022 IS - 1 PG - 12 SN - 1420-682X DO - 10.1007/s00018-021-04112-1 UR - https://m2.mtmt.hu/api/publication/32612583 ID - 32612583 LA - English DB - MTMT ER - TY - JOUR AU - Malinowski, D. AU - Grzegółkowski, P. AU - Piotrowska, K. AU - Słojewski, M. AU - Droździk, M. TI - Membrane Transporters and Carriers in Human Seminal Vesicles JF - JOURNAL OF CLINICAL MEDICINE J2 - J CLIN MED VL - 11 PY - 2022 IS - 8 SN - 2077-0383 DO - 10.3390/jcm11082213 UR - https://m2.mtmt.hu/api/publication/32811162 ID - 32811162 N1 - Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University, Szczecin, 70-111, Poland Department of Urology, Pomeranian Medical University, Szczecin, 70-111, Poland Department of Physiology, Pomeranian Medical University, Szczecin, 70-111, Poland Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, Szczecin, 70-111, Poland Export Date: 9 May 2022 Correspondence Address: Droździk, M.; Department of Experimental and Clinical Pharmacology, Poland; email: drozdzik@pum.edu.pl AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Tordai, Hedvig AU - Suhajda, Erzébet AU - Sillitoe, Ian AU - Nair, Sreenath AU - Varadi, Mihaly AU - Hegedűs, Tamás TI - Comprehensive Collection and Prediction of ABC Transmembrane Protein Structures in the AI Era of Structural Biology JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 16 PG - 16 SN - 1661-6596 DO - 10.3390/ijms23168877 UR - https://m2.mtmt.hu/api/publication/33084278 ID - 33084278 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Zattoni, I.F. AU - Delabio, L.C. AU - Dutra, J.D.P. AU - Kita, D.H. AU - Scheiffer, G. AU - Hembecker, M. AU - Pereira, G.D.S. AU - Moure, V.R. AU - Valdameri, G. TI - Targeting breast cancer resistance protein (BCRP/ABCG2): Functional inhibitors and expression modulators JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 237 PY - 2022 SN - 0223-5234 DO - 10.1016/j.ejmech.2022.114346 UR - https://m2.mtmt.hu/api/publication/32920302 ID - 32920302 N1 - Export Date: 5 July 2022 CODEN: EJMCA Correspondence Address: Valdameri, G.; Pharmaceutical Sciences Graduation Program, PR, Brazil; email: gvaldameri@ufpr.br Chemicals/CAS: ABCG2 protein, human; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Neoplasm Proteins Funding details: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, CAPES Funding details: Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq, 400953/2016–1 Funding details: Fundação Araucária Funding text 1: This work was supported by CNPq (grant number 400953/2016–1) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil ( CAPES ) (Finance code 001). GV was supported by Fundação Araucária. AB - 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 LA - English DB - MTMT ER - TY - JOUR AU - Engdahl, E. AU - van, Schijndel M.D.M. AU - Voulgaris, D. AU - Di, Criscio M. AU - Ramsbottom, K.A. AU - Rigden, D.J. AU - Herland, A. AU - Rüegg, J. TI - Bisphenol a inhibits the transporter function of the blood-brain barrier by directly interacting with the abc transporter breast cancer resistance protein (Bcrp) JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 11 SN - 1661-6596 DO - 10.3390/ijms22115534 UR - https://m2.mtmt.hu/api/publication/32118446 ID - 32118446 N1 - Environmental Toxicology, Department of Organismal Biology, Uppsala University, Uppsala, 75236, Sweden Division of Micro and Nanosystems, Department of Intelligent Systems, KTH Royal Institute of Technology, Stockholm, 11428, Sweden AIMES, Department of Neuroscience, Karolinska Institute, Solna, 17177, Sweden Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 3BX, United Kingdom Computational Biology Facility, Technology Directorate, University of Liverpool, Liverpool, L69 