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Kurz KS, Steinlein S, Kreuz M, Ziepert M, Staiger AM, Barth TFE, Möller P, Bernd H, Feller AC, Richter J, Klapper W, Stein H, Hartmann S, Hansmann M, Trümper L, Loeffler M, Schmitz N, Rosenwald A, Ott G, Horn H. Age- and gender-specific molecular characteristics of diffuse large B-cell lymphoma: Results from clinical trials of the DSHNHL/GLA. Hemasphere 2025; 9:e70093. [PMID: 40060117 PMCID: PMC11888124 DOI: 10.1002/hem3.70093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 12/11/2024] [Accepted: 01/06/2025] [Indexed: 03/27/2025] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. Despite a high cure rate, too many patients show refractory (ref) or relapsed (rel) disease. This study examines the frequency of recurring gene mutations and their interplay with well-known biomarkers in female and male patients between 18 and 80 years with ref/rel DLBCL compared to patients with complete remission (CR) to identify biological risk factors associated with treatment response, using cohorts of R-CHOP-like treated DLBCL enrolled in clinical trials of the DSHNHL. The biomarker profile of patients differed between younger and elderly patients with ref/rel DLBCL, with a higher frequency of BCL2 translocations in younger patients, and higher numbers of ABC subtypes and MYC protein expression in the elderly. Amplicon sequencing revealed generally higher mutation frequencies in the younger cohort. Mutations in CREBBP and TNFRSF14 were associated with shorter overall survival (OS) only in younger patients. A higher proportion of GNA13 mutations was detected in female patients of the elderly DLBCL patient cohort, clearly emphasizing the striking differences in biomarker distribution between younger and elderly as well as female and male patients.
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Affiliation(s)
- Katrin S. Kurz
- Department of Clinical PathologyRobert‐Bosch‐KrankenhausStuttgartGermany
| | - Sophia Steinlein
- Dr. Margarete Fischer‐Bosch‐Institute of Clinical PharmacologyStuttgart and University of TübingenTübingenGermany
| | - Markus Kreuz
- Institute for Medical Informatics, Statistics, and EpidemiologyUniversität LeipzigLeipzigGermany
- Department of DiagnosticsFraunhofer Institute for Cell Therapy and ImmunologyLeipzigGermany
| | - Marita Ziepert
- Institute for Medical Informatics, Statistics, and EpidemiologyUniversität LeipzigLeipzigGermany
| | - Annette M. Staiger
- Department of Clinical PathologyRobert‐Bosch‐KrankenhausStuttgartGermany
- Dr. Margarete Fischer‐Bosch‐Institute of Clinical PharmacologyStuttgart and University of TübingenTübingenGermany
| | | | - Peter Möller
- Institute of PathologyUniversitätsklinikum UlmUlmGermany
| | | | | | - Julia Richter
- Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig‐Holstein, Campus KielKielGermany
| | - Wolfram Klapper
- Institute of Pathology, Hematopathology Section and Lymph Node Registry, Universitätsklinikum Schleswig‐Holstein, Campus KielKielGermany
| | | | - Sylvia Hartmann
- Institute of Pathology, Universitätsklinikum FrankfurtFrankfurtGermany
| | | | - Lorenz Trümper
- Department of Hematology and OncologyGeorg‐August UniversitätGöttingenGermany
| | - Markus Loeffler
- Institute for Medical Informatics, Statistics, and EpidemiologyUniversität LeipzigLeipzigGermany
| | - Norbert Schmitz
- Department of Medicine AUniversity Hospital MünsterMünsterGermany
| | | | - German Ott
- Department of Clinical PathologyRobert‐Bosch‐KrankenhausStuttgartGermany
| | - Heike Horn
- Department of Clinical PathologyRobert‐Bosch‐KrankenhausStuttgartGermany
- Dr. Margarete Fischer‐Bosch‐Institute of Clinical PharmacologyStuttgart and University of TübingenTübingenGermany
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2
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Hoste E, Deldicque L, Muccioli GG, Panin N, Terrasi R, Paquot A, Lingurski M, Pyr Dit Ruys S, Haufroid V, Elens L. Silencing drug transporters in human primary muscle cells modulates atorvastatin pharmacokinetics: A pilot study. Br J Pharmacol 2025. [PMID: 39909477 DOI: 10.1111/bph.17449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 10/21/2024] [Accepted: 12/08/2024] [Indexed: 02/07/2025] Open
Abstract
BACKGROUND AND PURPOSE Non-adherence to atorvastatin treatment is relatively common and partly due to statin-related myotoxicities (SRMs). The risk of developing SRM is dose- and concentration-dependent, highlighting the importance of atorvastatin pharmacokinetics. This study explored the inter-individual variabilities in expression of the atorvastatin transporter gene contributing to modulation of atorvastatin within the muscle cell. EXPERIMENTAL APPROACH mRNA levels of efflux and influx transporters were measured and modulated with siRNAs to evaluate effects on intracellular accumulation of atorvastatin in primary cultures of differentiated myotubes from 12 human volunteers. KEY RESULTS All genes assessed were expressed with a high inter-individual variability. In differentiated myotubes, efflux transporters were expressed at higher levels than the influx carriers. When considering efflux and influx transporters separately, ABCC1 and SLCO2B1 are the most highly expressed efflux and influx transporters. Suppression of ABCC1, ABCC4 and/or ABCG2 mRNA levels with siRNA significantly increased intracellular accumulation of atorvastatin in differentiated myotubes. Interestingly, the siRNA targeting ABCG2 had a moderate effect on intracellular accumulation of atorvastatin in a volunteer expressing the ABCG2 variant rs2231142 (c.421C>A, p.Gln141Lys). This hypothesis was further validated in a HEK recombinant model overexpressing ABCG2 either wild-type (421C) or variant (421A). Reduction of SLCO1B1 and SLCO2B1 mRNA levels significantly modified intracellular accumulation of atorvastatin in only some volunteers, depending on the expression levels of transporters. CONCLUSION AND IMPLICATIONS Silencing ABCC1, ABCC4 or ABCG2 expression alters accumulation of atorvastatin in myotubes, whereas the effect of silencing influx transporters depends on the expression of these transporters.
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Affiliation(s)
- Emilia Hoste
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Louvain Centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Louise Deldicque
- Institute of Neuroscience (IoNS), Université catholique de Louvain (UCLouvain), Louvain-la-Neuve, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Nadtha Panin
- Louvain Centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Romano Terrasi
- Bioanalysis and Pharmacology of Bioactive Lipids, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Adrien Paquot
- Bioanalysis and Pharmacology of Bioactive Lipids, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Maxime Lingurski
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Sébastien Pyr Dit Ruys
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Vincent Haufroid
- Louvain Centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Department of Clinical Chemistry, Cliniques universitaires Saint-Luc, Brussels, Belgium
| | - Laure Elens
- Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
- Louvain Centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
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3
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Pan Y, Wu M, Cai H. Role of ABCC5 in cancer drug resistance and its potential as a therapeutic target. Front Cell Dev Biol 2024; 12:1446418. [PMID: 39563862 PMCID: PMC11573773 DOI: 10.3389/fcell.2024.1446418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 10/22/2024] [Indexed: 11/21/2024] Open
Abstract
Over 90% of treatment failures in cancer therapy can be attributed to multidrug resistance (MDR), which can develop intracellularly or through various routes. Numerous pathways contribute to treatment resistance in cancer, but one of the most significant pathways is intracellular drug efflux and reduced drug concentrations within cells, which are controlled by overexpressed drug efflux pumps. As a member of the family of ABC transporter proteins, ABCC5 (ATP Binding Cassette Subfamily C Member 5) reduces the intracellular concentration of a drug and its subsequent effectiveness using an ATP-dependent method to pump the drug out of the cell. Numerous studies have demonstrated that ABCC5 is strongly linked to both poor prognosis and poor treatment response. In addition, elevated ABCC5 expression is noted in a wide variety of malignancies. Given that ABCC5 is regulated by several pathways in a broad range of cancer types, it is a prospective target for cancer treatment. This review examined the expression, structure, function, and role of ABCC5 in various cancer types.
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Affiliation(s)
- Yinlong Pan
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Mengmeng Wu
- Department of Anesthesiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Huazhong Cai
- Department of Emergency, Affiliated Hospital of Jiangsu University, Zhenjiang, China
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4
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Bhattacharjya D, Sivalingam N. Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8445-8475. [PMID: 38878089 DOI: 10.1007/s00210-024-03189-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 05/27/2024] [Indexed: 10/30/2024]
Abstract
Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.
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Affiliation(s)
- Dorothy Bhattacharjya
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India.
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5
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Roghani AK, Garcia RI, Roghani A, Reddy A, Khemka S, Reddy RP, Pattoor V, Jacob M, Reddy PH, Sehar U. Treating Alzheimer's disease using nanoparticle-mediated drug delivery strategies/systems. Ageing Res Rev 2024; 97:102291. [PMID: 38614367 DOI: 10.1016/j.arr.2024.102291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 03/18/2024] [Accepted: 04/01/2024] [Indexed: 04/15/2024]
Abstract
The administration of promising medications for the treatment of neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) is significantly hampered by the blood-brain barrier (BBB). Nanotechnology has recently come to light as a viable strategy for overcoming this obstacle and improving drug delivery to the brain. With a focus on current developments and prospects, this review article examines the use of nanoparticles to overcome the BBB constraints to improve drug therapy for AD The potential for several nanoparticle-based approaches, such as those utilizing lipid-based, polymeric, and inorganic nanoparticles, to enhance drug transport across the BBB are highlighted. To shed insight on their involvement in aiding effective drug transport to the brain, methods of nanoparticle-mediated drug delivery, such as surface modifications, functionalization, and particular targeting ligands, are also investigated. The article also discusses the most recent findings on innovative medication formulations encapsulated within nanoparticles and the therapeutic effects they have shown in both preclinical and clinical testing. This sector has difficulties and restrictions, such as the need for increased safety, scalability, and translation to clinical applications. However, the major emphasis of this review aims to provide insight and contribute to the knowledge of how nanotechnology can potentially revolutionize the worldwide treatment of NDDs, particularly AD, to enhance clinical outcomes.