3BX, United Kingdom Export Date: 30 July 2021 Correspondence Address: Engdahl, E.; Environmental Toxicology, Sweden; email: elin.engdahl@ebc.uu.se Chemicals/CAS: 4,4' isopropylidenediphenol, 80-05-7; piperazinedione, 29990-68-9; sulfone, 67015-63-8; 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; ABCG2 protein, human; ATP Binding Cassette Transporter, Subfamily G, Member 2; Benzhydryl Compounds; Benzimidazoles; bis(4-hydroxyphenyl)sulfone; bisbenzimide ethoxide trihydrochloride; bisphenol A; bisphenol F; Diketopiperazines; Heterocyclic Compounds, 4 or More Rings; Neoplasm Proteins; Phenols; Sulfones Funding details: 2017-00513 Funding text 1: Funding: This research was funded by the Swedish Research Council for Sustainable Development (Formas), grant number 2017-00513. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Hamdoun, A. AU - Hellmich, U.A. AU - Szakács, Gergely AU - Kuchler, K. TI - The incredible diversity of structures and functions of ABC transporters JF - FEBS LETTERS J2 - FEBS LETT VL - 595 PY - 2021 IS - 6 SP - 671 EP - 674 PG - 4 SN - 0014-5793 DO - 10.1002/1873-3468.14061 UR - https://m2.mtmt.hu/api/publication/31953886 ID - 31953886 N1 - Scripps Institution of Oceanography, UC San DiegoCA, United States Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-University Jena, Germany Institute of Enzymology, Research Centre of Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary Institute of Cancer Research, Medical University of Vienna, Austria Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, Austria Export Date: 7 April 2021 CODEN: FEBLA Correspondence Address: Hamdoun, A.; Scripps Institution of Oceanography, United States; email: ahamdoun@ucsd.edu Correspondence Address: Hellmich, U.A.; Institute of Organic Chemistry and Macromolecular Chemistry, Germany; email: ute.hellmich@uni-jena.de Correspondence Address: Szakacs, G.; Institute of Enzymology, Hungary; email: gergely-szakacs@meduniwien.ac.at Correspondence Address: Szakacs, G.; Institute of Cancer Research, Austria; email: gergely-szakacs@meduniwien.ac.at Scripps Institution of Oceanography, UC San DiegoCA, United States Institute of Organic Chemistry and Macromolecular Chemistry, Cluster of Excellence 'Balance of the Microverse', Friedrich-Schiller-University Jena, Germany Institute of Enzymology, Research Centre of Natural Sciences, Eötvös Loránd Research Network, Budapest, Hungary Institute of Cancer Research, Medical University of Vienna, Austria Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University Vienna, Austria Export Date: 13 August 2021 CODEN: FEBLA Correspondence Address: Hamdoun, A.; Scripps Institution of Oceanography, United States; email: ahamdoun@ucsd.edu Correspondence Address: Hellmich, U.A.; Institute of Organic Chemistry and Macromolecular Chemistry, Germany; email: ute.hellmich@uni-jena.de Correspondence Address: Szakacs, G.; Institute of Enzymology, Hungary; email: gergely-szakacs@meduniwien.ac.at Correspondence Address: Szakacs, G.; Institute of Cancer Research, Austria; email: gergely-szakacs@meduniwien.ac.at LA - English DB - MTMT ER - TY - JOUR AU - He, Y.-Z. AU - Wang, H. AU - Fang, J.-H. AU - Cao, Y.-H. AU - Hong, Z.-Y. AU - Chai, Y.-F. TI - Research progress on the traditional Chinese medicine-pharmaceutical drug interaction mediated by the ABC transporter family JF - ACTA PHARMACEUTICA SINICA J2 - ACTA PHARMACEUTICA SINICA VL - 56 PY - 2021 IS - 7 SP - 1778 EP - 1788 PG - 11 SN - 0513-4870 DO - 10.16438/j.0513-4870.2021-0605 UR - https://m2.mtmt.hu/api/publication/33084733 ID - 33084733 N1 - Export Date: 8 September 2022 Correspondence Address: Hong, Z.