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Affiliation(s)
- Aryan Kia Roghani
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Frenship High School, Lubbock, TX 79382, USA.
| | - Ricardo Isaiah Garcia
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ali Roghani
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Aananya Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA.
| | - Sachi Khemka
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ruhananhad P Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA.
| | - Vasanthkumar Pattoor
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; University of South Florida, Tampa, FL 33620, USA.
| | - Michael Jacob
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA.
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Speech, Language and Hearing Services, School Health Professions, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
| | - Ujala Sehar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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6
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To KKW, Huang Z, Zhang H, Ashby CR, Fu L. Utilizing non-coding RNA-mediated regulation of ATP binding cassette (ABC) transporters to overcome multidrug resistance to cancer chemotherapy. Drug Resist Updat 2024; 73:101058. [PMID: 38277757 DOI: 10.1016/j.drup.2024.101058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 12/27/2023] [Accepted: 01/16/2024] [Indexed: 01/28/2024]
Abstract
Multidrug resistance (MDR) is one of the primary factors that produces treatment failure in patients receiving cancer chemotherapy. MDR is a complex multifactorial phenomenon, characterized by a decrease or abrogation of the efficacy of a wide spectrum of anticancer drugs that are structurally and mechanistically distinct. The overexpression of the ATP-binding cassette (ABC) transporters, notably ABCG2 and ABCB1, are one of the primary mediators of MDR in cancer cells, which promotes the efflux of certain chemotherapeutic drugs from cancer cells, thereby decreasing or abolishing their therapeutic efficacy. A number of studies have suggested that non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), play a pivotal role in mediating the upregulation of ABC transporters in certain MDR cancer cells. This review will provide updated information about the induction of ABC transporters due to the aberrant regulation of ncRNAs in cancer cells. We will also discuss the measurement and biological profile of circulating ncRNAs in various body fluids as potential biomarkers for predicting the response of cancer patients to chemotherapy. Sequence variations, such as alternative polyadenylation of mRNA and single nucleotide polymorphism (SNPs) at miRNA target sites, which may indicate the interaction of miRNA-mediated gene regulation with genetic variations to modulate the MDR phenotype, will be reviewed. Finally, we will highlight novel strategies that could be used to modulate ncRNAs and circumvent ABC transporter-mediated MDR.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
| | - Zoufang Huang
- Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou 341000, China
| | - Hang Zhang
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Charles R Ashby
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, United States
| | - Liwu Fu
- State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine; Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
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7
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Fan W, Shao K, Luo M. Structural View of Cryo-Electron Microscopy-Determined ATP-Binding Cassette Transporters in Human Multidrug Resistance. Biomolecules 2024; 14:231. [PMID: 38397468 PMCID: PMC10886794 DOI: 10.3390/biom14020231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 02/01/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
ATP-binding cassette (ABC) transporters, acting as cellular "pumps," facilitate solute translocation through membranes via ATP hydrolysis. Their overexpression is closely tied to multidrug resistance (MDR), a major obstacle in chemotherapy and neurological disorder treatment, hampering drug accumulation and delivery. Extensive research has delved into the intricate interplay between ABC transporter structure, function, and potential inhibition for MDR reversal. Cryo-electron microscopy has been instrumental in unveiling structural details of various MDR-causing ABC transporters, encompassing ABCB1, ABCC1, and ABCG2, as well as the recently revealed ABCC3 and ABCC4 structures. The newly obtained structural insight has deepened our understanding of substrate and drug binding, translocation mechanisms, and inhibitor interactions. Given the growing body of structural information available for human MDR transporters and their associated mechanisms, we believe it is timely to compile a comprehensive review of these transporters and compare their functional mechanisms in the context of multidrug resistance. Therefore, this review primarily focuses on the structural aspects of clinically significant human ABC transporters linked to MDR, with the aim of providing valuable insights to enhance the effectiveness of MDR reversal strategies in clinical therapies.
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Affiliation(s)
| | | | - Min Luo
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117543, Singapore; (W.F.); (K.S.)
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8
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Baron G, Altomare A, Della Vedova L, Gado F, Quagliano O, Casati S, Tosi N, Bresciani L, Del Rio D, Roda G, D'Amato A, Lammi C, Macorano A, Vittorio S, Vistoli G, Fumagalli L, Carini M, Leone A, Marino M, Del Bo' C, Miotto G, Ursini F, Morazzoni P, Aldini G. Unraveling the parahormetic mechanism underlying the health-protecting effects of grapeseed procyanidins. Redox Biol 2024; 69:102981. [PMID: 38104483 PMCID: PMC10770607 DOI: 10.1016/j.redox.2023.102981] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 12/19/2023] Open
Abstract
Proanthocyanidins (PACs), the predominant constituents within Grape Seed Extract (GSE), are intricate compounds composed of interconnected flavan-3-ol units. Renowned for their health-affirming properties, PACs offer a shield against a spectrum of inflammation associated diseases, such as diabetes, obesity, degenerations and possibly cancer. While monomeric and dimeric PACs undergo some absorption within the gastrointestinal tract, their larger oligomeric and polymeric counterparts are not bioavailable. However, higher molecular weight PACs engage with the colonic microbiota, fostering the production of bioavailable metabolites that undergo metabolic processes, culminating in the emergence of bioactive agents capable of modulating physiological processes. Within this investigation, a GSE enriched with polymeric PACs was employed to explore in detail their impact. Through comprehensive analysis, the present study unequivocally verified the gastrointestinal-mediated transformation of medium to high molecular weight polymeric PACs, thereby establishing the bioaccessibility of a principal catabolite termed 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (VL). Notably, our findings, encompassing cell biology, chemistry and proteomics, converge to the proposal of the notion of the capacity of VL to activate, upon oxidation to the corresponding quinone, the nuclear factor E2-related factor 2 (Nrf2) pathway-an intricate process that incites cellular defenses and mitigates stress-induced responses, such as a challenge brought by TNFα. This mechanistic paradigm seamlessly aligns with the concept of para-hormesis, ultimately orchestrating the resilience to stress and the preservation of cellular redox equilibrium and homeostasis as benchmarks of health.
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Affiliation(s)
- G Baron
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - A Altomare
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - L Della Vedova
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - F Gado
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - O Quagliano
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - S Casati
- Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Via Luigi Mangiagalli 37, 20133, Milan, Italy
| | - N Tosi
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Via Volturno 39, 43125, Parma, Italy
| | - L Bresciani
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Via Volturno 39, 43125, Parma, Italy
| | - D Del Rio
- Human Nutrition Unit, Department of Food & Drug, University of Parma, Via Volturno 39, 43125, Parma, Italy
| | - G Roda
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - A D'Amato
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - C Lammi
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - A Macorano
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - S Vittorio
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - G Vistoli
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - L Fumagalli
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - M Carini
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy
| | - A Leone
- International Center for the Assessment of Nutritional Status and the Development of Dietary Intervention Strategies (ICANS-DIS), Via Sandro Botticelli 21, 20133, Milan, Italy; Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Human Nutrition, Università degli Studi di Milano, Via Luigi Mangiagalli 25, 20133, Milan, Italy
| | - M Marino
- Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Human Nutrition, Università degli Studi di Milano, Via Luigi Mangiagalli 25, 20133, Milan, Italy
| | - C Del Bo'
- Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Human Nutrition, Università degli Studi di Milano, Via Luigi Mangiagalli 25, 20133, Milan, Italy
| | - G Miotto
- Department of Molecular Medicine, Viale G. Colombo, 3, University of Padova, 35121, Padova, Italy
| | - F Ursini
- Department of Molecular Medicine, Viale G. Colombo, 3, University of Padova, 35121, Padova, Italy
| | - P Morazzoni
- Divisione Nutraceutica, Distillerie Umberto Bonollo S.p.A, 35035, Mestrino, Italy
| | - G Aldini
- Department of Pharmaceutical Sciences (DISFARM), Università degli Studi di Milano, Via Mangiagalli 25, 20133, Milan, Italy.
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Chen Y, Zhang B, Zhong C, Zhou Y, Xue L, Luo C, Yi L, Gong Q, Long Y. let-7g sensitized liver cancer cells to 5-fluorouracil by downregulating ABCC10 expression. Chem Biol Drug Des 2024; 103:e14396. [PMID: 38054583 DOI: 10.1111/cbdd.14396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/08/2023] [Accepted: 11/05/2023] [Indexed: 12/07/2023]
Abstract
Patients with advanced liver cancer may benefit from 5-fluorouracil (5-FU) therapy. However, most of them eventually faced drug resistance, resulting in a poor prognosis. The present study aims to explore the potential mechanism of let-7g/ABCC10 axis in the regulation of 5-FU resistance in liver cancer cells. Huh-7 cells were used to construct 5-FU resistant Huh-7/4X cells. CCK8, flow cytometry, and TUNEL staining were used to detect the characterization of Huh-7 cells and Huh-7/4X cells. Double luciferase report, PCR, and western blot analyses were used to detect the regulatory effects between let-7g and ABCC10. The levels of biomarkers related to cell cycle progression and apoptosis were detected by western blot assays. The role of let-7g in 5-FU sensitivity of liver cancer cells was evaluated in nude mice. Compared with LX-2 cells, the expression of let-7g was decreased in Hep3B, HepG2, Huh-7, and SK-Hep1 cells, with the lowest expression in Huh-7 cells. The sensitivity of Huh-7 cell to 5-FU was positively correlated with let-7g expression. Transfection of let-7g mimics inhibited the viability of Huh-7/4X cells by prolonging the G1 phase, with the downregulation of ABCC10, PCNA, Cyclin D1, and CDK4. Meanwhile, let-7g promoted apoptosis to increase 5-FU sensitivity of Huh-7/4X by downregulating ABCC10, Bcl-XL as well as upregulating Bax, C-caspase 3, and C-PARP. Dual-luciferase assay further confirmed that let-7g inhibited ABCC10 expression by binding to the ABCC10 3'-UTR region. Furthermore, let-7g increased the sensitivity of Huh-7/4X to 5-FU in vitro and in vivo, which can be reversed by ABCC10 overexpression. In conclusion, let-7g sensitized liver cancer cells to 5-FU by downregulating ABCC10 expression.
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Affiliation(s)
- Yun Chen
- Department of Pharmacy, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Translational Medicine Centre, Hunan Cancer Hospital / The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Hunan Provincial Clinical Research Centre for Oncoplastic Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Bocheng Zhang
- Translational Medicine Centre, Hunan Cancer Hospital / The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Hunan Provincial Clinical Research Centre for Oncoplastic Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Department of Pathology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Graduate Collaborative Training Base of Hunan Cancer Hospital, Hengyang Medical School, University of South China, Hengyang, P. R. China
| | - Cui Zhong
- College of Life Sciences, Hunan Normal University, Changsha, P. R. China
| | - Yuqing Zhou
- College of Life Sciences, Hunan Normal University, Changsha, P. R. China
| | - Lei Xue
- Department of Pathology, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Chenhui Luo
- Hunan Provincial Clinical Research Centre for Oncoplastic Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Liang Yi
- Hunan Provincial Clinical Research Centre for Oncoplastic Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Qian Gong
- Department of Pharmacy, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
| | - Ying Long
- Translational Medicine Centre, Hunan Cancer Hospital / The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
- Hunan Provincial Clinical Research Centre for Oncoplastic Surgery, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, P. R. China
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10
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Chen JY, Sung CJ, Chen SC, Hsiang YP, Hsu YC, Teng YN. Redefine the role of d-α-Tocopheryl polyethylene glycol 1000 succinate on P-glycoprotein, multidrug resistance protein 1, and breast cancer resistance protein mediated cancer multidrug resistance. Eur J Pharm Sci 2023; 190:106579. [PMID: 37689120 DOI: 10.1016/j.ejps.2023.106579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/22/2023] [Accepted: 09/06/2023] [Indexed: 09/11/2023]
Abstract
Cancer drug resistance is an ever-changing problem that most patients need to face in their later stages of treatment, especially the multidrug resistant (MDR) type. The drug efflux transporters, including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP), play the crucial roles in this sophisticated battle. In recent decades, researchers try to find potential inhibitors to impede the drug efflux function of above transporters. d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) is a prevalently used excipient in the formulation design. In the present study, the modulatory effects and mechanisms of vitamin E TPGS on the efflux transporters were investigated. And the cancer MDR reversing ability of vitamin E TPGS was evaluated as well. Stable-cloned transporter over-expressed cell lines were used for mechanisms study, while several types of MDR cancer cell lines were adopted as reversing evaluation models. The results exhibited that vitamin E TPGS significantly inhibited the efflux function of P-gp, MRP1, and BCRP under non-cytotoxic concentrations, but not influencing the protein expression levels. Through efflux assay and molecular docking, vitamin E TPGS was found to be an uncompetitive, non-competitive, and competitive inhibitor on chemotherapeutic drug doxorubicin efflux in P-gp, MRP1, and BCRP over-expressing cell lines, respectively. Furthermore, the basal ATPase activity of three transporters were significantly inhibited by vitamin E TPGS at 10 μM. And the cell membrane fluidity of P-gp over-expressing cell line was enhanced by 22.58% with 5 μM vitamin E TPGS treatment, compared to the parental Flp-In™-293 cell line (without P-gp). The resistance reversing ability of vitamin E TPGS was prominent in MCF-7/DOX MDR breast cancer cell line, which over-expressed P-gp, MRP1, and BCRP. These significant results suggested that vitamin E TPGS is a promising modulator on transporters mediated cancer MDR. Vitamin E TPGS is not an inert excipient, but possesses MDR-reversing pharmacological effects, and deserves a re-purposing application on the future combinatorial regimen design for MDR cancer treatment.
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Affiliation(s)
- Jing-Yi Chen
- Department of Medical Laboratory Science, College of medical science and technology, I-Shou University, 8 Yida Road, Kaohsiung 82445, Taiwan, R.O.C; School of Medicine for International Students, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung 82445, Taiwan, R.O.C
| | - Chieh-Ju Sung
- Institute of Molecular Medicine, College of Medicine, National Taiwan University, No.1 Jen Ai road section 1, Taipei 100233, Taiwan, R.O.C
| | - Ssu-Chi Chen
- School of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung 82445, Taiwan, R.O.C
| | - Yi-Ping Hsiang
- Department of Pharmacy, E-Da Hospital, 1 Yida Road, Kaohsiung 82445, Taiwan, R.O.C
| | - Yung-Chia Hsu
- Department of Pharmacy, E-Da Cancer Hospital, 21 Yida Road, Kaohsiung 82445, Taiwan, R.O.C
| | - Yu-Ning Teng
- School of Medicine, College of Medicine, I-Shou University, 8 Yida Road, Kaohsiung 82445, Taiwan, R.O.C; Department of Pharmacy, E-Da Cancer Hospital, 21 Yida Road, Kaohsiung 82445, Taiwan, R.O.C.
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11
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Wang Y, Wang T, Wang H, Liu W, Li X, Wang X, Zhang Y. A mechanistic updated overview on Cepharanthine as potential anticancer agent. Biomed Pharmacother 2023; 165:115107. [PMID: 37423171 DOI: 10.1016/j.biopha.2023.115107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/25/2023] [Accepted: 06/28/2023] [Indexed: 07/11/2023] Open
Abstract
The antitumor effects of traditional drugs have received increasing attention and active antitumor components extracted from traditional drugs have shown good efficacy with minimal adverse events. Cepharanthine(CEP for short) is an active component derived from the Stephania plants of Menispermaceae, which can regulate multiple signaling pathways alone or in combination with other therapeutic drugs to inhibit tumor cell proliferation, induce apoptosis, regulate autophagy, and inhibit angiogenesis, thereby inhibiting tumor progression. Therefore, we retrieved studies concerning CEP's antitumor effects in recent years and summarized the antitumor mechanism and targets, in order to gain new insights and establish a theoretical basis for further development and application of CEP.
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Affiliation(s)
- YingZheng Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Tong Wang
- School of Nursing, Shandong University of Traditional Chinese Medicine, Jinan, Shangdong Province 250355, China
| | - HuaXin Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - WeiDong Liu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - Xiao Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - XiaoYan Wang
- College of Acupuncture and Tuina, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China
| | - YaNan Zhang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province 250355, China.
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12
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Arvelo F, Sojo F. Transición epitelio – mesenquima y cáncer. INVESTIGACIÓN CLÍNICA 2023; 64:379-404. [DOI: 10.54817/ic.v64n3a10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Cancer cell migration and invasion are critical components of metastatic disease, the leading cause of death in cancer patients. The epithe-lium-mesenchyme-transition (EMT) and mesenchyme-epithelium-transition (MET) are pathways involved in cancer metastasis. This process involves the degradation of cell-cell and cell-extracellular matrix junctions and the subse-quent loss of regulation of binding proteins such as E-cadherin. Cells undergo a reorganization of the cytoskeleton. These alterations are associated with a change in cell shape from epithelial to mesenchymal morphology. Understand-ing EMT and MET’s molecular and cellular basis provides fundamental insights into cancer etiology and may lead to new therapeutic strategies. In this review, we discuss some of the regulatory mechanisms and pathological role of epitheli-al-mesenchymal plasticity, focusing on the knowledge about the complexity and dynamics of this phenomenon in cancer
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Affiliation(s)
- Francisco Arvelo
- Fundación Instituto de Estudios Avanzados-IDEA, Area Salud, Caracas-Venezuela. Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental, Universidad Central de Venezuela, Caracas, Venezuela
| | - Felipe Sojo
- Fundación Instituto de Estudios Avanzados-IDEA, Area Salud, Caracas-Venezuela. Laboratorio de Cultivo de Tejidos y Biología de Tumores, Instituto de Biología Experimental, Universidad Central de Venezuela, Caracas, Venezuela
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13
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García-de-Diego AM. C-subfamily ATP binding cassette transporters extrude the calcium fluorescent probe fluo-4 from a cone photoreceptor cell line. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:1727-1740. [PMID: 36805766 DOI: 10.1007/s00210-023-02422-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 02/07/2023] [Indexed: 02/23/2023]
Abstract
Whole transcriptome sequencing has revealed the existence of mRNAs for multiple membrane transporters in photoreceptors. Except for ATP binding cassette (ABC) member A4, involved in the retinoid cycle, an understanding of the function of most transport proteins in photoreceptors is lacking. In this research paper, extrusion of fluo-4, a Ca2+ fluorescent probe, from 661W cells, a cone photoreceptor murine cell line was studied with online fluorometry and immunocytochemistry. Fluo-4 efflux was temperature dependent, required ATP but not extracellular Na+, was not affected by pH in the range 5.4-8.4, and followed saturating kinetics with a Km of nearly 4 μM, suggesting it was effected by ABC type transporters. A panel of antagonists showed an inhibitory profile typical of the C subfamily of ABC transporters. Immunofluorescence staining was positive for ABCC3, ABCC4 and ABCC5. These experimental results are compatible with fluo-4 being extruded from 661W cones by one or a combination of C-type ABC transporters. Examination of physicochemical descriptors related to drug membrane permeability and ABC substrate binding region further suggested efflux of fluo-4 by C-type ABC transporters. Possible functions of this transport mechanism in photoreceptors are discussed.