-Y.; School of Pharmacy, China; email: hongzhy001@163.com AB - 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. LA - Chinese DB - MTMT ER - TY - JOUR AU - Homolya, László TI - Medically important alterations in transport function and trafficking of abcg2 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 6 PG - 30 SN - 1661-6596 DO - 10.3390/ijms22062786 UR - https://m2.mtmt.hu/api/publication/31960289 ID - 31960289 N1 - Export Date: 12 April 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu Funding details: National Research, Development and Innovation Office, FIEK_16-1-2016-0005, OTKA_K 128123 Funding text 1: This work has been supported by National Research, Development and Innovation Office, Hungary (grant numbers: OTKA_K 128123 and FIEK_16-1-2016-0005). The author is grateful to ?gnes Enyedi, Bal?zs Sarkadi, and Tam?s Heged?s for their advices and help in revising the manuscript. The author also thanks Rita D?ra Homolya for her contribution to the graphical design. Funding Agency and Grant Number: National Research, Development and Innovation Office, Hungary [OTKA_K 128123, FIEK_16-1-2016-0005] Funding text: This work has been supported by National Research, Development and Innovation Office, Hungary (grant numbers: OTKA_K 128123 and FIEK_16-1-2016-0005). Export Date: 2 June 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu Cited By :2 Export Date: 25 August 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu Chemicals/CAS: ATP Binding Cassette Transporter, Subfamily G, Member 2 Funding details: National Research, Development and Innovation Office, FIEK_16-1-2016-0005, OTKA_K 128123 Funding text 1: This work has been supported by National Research, Development and Innovation Office, Hungary (grant numbers: OTKA_K 128123 and FIEK_16-1-2016-0005). The author is grateful to ?gnes Enyedi, Bal?zs Sarkadi, and Tam?s Heged?s for their advices and help in revising the manuscript. The author also thanks Rita D?ra Homolya for her contribution to the graphical design. Cited By :2 Export Date: 28 August 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu Cited By :2 Export Date: 8 September 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu Cited By :2 Export Date: 15 September 2021 Correspondence Address: Homolya, L.; Research Centre for Natural Sciences, Hungary; email: homolya.laszlo@ttk.hu AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Katzeff, Jared S AU - Kim, Woojin Scott TI - ATP-binding cassette transporters and neurodegenerative diseases JF - ESSAYS IN BIOCHEMISTRY J2 - ESSAYS BIOCHEM VL - 65 PY - 2021 IS - 7 SP - 1013 EP - 1024 PG - 12 SN - 0071-1365 DO - 10.1042/EBC20210012 UR - https://m2.mtmt.hu/api/publication/32613108 ID - 32613108 N1 - Cited By :7 Export Date: 15 December 2023 Correspondence Address: Kim, W.S.; University of Sydney, Australia; email: woojin.kim@sydney.edu.au LA - English DB - MTMT ER - TY - JOUR AU - Khunweeraphong, Narakorn AU - Kuchler, Karl TI - Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 9 PG - 31 SN - 1661-6596 DO - 10.3390/ijms22094806 UR - https://m2.mtmt.hu/api/publication/32058564 ID - 32058564 N1 - Cited By :4 Export Date: 11 February 2022 Correspondence Address: Kuchler, K.; Center for Medical Biochemistry, Dr. Bohr-Gasse 9/2, Austria; email: karl.kuchler@meduniwien.ac.at Chemicals/CAS: ABC transporter subfamily B, 149200-37-3, 208997-77-7; Antifungal Agents; Antineoplastic Agents; ATP-Binding Cassette Transporters; Fungal Proteins; Nucleocytoplasmic Transport Proteins LA - English DB - MTMT ER - TY - JOUR AU - Lei, X. AU - He, Q. AU - Li, Z. AU - Zou, Q. AU - Xu, P. AU - Yu, H. AU - Ding, Y. AU - Zhu, W. TI - Cancer stem cells in colorectal cancer and the association with chemotherapy resistance JF - MEDICAL ONCOLOGY