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Affiliation(s)
- Antonio-Miguel García-de-Diego
- Instituto Teófilo Hernando de I+D del Medicamento, Madrid, Spain.
- Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain.
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14
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Baril SA, Gose T, Schuetz JD. How Cryo-EM Has Expanded Our Understanding of Membrane Transporters. Drug Metab Dispos 2023; 51:904-922. [PMID: 37438132 PMCID: PMC10353158 DOI: 10.1124/dmd.122.001004] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 04/14/2023] [Accepted: 05/04/2023] [Indexed: 07/14/2023] Open
Abstract
Over the past two decades, technological advances in membrane protein structural biology have provided insight into the molecular mechanisms that transporters use to move diverse substrates across the membrane. However, the plasticity of these proteins' ligand binding pockets, which allows them to bind a range of substrates, also poses a challenge for drug development. Here we highlight the structure, function, and transport mechanism of ATP-binding cassette/solute carrier transporters that are related to several diseases and multidrug resistance: ABCB1, ABCC1, ABCG2, SLC19A1, and SLC29A1. SIGNIFICANCE STATEMENT: ATP-binding cassette transporters and solute carriers play vital roles in clinical chemotherapeutic outcomes. This paper describes the current understanding of the structure of five pharmacologically relevant transporters and how they interact with their ligands.
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Affiliation(s)
- Stefanie A Baril
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Tomoka Gose
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - John D Schuetz
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
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15
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Bucci-Muñoz M, Gola AM, Rigalli JP, Ceballos MP, Ruiz ML. Extracellular Vesicles and Cancer Multidrug Resistance: Undesirable Intercellular Messengers? Life (Basel) 2023; 13:1633. [PMID: 37629489 PMCID: PMC10455762 DOI: 10.3390/life13081633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/10/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer multidrug resistance (MDR) is one of the main mechanisms contributing to therapy failure and mortality. Overexpression of drug transporters of the ABC family (ATP-binding cassette) is a major cause of MDR. Extracellular vesicles (EVs) are nanoparticles released by most cells of the organism involved in cell-cell communication. Their cargo mainly comprises, proteins, nucleic acids, and lipids, which are transferred from a donor cell to a target cell and lead to phenotypical changes. In this article, we review the scientific evidence addressing the regulation of ABC transporters by EV-mediated cell-cell communication. MDR transfer from drug-resistant to drug-sensitive cells has been identified in several tumor entities. This was attributed, in some cases, to the direct shuttle of transporter molecules or its coding mRNA between cells. Also, EV-mediated transport of regulatory proteins (e.g., transcription factors) and noncoding RNAs have been indicated to induce MDR. Conversely, the transfer of a drug-sensitive phenotype via EVs has also been reported. Additionally, interactions between non-tumor cells and the tumor cells with an impact on MDR are presented. Finally, we highlight uninvestigated aspects and possible approaches to exploiting this knowledge toward the identification of druggable processes and molecules and, ultimately, the development of novel therapeutic strategies.
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Affiliation(s)
- María Bucci-Muñoz
- Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Instituto de Fisiología Experimental (CONICET), Rosario 2000, Argentina; (M.B.-M.); (A.M.G.); (M.P.C.)
| | - Aldana Magalí Gola
- Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Instituto de Fisiología Experimental (CONICET), Rosario 2000, Argentina; (M.B.-M.); (A.M.G.); (M.P.C.)
| | - Juan Pablo Rigalli
- Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg University Hospital, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany;
| | - María Paula Ceballos
- Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Instituto de Fisiología Experimental (CONICET), Rosario 2000, Argentina; (M.B.-M.); (A.M.G.); (M.P.C.)
| | - María Laura Ruiz
- Facultad de Ciencias Bioquímicas y Farmacéuticas (UNR), Instituto de Fisiología Experimental (CONICET), Rosario 2000, Argentina; (M.B.-M.); (A.M.G.); (M.P.C.)
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16
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Huang Y, Xue C, Wang L, Bu R, Mu J, Wang Y, Liu Z. Structural basis for substrate and inhibitor recognition of human multidrug transporter MRP4. Commun Biol 2023; 6:549. [PMID: 37217525 PMCID: PMC10202912 DOI: 10.1038/s42003-023-04935-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023] Open
Abstract
Human multidrug resistance protein 4 (hMRP4, also known as ABCC4), with a representative topology of the MRP subfamily, translocates various substrates across the membrane and contributes to the development of multidrug resistance. However, the underlying transport mechanism of hMRP4 remains unclear due to a lack of high-resolution structures. Here, we use cryogenic electron microscopy (cryo-EM) to resolve its near-atomic structures in the apo inward-open and the ATP-bound outward-open states. We also capture the PGE1 substrate-bound structure and, importantly, the inhibitor-bound structure of hMRP4 in complex with sulindac, revealing that substrate and inhibitor compete for the same hydrophobic binding pocket although with different binding modes. Moreover, our cryo-EM structures, together with molecular dynamics simulations and biochemical assay, shed light on the structural basis of the substrate transport and inhibition mechanism, with implications for the development of hMRP4-targeted drugs.
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Affiliation(s)
- Ying Huang
- Department Of Immunology And Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Chenyang Xue
- Department Of Immunology And Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Liangdong Wang
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China
| | - Ruiqian Bu
- Department Of Immunology And Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Jianqiang Mu
- Department Of Immunology And Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China
| | - Yong Wang
- College of Life Sciences, Zhejiang University, Hangzhou, 310027, China.
- The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, 314400, China.
| | - Zhongmin Liu
- Department Of Immunology And Microbiology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
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17
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Vázquez-Meza H, Vilchis-Landeros MM, Vázquez-Carrada M, Uribe-Ramírez D, Matuz-Mares D. Cellular Compartmentalization, Glutathione Transport and Its Relevance in Some Pathologies. Antioxidants (Basel) 2023; 12:antiox12040834. [PMID: 37107209 PMCID: PMC10135322 DOI: 10.3390/antiox12040834] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 03/31/2023] Open
Abstract
Reduced glutathione (GSH) is the most abundant non-protein endogenous thiol. It is a ubiquitous molecule produced in most organs, but its synthesis is predominantly in the liver, the tissue in charge of storing and distributing it. GSH is involved in the detoxification of free radicals, peroxides and xenobiotics (drugs, pollutants, carcinogens, etc.), protects biological membranes from lipid peroxidation, and is an important regulator of cell homeostasis, since it participates in signaling redox, regulation of the synthesis and degradation of proteins (S-glutathionylation), signal transduction, various apoptotic processes, gene expression, cell proliferation, DNA and RNA synthesis, etc. GSH transport is a vital step in cellular homeostasis supported by the liver through providing extrahepatic organs (such as the kidney, lung, intestine, and brain, among others) with the said antioxidant. The wide range of functions within the cell in which glutathione is involved shows that glutathione’s role in cellular homeostasis goes beyond being a simple antioxidant agent; therefore, the importance of this tripeptide needs to be reassessed from a broader metabolic perspective.
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18
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da Costa KM, Freire-de-Lima L, da Fonseca LM, Previato JO, Mendonça-Previato L, Valente RDC. ABCB1 and ABCC1 Function during TGF-β-Induced Epithelial-Mesenchymal Transition: Relationship between Multidrug Resistance and Tumor Progression. Int J Mol Sci 2023; 24:ijms24076046. [PMID: 37047018 PMCID: PMC10093952 DOI: 10.3390/ijms24076046] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/17/2023] [Accepted: 03/21/2023] [Indexed: 04/14/2023] Open
Abstract
Multidrug resistance (MDR) and induction of metastasis are some of the puzzles encountered during cancer chemotherapy. The MDR phenotype is associated with overexpression of ABC transporters, involved in drug efflux. Metastasis originates from the epithelial-mesenchymal transition (EMT), in which cells acquire a migratory phenotype, invading new tissues. ABC transporters' role during EMT is still elusive, though cells undergoing EMT exhibit enhanced ABCB1 expression. We demonstrated increased ABCB1 expression but no change in activity after TGF-β-induced EMT in A549 cells. Moreover, ABCB1 inhibition by verapamil increased snail and fibronectin expression, an event associated with upregulation of ABCB1, evidencing coincident cell signaling pathways leading to ABCB1 and EMT-related markers transcription, rather than a direct effect of transport. Additionally, for the first time, increased ABCC1 expression and activity was observed after EMT, and use of ABCC1 inhibitors partially inhibited EMT-marker snail, although increased ABCC1 function translated into collateral sensibility to daunorubicin. More investigations must be done to evaluate the real benefits that the gain of ABC transporters might have on the process of metastasis. Considering ABCC1 is involved in the stress response, affecting intracellular GSH content and drug detoxification, this transporter could be used as a therapeutic target in cancer cells undergoing EMT.
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Affiliation(s)
- Kelli Monteiro da Costa
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Leonardo Freire-de-Lima
- Laboratório de Biologia Celular de Glicoconjugados, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Leonardo Marques da Fonseca
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - José Osvaldo Previato
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Lucia Mendonça-Previato
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Raphael do Carmo Valente
- Núcleo Multidisciplinar de Pesquisa em Biologia (Numpex-Bio), Campus Duque de Caxias Professor Geraldo Cidade, Duque de Caxias, Universidade Federal do Rio de Janeiro, Rio de Janeiro 25250-470, Brazil
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19
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Silva JA, Colquhoun A. Effect of Polyunsaturated Fatty Acids on Temozolomide Drug-Sensitive and Drug-Resistant Glioblastoma Cells. Biomedicines 2023; 11:biomedicines11030779. [PMID: 36979758 PMCID: PMC10045395 DOI: 10.3390/biomedicines11030779] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 03/08/2023] Open
Abstract
Glioblastomas (GBMs) are notoriously difficult to treat, and the development of multiple drug resistance (MDR) is common during the course of the disease. The polyunsaturated fatty acids (PUFAs) gamma-linolenic acid (GLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have been reported to improve MDR in several tumors including breast, bladder, and leukaemia. However, the effects of PUFAs on GBM cell MDR are poorly understood. The present study investigated the effects of PUFAs on cellular responses to temozolomide (TMZ) in U87MG cells and the TMZ-resistant (TMZR) cells derived from U87MG. Cells were treated with PUFAs in the absence or presence of TMZ and dose–response, viable cell counting, gene expression, Western blotting, flow cytometry, gas chromatography-mass spectrometry (GCMS), and drug efflux studies were performed. The development of TMZ resistance caused an increase in ABC transporter ABCB1 and ABCC1 expression. GLA-, EPA-, and DHA-treated cells had altered fatty acid composition and accumulated lipid droplets in the cytoplasm. The most significant reduction in cell growth was seen for the U87MG and TMZR cells in the presence of EPA. GLA and EPA caused more significant effects on ABC transporter expression than DHA. GLA and EPA in combination with TMZ caused significant reductions in rhodamine 123 efflux from U87MG cells but not from TMZR cells. Overall, these findings support the notion that PUFAs can modulate ABC transporters in GBM cells.
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20
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Nigam SK, Granados JC. OAT, OATP, and MRP Drug Transporters and the Remote Sensing and Signaling Theory. Annu Rev Pharmacol Toxicol 2023; 63:637-660. [PMID: 36206988 DOI: 10.1146/annurev-pharmtox-030322-084058] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The coordinated movement of organic anions (e.g., drugs, metabolites, signaling molecules, nutrients, antioxidants, gut microbiome products) between tissues and body fluids depends, in large part, on organic anion transporters (OATs) [solute carrier 22 (SLC22)], organic anion transporting polypeptides (OATPs) [solute carrier organic (SLCO)], and multidrug resistance proteins (MRPs) [ATP-binding cassette, subfamily C (ABCC)]. Depending on the range of substrates, transporters in these families can be considered multispecific, oligospecific, or (relatively) monospecific. Systems biology analyses of these transporters in the context of expression patterns reveal they are hubs in networks involved in interorgan and interorganismal communication. The remote sensing and signaling theory explains how the coordinated functions of drug transporters, drug-metabolizing enzymes, and regulatory proteins play a role in optimizing systemic and local levels of important endogenous small molecules. We focus on the role of OATs, OATPs, and MRPs in endogenous metabolism and how their substrates (e.g., bile acids, short chain fatty acids, urate, uremic toxins) mediate interorgan and interorganismal communication and help maintain and restore homeostasis in healthy and disease states.
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Affiliation(s)
- Sanjay K Nigam
- Department of Pediatrics and Medicine (Nephrology), University of California San Diego, La Jolla, California, USA;
| | - Jeffry C Granados
- Department of Bioengineering, University of California San Diego, La Jolla, California, USA
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21
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Qattan MY, Khan MI, Alharbi SH, Verma AK, Al-Saeed FA, Abduallah AM, Al Areefy AA. Therapeutic Importance of Kaempferol in the Treatment of Cancer through the Modulation of Cell Signalling Pathways. Molecules 2022; 27:8864. [PMID: 36557997 PMCID: PMC9788613 DOI: 10.3390/molecules27248864] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/08/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Plant-derived flavonoids are considered natural nontoxic chemo-preventers and have been widely studied for cancer treatment in recent decades. Mostly all flavonoid compounds show significant anti-inflammatory, anticancer and antioxidant properties. Kaempferol (Kmp) is a well-studied compound and exhibits remarkable anticancer and antioxidant potential. Kmp can regulate various cancer-related processes and activities such as cell cycle, oxidative stress, apoptosis, proliferation, metastasis, and angiogenesis. The anti-cancer properties of Kmp primarily occur via modulation of apoptosis, MAPK/ERK1/2, P13K/Akt/mTOR, vascular endothelial growth factor (VEGF) signalling pathways. The anti-cancer property of Kmp has been recognized in several in-vivo and in-vitro studies which also includes numerous cell lines and animal models. This flavonoid possesses toxic activities against only cancer cells and have restricted toxicity on healthy cells. In this review, we present extensive research investigations about the therapeutic potential of Kmp in the management of different types of cancers. The anti-cancer properties of Kmp are discussed by concentration on its capability to target molecular-signalling pathway such as VEGF, STAT, p53, NF-κB and PI3K-AKT signalling pathways. The anti-cancer property of Kmf has gained a lot of attention, but the accurate action mechanism remains unclear. However, this natural compound has a great pharmacological capability and is now considered to be an alternative cancer treatment.
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Affiliation(s)
- Malak Yahia Qattan
- Department of Health Sciences, College of Applied Studies and Community Service, King Saud University, KSA- 4545, Riyadh 11451, Saudi Arabia
| | - Mohammad Idreesh Khan
- Department of Clinical Nutrition, College of Applied Health Sciences in Ar Rass, Qassim University, Ar Rass 51921, Saudi Arabia
| | - Shudayyed Hasham Alharbi
- Pharmacy Department, Maternity and Children Hospital (MCH), Qassim Cluster, Ministry of Health, Buraydah 52384, Saudi Arabia
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
| | - Amit Kumar Verma
- Department of Biotechnology, Jamia Millia Islamia University, New Delhi 110025, India
| | - Fatimah A. Al-Saeed
- Department of Biology, College of Science, King Khalid University, Abha 61413, Saudi Arabia
- Research Centre for Advanced Materials Science (RCAMS), King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia
| | - Alduwish Manal Abduallah
- Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Alkarj 11942, Saudi Arabia
| | - Azza A. Al Areefy
- Department of Clinical Nutrition, College of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
- Nutrition & Food Science Department, Faculty of Home Economics, Helwan University, P.O. Box 11795, Cairo 11281, Egypt
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22
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Fashe MM, Fallon JK, Miner TA, Tiley JB, Smith PC, Lee CR. Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes. Front Pharmacol 2022; 13:1004010. [PMID: 36210832 PMCID: PMC9532936 DOI: 10.3389/fphar.2022.1004010] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Pregnancy alters the disposition and exposure to multiple drugs indicated for pregnancy-related complications. Previous in vitro studies have shown that pregnancy-related hormones (PRHs) alter the expression and function of certain cytochrome P450s (CYPs) in human hepatocytes. However, the impact of PRHs on hepatic concentrations of non-CYP drug-metabolizing enzymes (DMEs) and transport proteins remain largely unknown. In this study, sandwich-cultured human hepatocytes (SCHH) from five female donors were exposed to vehicle or PRHs (estrone, estradiol, estriol, progesterone, cortisol, and placental growth hormone), administered individually or in combination, across a range of physiologically relevant PRH concentrations for 72 h. Absolute concentrations of 33 hepatic non-CYP DMEs and transport proteins were quantified in SCHH membrane fractions using a quantitative targeted absolute proteomics (QTAP) isotope dilution nanoLC-MS/MS method. The data revealed that PRHs altered the absolute protein concentration of various DMEs and transporters in a concentration-, isoform-, and hepatocyte donor-dependent manner. Overall, eight of 33 (24%) proteins exhibited a significant PRH-evoked net change in absolute protein concentration relative to vehicle control (ANOVA p < 0.05) across hepatocyte donors: 1/11 UGTs (9%; UGT1A4), 4/6 other DMEs (67%; CES1, CES2, FMO5, POR), and 3/16 transport proteins (19%; OAT2, OCT3, P-GP). An additional 8 (24%) proteins (UGT1A1, UGT2B4, UGT2B10, FMO3, OCT1, MRP2, MRP3, ENT1) exhibited significant PRH alterations in absolute protein concentration within at least two individual hepatocyte donors. In contrast, 17 (52%) proteins exhibited no discernable impact by PRHs either within or across hepatocyte donors. Collectively, these results provide the first comprehensive quantitative proteomic evaluation of PRH effects on non-CYP DMEs and transport proteins in SCHH and offer mechanistic insight into the altered disposition of drug substrates cleared by these pathways during pregnancy.
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Affiliation(s)
- Muluneh M. Fashe
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - John K. Fallon
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Taryn A. Miner
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jacqueline B. Tiley
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Philip C. Smith
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Craig R. Lee
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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Zhang Y, Li C, Xia C, Wah To KK, Guo Z, Ren C, Wen L, Wang F, Fu L, Liao N. Adagrasib, a KRAS G12C inhibitor, reverses the multidrug resistance mediated by ABCB1 in vitro and in vivo. Cell Commun Signal 2022; 20:142. [PMID: 36104708 PMCID: PMC9472360 DOI: 10.1186/s12964-022-00955-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 08/03/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Multidrug resistance (MDR) is a complex phenomenon that frequently leads to chemotherapy failure during cancer treatment. The overexpression of ATP-binding cassette (ABC) transporters represents the major mechanism contributing to MDR. To date, no effective MDR modulator has been applied in clinic. Adagrasib (MRTX849), a specific inhibitor targeting KRAS G12C mutant, is currently under investigation in clinical trials for the treatment of non-small cell lung cancer (NSCLC). This study focused on investigating the circumvention of MDR by MRTX849.
Methods
The cytotoxicity and MDR reversal effect of MRTX849 were assessed by MTT assay. Drug accumulation and drug efflux were evaluated by flow cytometry. The MDR reversal by MRTX849 in vivo was investigated in two ABCB1-overexpressing tumor xenograft models in nude mice. The interaction between MRTX849 and ABCB1 substrate binding sites was studied by the [125I]-IAAP-photoaffinity labeling assay. The vanadate-sensitive ATPase assay was performed to identify whether MRTX849 would change ABCB1 ATPase activity. The effect of MRTX849 on expression of ABCB1 and PI3K/AKT signaling molecules was examined by flow cytometry, Western blot and Quantitative Real-time PCR analyses.