J2 - MED ONCOL VL - 38 PY - 2021 IS - 4 SN - 1357-0560 DO - 10.1007/s12032-021-01488-9 UR - https://m2.mtmt.hu/api/publication/31960379 ID - 31960379 N1 - Department of Pathology, Guangdong Medical University, No.1 Xincheng Road, Dongguan, Guangdong Province 523808, China School of Public Health, Guangdong Medical University, Dongguan, Guangdong Province 523808, China Export Date: 12 April 2021 CODEN: MONCE Correspondence Address: Zhu, W.; Department of Pathology, No.1 Xincheng Road, China; email: zhuwei@gdmu.edu.cn Funding details: National Natural Science Foundation of China, NSFC, NNSF, NNSFC, 81472275 Funding details: Natural Science Foundation of Guangdong Province, 2014A030313542, 2020A151501303 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Markowicz-Piasecka, M. AU - Huttunen, J. AU - Montaser, A. AU - Adla, S.K. AU - Auriola, S. AU - Lehtonen, M. AU - Huttunen, K.M. TI - Ganciclovir and its hemocompatible more lipophilic derivative can enhance the apoptotic effects of methotrexate by inhibiting breast cancer resistance protein (Bcrp) JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 14 SN - 1661-6596 DO - 10.3390/ijms22147727 UR - https://m2.mtmt.hu/api/publication/32118445 ID - 32118445 N1 - Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, Lodz, 90-151, Poland School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, Kuopio, FI-70211, Finland Institute of Organic Chemistry and Biochemistry (IOCB), Czech Academy of Sciences, Flemingovo Namesti 542/2, Prague, 160 00, Czech Republic Export Date: 30 July 2021 Correspondence Address: Huttunen, K.M.; School of Pharmacy, P.O. Box 1627, Finland; email: kristiina.huttunen@uef.fi Funding details: Academy of Finland, 294227, 294229, 307057, 311939 Funding details: European Social Fund, ESF, CZ.02.2.69/0.0/0.0/20_079/ 0017783 Funding details: Uniwersytet Medyczny w Lodzi, UMED, 503/3-015-01/503-31-001-19-00 Funding details: Biocenter Finland, BF Funding text 1: The study was financially supported by the Academy of Finland [grant numbers 294227, 294229, 307057, 311939], Medical University of Lodz (grant number 503/3-015-01/503-31-001-19-00), and European Social Fund, OP RDE (Project IOCB MSCA Mobility IV, No. CZ.02.2.69/0.0/0.0/20_079/ 0017783. We also appreciate Biocenter Finland and Biocenter Kuopio for supporting LC-MS laboratory facilities.The authors would like to thank Joanna Sikora for her valuable assistance in biological material collection. AB - 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/). LA - English DB - MTMT ER - TY - JOUR AU - Qian, Jiajun AU - Cui, Jiahua AU - Li, Shaoshun AU - Chen, Jun AU - Jia, Jinping TI - Anticancer Natural Products with Collateral Sensitivity: A Review JF - MINI-REVIEWS IN MEDICINAL CHEMISTRY J2 - MINI REV MED CHEM VL - 21 PY - 2021 IS - 12 SP - 1465 EP - 1486 PG - 22 SN - 1389-5575 DO - 10.2174/1389557521666210112141455 UR - https://m2.mtmt.hu/api/publication/32281343 ID - 32281343 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Szabó, Edit Zsuzsanna AU - Kulin, Anna AU - Mózner, Orsolya AU - Korányi, László AU - Literáti-Nagy, Botond AU - Vitai, Márta AU - Cserepes, Judit AU - Sarkadi, Balázs AU - Várady, György TI - Potential role of the ABCG2-Q141K polymorphism in type 2 diabetes JF - PLOS ONE J2 - PLOS ONE VL - 16 PY - 2021 IS - 12 PG - 9 SN - 1932-6203 DO - 10.1371/journal.pone.0260957 UR - https://m2.mtmt.hu/api/publication/32522070 ID - 32522070 N1 - Institute of Enzymology, ELKH Research Centre for Natural Sciences, Center of Excellence by Hungarian Academy of Sciences, Budapest, Hungary Doctoral School of Molecular Medicine, Semmelweis University, Budapest, Hungary Drug Research Center, Balatonfüred, Hungary Research Institute of Biomolecular and Chemical Engineering, University of Pannonia, Veszprém, Hungary CellPharma Kft, Budapest, Hungary Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary Cited By :4 Export Date: 12 January 2024 CODEN: POLNC Correspondence Address: Szabó, E.; Institute of Enzymology, Hungary; email: szabo.edit@ttk.hu Correspondence Address: Várady, G.; Institute of Enzymology, Hungary; email: varady.gyorgy@ttk.hu LA - English DB - MTMT ER - TY - JOUR AU - Toyoda, Y. AU - Pavelcová, K. AU - Bohatá, J. AU - Ješina, P. AU - Kubota, Y. AU - Suzuki, H. AU - Takada, T. AU - Stiburkova, B. TI - Identification of two dysfunctional variants in the abcg2 urate transporter associated with pediatric-onset of familial hyperuricemia and early-onset gout JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 4 PG - 14 SN - 1661-6596 DO - 10.3390/ijms22041935 UR - https://m2.mtmt.hu/api/publication/31906470 ID - 31906470 N1 - Department of Pharmacy, The University of Tokyo Hospital, Tokyo, 113-8655, Japan Institute of Rheumatology, Prague, 128 00, Czech Republic Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, 121 08, Czech Republic Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, 121 00, Czech Republic Export Date: 9 March 2021 Correspondence Address: Stiburkova, B.; Institute of RheumatologyCzech Republic; email: stiburkova@revma.cz Correspondence Address: Stiburkova, B.; Department of Pediatrics and Inherited Metabolic Disorders, Czech Republic; email: stiburkova@revma.cz Funding details: Suzuken Memorial Foundation Funding details: Takeda Science Foundation Funding details: Japan Society for the Promotion of Science, KAKEN, 16H01808, 18KK0247, 19K16441, 20H00568 Funding details: Ministerstvo Zdravotnictví Ceské Republiky, MZCR, BBMRI-CZ LM2018125, RVO 00023728, RVO VFN64165 Funding details: Mochida Memorial Foundation for Medical and Pharmaceutical Research Funding text 1: Funding: The study was supported by the JSPS KAKENHI Grant, numbers 19K16441 (to Y.T.); 16H01808, 18KK0247, and 20H00568 (to T.T.). The study was also supported by grants from the Czech Republic Ministry of Health RVO 00023728 (Institute of Rheumatology), RVO VFN64165, and BBMRI-CZ LM2018125 (to B.S.); T.T. received research grants from “Gout and uric acid foundation of Japan”; “Takeda Science Foundation”; “Suzuken Memorial Foundation”; “Mochida Memorial Foundation for Medical and Pharmaceutical Research”; “The Pharmacological Research Foundation, Tokyo.” Institutional Review Board Statement: The studied proband and her family members were Czechs of Roma ethnicity diagnosed with familial (early-onset) hyperuricemia/gout. Written informed consent was obtained from each subject before enrollment in the study. All tests were performed in accordance with standards set by the institutional ethics committees, which approved the project (no. 6181/2015). All the procedures were performed in accordance with the Declaration of Helsinki. Department of Pharmacy, The University of Tokyo Hospital, Tokyo, 113-8655, Japan Institute of Rheumatology, Prague, 128 00, Czech Republic Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, 121 08, Czech Republic Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, 121 00, Czech Republic Export Date: 12 April 2021 Correspondence Address: Stiburkova, B.; Institute of RheumatologyCzech Republic; email: stiburkova@revma.cz Correspondence Address: Stiburkova, B.; Department of Pediatrics and Inherited Metabolic Disorders, Czech Republic; email: stiburkova@revma.cz Funding details: Suzuken Memorial Foundation Funding details: Takeda Science Foundation Funding details: Japan Society for the Promotion of Science, KAKEN, 