Results
MRTX849 was shown to enhance the anticancer efficacy of ABCB1 substrate drugs in the transporter-overexpressing cells both in vitro and in vivo. The MDR reversal effect was specific against ABCB1 because no similar effect was observed in the parental sensitive cells or in ABCG2-mediated MDR cells. Mechanistically, MRTX849 increased the cellular accumulation of ABCB1 substrates including doxorubicin (Dox) and rhodamine 123 (Rho123) in ABCB1-overexpressing MDR cells by suppressing ABCB1 efflux activity. Additionally, MRTX849 stimulated ABCB1 ATPase activity and competed with [125I]-IAAP for photolabeling of ABCB1 in a concentration-dependent manner. However, MRTX849 did not alter ABCB1 expression or phosphorylation of AKT/ERK at the effective MDR reversal drug concentrations.
Conclusions
In summary, MRTX849 was found to overcome ABCB1-mediated MDR both in vitro and in vivo by specifically attenuating ABCB1 efflux activity in drug-resistant cancer cells. Further studies are warranted to translate the combination of MRTX849 and conventional chemotherapy to clinical application for circumvention of MDR.
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da Costa KM, Valente RDC, da Fonseca LM, Freire-de-Lima L, Previato JO, Mendonça-Previato L. The History of the ABC Proteins in Human Trypanosomiasis Pathogens. Pathogens 2022; 11:pathogens11090988. [PMID: 36145420 PMCID: PMC9505544 DOI: 10.3390/pathogens11090988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 08/24/2022] [Accepted: 08/25/2022] [Indexed: 11/16/2022] Open
Abstract
Human trypanosomiasis affects nearly eight million people worldwide, causing great economic and social impact, mainly in endemic areas. T. cruzi and T. brucei are protozoan parasites that present efficient mechanisms of immune system evasion, leading to disease chronification. Currently, there is no vaccine, and chemotherapy is effective only in the absence of severe clinical manifestations. Nevertheless, resistant phenotypes to chemotherapy have been described in protozoan parasites, associated with cross-resistance to other chemically unrelated drugs. Multidrug resistance is multifactorial, involving: (i) drug entry, (ii) activation, (iii) metabolism and (iv) efflux pathways. In this context, ABC transporters, initially discovered in resistant tumor cells, have drawn attention in protozoan parasites, owing to their ability to decrease drug accumulation, thus mitigating their toxic effects. The discovery of these transporters in the Trypanosomatidae family started in the 1990s; however, few members were described and functionally characterized. This review contains a brief history of the main ABC transporters involved in resistance that propelled their investigation in Trypanosoma species, the main efflux modulators, as well as ABC genes described in T. cruzi and T. brucei according to the nomenclature HUGO. We hope to convey the importance that ABC transporters play in parasite physiology and chemotherapy resistance.
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Affiliation(s)
- Kelli Monteiro da Costa
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: (K.M.C.); (L.M.P.)
| | - Raphael do Carmo Valente
- Núcleo de Pesquisa Multidisciplinar em Biologia, Universidade Federal do Rio de Janeiro, Campus Duque de Caxias Prof. Geraldo Cidade, Duque de Caxias 25250-470, Brazil
| | - Leonardo Marques da Fonseca
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Leonardo Freire-de-Lima
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Jose Osvaldo Previato
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Lucia Mendonça-Previato
- Laboratório de Glicobiologia, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Correspondence: (K.M.C.); (L.M.P.)
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25
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Hu F, Chen XQ, Li XP, Lu YX, Chen SL, Wang DW, Liang Y, Dai YJ. Drug resistance biomarker ABCC4 of selinexor and immune feature in multiple myeloma. Int Immunopharmacol 2022; 108:108722. [DOI: 10.1016/j.intimp.2022.108722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/17/2022] [Accepted: 03/18/2022] [Indexed: 11/26/2022]
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26
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Grange RMH, Preedy MEJ, Renukanthan A, Dignam JP, Lowe VJ, Moyes AJ, Pérez-Ternero C, Aubdool AA, Baliga RS, Hobbs AJ. Multidrug resistance proteins preferentially regulate natriuretic peptide-driven cGMP signalling in the heart and vasculature. Br J Pharmacol 2022; 179:2443-2459. [PMID: 34131904 DOI: 10.1111/bph.15593] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 05/07/2021] [Accepted: 05/14/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND AND PURPOSE cGMP underpins the bioactivity of NO and natriuretic peptides and is key to cardiovascular homeostasis. cGMP-driven responses are terminated primarily by PDEs, but cellular efflux via multidrug resistance proteins (MRPs) might contribute. Herein, the effect of pharmacological blockade of MRPs on cGMP signalling in the heart and vasculature was investigated in vitro and in vivo. EXPERIMENTAL APPROACH Proliferation of human coronary artery smooth muscle cells (hCASMCs), vasorelaxation of murine aorta and reductions in mean arterial BP (MABP) in response to NO donors or natriuretic peptides were determined in the absence and presence of the MRP inhibitor MK571. The ability of MRP inhibition to reverse morphological and contractile deficits in a murine model of pressure overload-induced heart failure was also explored. KEY RESULTS MK571 attenuated hCASMC growth and enhanced the anti-proliferative effects of NO and atrial natriuretic peptide (ANP). MRP blockade caused concentration-dependent relaxations of murine aorta and augmented responses to ANP (and to a lesser extent NO). MK571 did not decrease MABP per se but enhanced the hypotensive actions of ANP and improved structural and functional indices of disease severity in experimental heart failure. These beneficial actions of MRP inhibition were associated with a greater intracellular:extracellular cGMP ratio in vitro and in vivo. CONCLUSIONS AND IMPLICATIONS MRP blockade promotes the cardiovascular functions of natriuretic peptides in vitro and in vivo, with more modest effects on NO. MRP inhibition may have therapeutic utility in cardiovascular diseases triggered by dysfunctional cGMP signalling, particularly those associated with altered natriuretic peptide bioactivity. LINKED ARTICLES This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
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Affiliation(s)
- Robert M H Grange
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Michael E J Preedy
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Aniruthan Renukanthan
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Joshua P Dignam
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Vanessa J Lowe
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Amie J Moyes
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Cristina Pérez-Ternero
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Aisah A Aubdool
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Reshma S Baliga
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Adrian J Hobbs
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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27
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Polewko-Klim A, Zhu S, Wu W, Xie Y, Cai N, Zhang K, Zhu Z, Qing T, Yuan Z, Xu K, Zhang T, Lu M, Ye W, Chen X, Suo C, Rudnicki WR. Identification of Candidate Therapeutic Genes for More Precise Treatment of Esophageal Squamous Cell Carcinoma and Adenocarcinoma. Front Genet 2022; 13:844542. [PMID: 35664298 PMCID: PMC9161154 DOI: 10.3389/fgene.2022.844542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 04/20/2022] [Indexed: 11/23/2022] Open
Abstract
The standard therapy administered to patients with advanced esophageal cancer remains uniform, despite its two main histological subtypes, namely esophageal squamous cell carcinoma (SCC) and esophageal adenocarcinoma (AC), are being increasingly considered to be different. The identification of potential drug target genes between SCC and AC is crucial for more effective treatment of these diseases, given the high toxicity of chemotherapy and resistance to administered medications. Herein we attempted to identify and rank differentially expressed genes (DEGs) in SCC vs. AC using ensemble feature selection methods. RNA-seq data from The Cancer Genome Atlas and the Fudan-Taizhou Institute of Health Sciences (China). Six feature filters algorithms were used to identify DEGs. We built robust predictive models for histological subtypes with the random forest (RF) classification algorithm. Pathway analysis also be performed to investigate the functional role of genes. 294 informative DEGs (87 of them are newly discovered) have been identified. The areas under receiver operator curve (AUC) were higher than 99.5% for all feature selection (FS) methods. Nine genes (i.e., ERBB3, ATP7B, ABCC3, GALNT14, CLDN18, GUCY2C, FGFR4, KCNQ5, and CACNA1B) may play a key role in the development of more directed anticancer therapy for SCC and AC patients. The first four of them are drug targets for chemotherapy and immunotherapy of esophageal cancer and involved in pharmacokinetics and pharmacodynamics pathways. Research identified novel DEGs in SCC and AC, and detected four potential drug targeted genes (ERBB3, ATP7B, ABCC3, and GALNT14) and five drug-related genes.
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Affiliation(s)
- Aneta Polewko-Klim
- Institute of Computer Science, University in Bialystok, Białystok, Poland
| | - Sibo Zhu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Weicheng Wu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Yijing Xie
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Ning Cai
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Kexun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Zhen Zhu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Tao Qing
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Ziyu Yuan
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Kelin Xu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Tiejun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
| | - Ming Lu
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
- Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Weimin Ye
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
- Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
| | - Xingdong Chen
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Chen Suo
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, China
- Fudan-Taizhou Institute of Health Sciences, Taizhou, China
- Shanghai Institute of Infectious Disease and Biosecurity, Shanghai, China
| | - Witold R. Rudnicki
- Institute of Computer Science, University in Bialystok, Białystok, Poland
- Computational Centre, University of Bialystok, Białystok, Poland
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28
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Ferraro MG, Piccolo M, Misso G, Santamaria R, Irace C. Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics. Pharmaceutics 2022; 14:pharmaceutics14050954. [PMID: 35631543 PMCID: PMC9147010 DOI: 10.3390/pharmaceutics14050954] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 04/22/2022] [Accepted: 04/25/2022] [Indexed: 02/04/2023] Open
Abstract
Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer.
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Affiliation(s)
- Maria Grazia Ferraro
- BioChemLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy; (M.G.F.); (M.P.); (R.S.)
| | - Marialuisa Piccolo
- BioChemLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy; (M.G.F.); (M.P.); (R.S.)
| | - Gabriella Misso
- Department of Precision Medicine, School of Medicine and Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
- Correspondence: (G.M.); (C.I.)
| | - Rita Santamaria
- BioChemLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy; (M.G.F.); (M.P.); (R.S.)
| | - Carlo Irace
- BioChemLab, Department of Pharmacy, School of Medicine and Surgery, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy; (M.G.F.); (M.P.); (R.S.)
- Correspondence: (G.M.); (C.I.)
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29
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Console L, Scalise M. Extracellular Vesicles and Cell Pathways Involved in Cancer Chemoresistance. Life (Basel) 2022; 12:life12050618. [PMID: 35629286 PMCID: PMC9143651 DOI: 10.3390/life12050618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/15/2022] [Accepted: 04/16/2022] [Indexed: 02/07/2023] Open
Abstract
Chemoresistance is a pharmacological condition that allows transformed cells to maintain their proliferative phenotype in the presence of administered anticancer drugs. Recently, extracellular vesicles, including exosomes, have been identified as additional players responsible for the chemoresistance of cancer cells. These are nanovesicles that are released by almost all cell types in both physiological and pathological conditions and contain proteins and nucleic acids as molecular cargo. Extracellular vesicles released in the bloodstream reach recipient cells and confer them novel metabolic properties. Exosomes can foster chemoresistance by promoting prosurvival and antiapoptotic pathways, affecting cancer stem cells and immunotherapies, and stimulating drug efflux. In this context, a crucial role is played by membrane transporters belonging to ABC, SLC, and P-type pump families. These proteins are fundamental in cell metabolism and drug transport in either physiological or pathological conditions. In this review, different roles of extracellular vesicles in drug resistance of cancer cells will be explored.
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Affiliation(s)
- Lara Console
- Correspondence: (L.C.); (M.S.); Tel.: +39-0984-492919 (L.C.); +39-0984-492938 (M.S.)
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Drug combination study of novel oxorhenium(V) complexes. J Inorg Biochem 2022; 231:111807. [DOI: 10.1016/j.jinorgbio.2022.111807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/11/2022] [Accepted: 03/21/2022] [Indexed: 11/23/2022]
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Meng X, Dong S, Yangyang L, Wang S, Xu X, Liu T, Zhuang X. Adenosine triphosphate-binding cassette subfamily C members in liver hepatocellular carcinoma: Bioinformatics-driven prognostic value. Medicine (Baltimore) 2022; 101:e28869. [PMID: 35363194 PMCID: PMC9282002 DOI: 10.1097/md.0000000000028869] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 12/16/2021] [Indexed: 01/04/2023] Open
Abstract
Aberrant expression of adenosine triphosphate-binding cassette subfamily C (ABCC), one of the largest superfamilies and transporter gene families of membrane proteins, is associated with various tumors. However, its relationship with liver hepatocellular carcinoma (LIHC) remains unclear.We used the Oncomine, UALCAN, Human Protein Atlas, GeneMANIA, GO, Kyoto Encyclopedia of Genes and Genomes (KEGG), TIMER, and Kaplan-Meier Plotter databases. On May 20, 2021, we searched these databases for the terms ABCC1, ABCC2, ABCC3, ABCC4, ABCC5, ABCC6, ABCC7, ABCC8, ABCC9, ABCC10, ABCC11, ABCC12, ABCC13, and "liver cancer." The exposure group comprised LIHC patients, and the control group comprised normal patients (those with noncancerous liver tissue). All patients shown in the retrieval language search were included. We compared the mRNA expression of these proteins in LIHC and control patients to examine the potential role of ABCC1-13 in LIHC.Relative to the normal liver tissue, mRNA expression of ABCC1/2/3/4/5/6/10 was significantly upregulated (P < .001), and that of ABCC9/11 significantly downregulated (both P < .001), in LIHC. ABCC mRNA expression varied with gender (P < .05), except for ABCC11-13; with tumor grade (P < 0.05), except for ABCC7/12/13; with tumor stage (P < .05), except for ABCC11-13; and with lymph node metastasis status (P < .05), except for ABCC7/8/11/12/13. Based on KEGG enrichment analysis, these genes were associated with the following pathways: ABC transporters, Bile secretion, Antifolate resistance, and Peroxisome (P < .05). Except for ABCC12/13, the ABCCs were significantly associated with B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell infiltration (P < .05). High mRNA expression of ABCC1/4/5/8 (P < .05) and low expression of ABCC6/7/9/12/13 (P < .05) indicated poor prognosis. Prognostic significance was indicated for ABCC2/13 for both men and women (P < .05); for ABCC1/6/12/13 for tumor grades 1-3 (P < .05); for ABCC5/11/12/13 for all tumor stages (P < .05); for ABCC1/11/12/13 for American Joint Committee on Cancer T stages 1-3 (P < .05); and for ABCC1/5/6/13 for vascular invasion. None showed prognostic significance for microvascular invasion (P < .05).We identified ABCC1/2/3/4/5/6/9/10/11 as potential diagnostic markers, and ABCC1/4/5/6/7/8/9/12/13 as prognostic markers, of LIHC. Our future work will promote the use of ABCCs in the diagnosis and treatment of LIHC.
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Affiliation(s)
- Xiangtong Meng
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Shen Dong
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Liu Yangyang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Endocrinology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Song Wang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
| | - Xiaohao Xu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Research Center of Traditional Chinese Medicine, First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun City, Jilin Province, China
| | - Tiejun Liu
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
| | - Xiong Zhuang
- Changchun University of Chinese Medicine, 1035 Bo Shuo Road, Changchun City, Jilin Province, China
- Department of Hepatology, First Affiliated Hospital to Changchun University of Chinese Medicine, 1478 Gongnong Road, Changchun City, Jilin Province, China
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Yang H, Zhai B, Wang M, Fan Y, Wang J, Cheng J, Zou J, Zhang X, Shi Y, Guo D, Tang Z. The influence of rhein on the absorption of rehmaionoside D: In vivo, in situ, in vitro, and in silico studies. JOURNAL OF ETHNOPHARMACOLOGY 2022; 282:114650. [PMID: 34536515 DOI: 10.1016/j.jep.2021.114650] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In traditional Chinese Medicine, Rehmannia glutinosa (Gaertn.) DC., as the principle herb of ShengDiHuang Decotion (SDHD), has the effect of cooling blood and hemostasis, and tonifying the yin and kidney. Rheum L., as adjuvant herbs, assist Rehmannia glutinosa (Gaertn.) DC. to promote blood circulation to remove blood stasis. AIM OF STUDY To study the mechanism of Rhein (RH) involved in the promotion of Rehmannioside D (RD) absorption by pharmacokinetic studies, single-pass intestinal perfusion, Caco-2 cell models, molecular docking technique and western blotting. MATERIALS AND METHODS Initially, the intestinal absorption of RD in the presence or absence of RH was conducted through pharmacokinetic studies. Thereafter, the intestinal absorption of RD and RH was studied using the single-pass intestinal perfusion and Caco-2 cell models. Finally, using molecular docking technique and western blotting. RESULTS We found that the promotion of RD absorption by RH was mediated by breast cancer resistance and multidrug resistance-associated protein 2, thereby affecting the permeability of the intestinal epithelium. Additionally, RH and RD can competitively bind to breast cancer resistance and multidrug resistance-associated protein 2, and that RH inhibits the expression of breast cancer resistance and multidrug resistance-associated protein 2 in the ileum to promote the intestinal absorption of RD. CONCLUSION This study reveals the mechanisms associated with the RH-mediated promotion of RD absorption and provides a basis for further exploring the synergistic effect of Rehmannia glutinosa (Gaertn.) DC and rhubarb.
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Affiliation(s)
- Hui Yang
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Bingtao Zhai
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Mei Wang
- The Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yu Fan
- School of Basic Medical Science, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Jing Wang
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Jiangxue Cheng
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Junbo Zou
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Xiaofei Zhang
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Yajun Shi
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China
| | - Dongyan Guo
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China.
| | - Zhishu Tang
- Shaanxi Province Key Laboratory of New Drugs and Chinese Medicine Foundation Research, College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang, 712046, China; Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, Xianyang, 712046, China.
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Namasivayam V, Stefan K, Pahnke J, Stefan SM. Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics. Comput Struct Biotechnol J 2021; 19:6490-6504. [PMID: 34976306 PMCID: PMC8666613 DOI: 10.1016/j.csbj.2021.11.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/17/2022] Open
Abstract
The adenosine-triphosphate-(ATP)-binding cassette (ABC) transporter ABCA7 is a genetic risk factor for Alzheimer's disease (AD). Defective ABCA7 promotes AD development and/or progression. Unfortunately, ABCA7 belongs to the group of 'under-studied' ABC transporters that cannot be addressed by small-molecules. However, such small-molecules would allow for the exploration of ABCA7 as pharmacological target for the development of new AD diagnostics and therapeutics. Pan-ABC transporter modulators inherit the potential to explore under-studied ABC transporters as novel pharmacological targets by potentially binding to the proposed 'multitarget binding site'. Using the recently reported cryogenic-electron microscopy (cryo-EM) structures of ABCA1 and ABCA4, a homology model of ABCA7 has been generated. A set of novel, diverse, and potent pan-ABC transporter inhibitors has been docked to this ABCA7 homology model for the discovery of the multitarget binding site. Subsequently, application of pharmacophore modelling identified the essential pharmacophore features of these compounds that may support the rational drug design of innovative diagnostics and therapeutics against AD.