16H01808, 18KK0247, 19K16441, 20H00568 Funding details: Ministerstvo Zdravotnictví Ceské Republiky, MZCR, BBMRI-CZ LM2018125, RVO 00023728, RVO VFN64165 Funding details: Mochida Memorial Foundation for Medical and Pharmaceutical Research Funding text 1: Funding: The study was supported by the JSPS KAKENHI Grant, numbers 19K16441 (to Y.T.); 16H01808, 18KK0247, and 20H00568 (to T.T.). The study was also supported by grants from the Czech Republic Ministry of Health RVO 00023728 (Institute of Rheumatology), RVO VFN64165, and BBMRI-CZ LM2018125 (to B.S.); T.T. received research grants from “Gout and uric acid foundation of Japan”; “Takeda Science Foundation”; “Suzuken Memorial Foundation”; “Mochida Memorial Foundation for Medical and Pharmaceutical Research”; “The Pharmacological Research Foundation, Tokyo.” Institutional Review Board Statement: The studied proband and her family members were Czechs of Roma ethnicity diagnosed with familial (early-onset) hyperuricemia/gout. Written informed consent was obtained from each subject before enrollment in the study. All tests were performed in accordance with standards set by the institutional ethics committees, which approved the project (no. 6181/2015). All the procedures were performed in accordance with the Declaration of Helsinki. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Wang, L. AU - Sun, C. AU - Li, X. AU - Mao, C. AU - Qian, J. AU - Wang, J. AU - Wu, J. AU - Li, Q. AU - Bai, C. AU - Han, B. AU - Gao, Z. AU - Xu, J. AU - Yin, J. AU - Liu, Z. AU - Lu, D. AU - Jin, L. AU - Wang, H. TI - A pharmacogenetics study of platinum-based chemotherapy in lung cancer: ABCG2 polymorphism and its genetic interaction with SLC31A1 are associated with response and survival JF - JOURNAL OF CANCER J2 - J CANCER VL - 12 PY - 2021 IS - 5 SP - 1270 EP - 1283 PG - 14 SN - 1837-9664 DO - 10.7150/JCA.51621 UR - https://m2.mtmt.hu/api/publication/31960380 ID - 31960380 N1 - Center for Medical Research and Innovation, Shanghai Pudong Hospital, Pudong Medical Center, Shanghai Medical College, Fudan University, Shanghai, China Ministry of Education Key Laboratory of Contemporary Anthropology, Department of Anthropology and Human Genetics, School of Life Sciences, Fudan University, Shanghai, China Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China Department of Pneumology, Chest Hospital, Shanghai Jiao Tong University, Shanghai, China Department of Cardiothoracic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai, China Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenomics, Institute of Clinical Pharmacology, Central South University, Changsha, China Export Date: 12 April 2021 Correspondence Address: Wang, H.; Shanghai Pudong Hospital, China; email: haijianwang@fudan.edu.cn Funding details: 11PJD005 Funding details: National Natural Science Foundation of China, NSFC, 81172093, 81372236, 81372526, 81572404 Funding details: National Key Research and Development Program of China, NKRDPC, 2016YFC0901903, 2016YFC0905000, 2018-YFC0910700 Funding details: International Science and Technology Cooperation Programme, ISTCP, 2015DFE32790 Funding text 1: We thank all the enrolled patients who made this study possible, and acknowledge greatly the collaboration from the participating hospitals and staff. This work was supported by the National Key Research Development Programs of China (2018-YFC0910700, 2016YFC0901903, 2016YFC0905000), the International S&T Cooperation Program of China (2015DFE32790), National Natural Science Foundation of China (81172093, 81372526, 81572404, 81372236) and Shanghai Pujiang Program (11PJD005). AB - 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. LA - English DB - MTMT ER -