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Key Words
- ABC transporter (ABCA1, ABCA4, ABCA7)
- ABC, ATP-binding cassette
- AD, Alzheimer’s disease
- APP, amyloid precursor protein
- ATP, Adenosine-triphosphate
- Alzheimer’s disease (AD)
- BBB, blood-brain barrier
- BODIPY-cholesterol, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene-cholesterol
- ECD, extracellular domain
- EH, extracellular helix
- GSH, reduced glutathione
- HTS, high-throughput screening
- IC, intracellular helix
- MOE, Molecular Operating Environment
- MSD, membrane spanning domain
- Multitarget modulation (PANABC)
- NBD, nucleotide binding domain
- NBD-cholesterol, 7-nitro-2-1,3-benzoxadiazol-4-yl-cholesterol
- PDB, protein data bank
- PET tracer (PETABC)
- PET, positron emission tomography
- PLIF, protein ligand interaction
- PSO, particle swarm optimization
- Polypharmacology
- R-domain/region, regulatory domain/region
- RMSD, root mean square distance
- Rational drug design and development
- SNP, single-nucleotide polymorphism
- TM, transmembrane helix
- cryo-EM, cryogenic-electron microscopy
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Affiliation(s)
- Vigneshwaran Namasivayam
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Katja Stefan
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
| | - Jens Pahnke
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
- LIED, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
- Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 1, 1004 Rīga, Latvia
| | - Sven Marcel Stefan
- Department of Pathology, Section of Neuropathology, Translational Neurodegeneration Research and Neuropathology Lab (www.pahnkelab.eu), University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
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Radhakrishnan A, Kuppusamy G, Ponnusankar S, Mutalik S. Towards next-generation personalization of tacrolimus treatment: a review on advanced diagnostic and therapeutic approaches. Pharmacogenomics 2021; 22:1151-1175. [PMID: 34719935 DOI: 10.2217/pgs-2021-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The benefit of personalized medicine is that it allows the customization of drug therapy - maximizing efficacy while avoiding side effects. Genetic polymorphisms are one of the major contributors to interindividual variability. Currently, the only gold standard for applying personalized medicine is dose titration. Because of technological advancements, converting genotypic data into an optimum dose has become easier than in earlier years. However, for many medications, determining a personalized dose may be difficult, leading to a trial-and-error method. On the other hand, the technologically oriented pharmaceutical industry has a plethora of smart drug delivery methods that are underutilized in customized medicine. This article elaborates the genetic polymorphisms of tacrolimus as case study, and extensively covers the diagnostic and therapeutic technologies which aid in the delivery of personalized tacrolimus treatment for better clinical outcomes, thereby providing a new strategy for implementing personalized medicine.
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Affiliation(s)
- Arun Radhakrishnan
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Gowthamarajan Kuppusamy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Sivasankaran Ponnusankar
- Department of Pharmacy Practice, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, Tamilnadu, India
| | - Srinivas Mutalik
- Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Karnataka, India
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Kater L, Kater B, Jakupec MA, Keppler BK, Prokop A. KP772 overcomes multiple drug resistance in malignant lymphoma and leukemia cells in vitro by inducing Bcl-2-independent apoptosis and upregulation of Harakiri. J Biol Inorg Chem 2021; 26:897-907. [PMID: 34617137 PMCID: PMC8557194 DOI: 10.1007/s00775-021-01900-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 08/10/2021] [Indexed: 11/29/2022]
Abstract
Despite high cure rates in pediatric patients with acute leukemia, development of resistance limits the efficacy of antileukemic therapy. Tris(1,10-phenanthroline)tris(thiocyanato-κN)lanthanum(III) (KP772) is an experimental antineoplastic agent to which multidrug-resistant cell models have shown hypersensitivity. Antiproliferative and apoptotic activities of KP772 were tested in leukemia, lymphoma and solid tumor cell lines as well as primary leukemia cells (isolated from the bone marrow of a child with acute myeloid leukemia (AML). The ability to overcome drug resistances was investigated in doxorubicin- and vincristine-resistant cell lines. Real-time PCR was used to gain insight into the mechanism of apoptosis induction. KP772 inhibited proliferation and induced apoptosis in various leukemia and lymphoma cell lines in a concentration-dependent manner (LC50 = 1-2.5 µM). Primary AML cells were also sensitive to KP772, whereas daunorubicin showed no significant effect. KP772 induces apoptosis independently of Bcl-2, Smac, and the CD95 receptor and is also effective in caspase 3-deficient MCF7 cells, indicating that apoptosis is partly triggered independently of caspase 3. mRNA expression profiling revealed an upregulation of the BH3-only Bcl-2 protein Harakiri in the course of KP772-induced apoptosis. Remarkably, KP772 overcame drug resistance to doxorubicin and vincristine in vitro, and the apoptotic effect in resistant cells was even superior to that in non-resistant parental cells. In combination with vincristine, doxorubicin and cytarabine, synergistic effects were observed in BJAB cells. The cytotoxic potency in vitro/ex vivo and the remarkable ability to overcome multidrug resistance propose KP772 as a promising candidate drug for antileukemic therapy, especially of drug-refractory malignancies.Graphic abstract.
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Affiliation(s)
- Lisa Kater
- Department of Pediatric Oncology/Hematology, University Medical Center Charité, Campus Virchow, Augustenburger Platz 1, 13353, Berlin, Germany.,Department of Naturopathy, Immanuel Hospital Berlin, Königstraße 63, 14109, Berlin, Germany
| | - Benjamin Kater
- Department of Pediatric Oncology/Hematology, University Medical Center Charité, Campus Virchow, Augustenburger Platz 1, 13353, Berlin, Germany.,MVZ Nuclear Medicine, Vivantes Hospital "Am Urban", Dieffenbachstraße 1, 10967, Berlin, Germany
| | - Michael A Jakupec
- Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria. .,Research Cluster "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090, Vienna, Austria.
| | - Bernhard K Keppler
- Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Währinger Straße 42, 1090, Vienna, Austria.,Research Cluster "Translational Cancer Therapy Research", University of Vienna, Währinger Straße 42, 1090, Vienna, Austria
| | - Aram Prokop
- Department of Pediatric Oncology/Hematology, University Medical Center Charité, Campus Virchow, Augustenburger Platz 1, 13353, Berlin, Germany.,Department of Pediatric Hematology/Oncology, Helios Clinic Schwerin, Wismarsche Straße 393-397, 19049, Schwerin, Germany.,Department of Pediatric Hematology/Oncology, Children's Hospital Cologne, Amsterdamerstraße 59, 50735, Cologne, Germany.,Medical School Hamburg (MSH), University of Applied Sciences and Medical University, Am Kaiserkai 1, 20457, Hamburg, Germany
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Ambrus C, Bakos É, Sarkadi B, Özvegy-Laczka C, Telbisz Á. Interactions of anti-COVID-19 drug candidates with hepatic transporters may cause liver toxicity and affect pharmacokinetics. Sci Rep 2021; 11:17810. [PMID: 34497279 PMCID: PMC8426393 DOI: 10.1038/s41598-021-97160-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 07/22/2021] [Indexed: 12/15/2022] Open
Abstract
Transporters in the human liver play a major role in the clearance of endo- and xenobiotics. Apical (canalicular) transporters extrude compounds to the bile, while basolateral hepatocyte transporters promote the uptake of, or expel, various compounds from/into the venous blood stream. In the present work we have examined the in vitro interactions of some key repurposed drugs advocated to treat COVID-19 (lopinavir, ritonavir, ivermectin, remdesivir and favipiravir), with the key drug transporters of hepatocytes. These transporters included ABCB11/BSEP, ABCC2/MRP2, and SLC47A1/MATE1 in the canalicular membrane, as well as ABCC3/MRP3, ABCC4/MRP4, SLC22A1/OCT1, SLCO1B1/OATP1B1, SLCO1B3/OATP1B3, and SLC10A1/NTCP, residing in the basolateral membrane. Lopinavir and ritonavir in low micromolar concentrations inhibited BSEP and MATE1 exporters, as well as OATP1B1/1B3 uptake transporters. Ritonavir had a similar inhibitory pattern, also inhibiting OCT1. Remdesivir strongly inhibited MRP4, OATP1B1/1B3, MATE1 and OCT1. Favipiravir had no significant effect on any of these transporters. Since both general drug metabolism and drug-induced liver toxicity are strongly dependent on the functioning of these transporters, the various interactions reported here may have important clinical relevance in the drug treatment of this viral disease and the existing co-morbidities.
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Affiliation(s)
- Csilla Ambrus
- SOLVO Biotechnology, Irinyi József street 4-20, 1117, Budapest, Hungary.,Doctoral School of Molecular Medicine, Semmelweis University, Tűzoltó u. 37-47, 1094, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, 1117, Budapest, Hungary
| | - Balázs Sarkadi
- Institute of Enzymology, ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, 1117, Budapest, Hungary.,Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094, Budapest, Hungary
| | - Csilla Özvegy-Laczka
- Institute of Enzymology, ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, 1117, Budapest, Hungary
| | - Ágnes Telbisz
- Institute of Enzymology, ELKH Research Centre for Natural Sciences, Magyar Tudósok krt. 2, 1117, Budapest, Hungary.
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Bleasby K, Houle R, Hafey M, Lin M, Guo J, Lu B, Sanchez RI, Fillgrove KL. Islatravir Is Not Expected to Be a Victim or Perpetrator of Drug-Drug Interactions via Major Drug-Metabolizing Enzymes or Transporters. Viruses 2021; 13:1566. [PMID: 34452431 PMCID: PMC8402619 DOI: 10.3390/v13081566] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 07/16/2021] [Accepted: 07/23/2021] [Indexed: 12/11/2022] Open
Abstract
Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for the treatment and prevention of HIV-1. The potential for islatravir to interact with commonly co-prescribed medications was studied in vitro. Elimination of islatravir is expected to be balanced between adenosine deaminase-mediated metabolism and renal excretion. Islatravir did not inhibit uridine diphosphate glucuronosyltransferase 1A1 or cytochrome p450 (CYP) enzymes CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4, nor did it induce CYP1A2, 2B6, or 3A4. Islatravir did not inhibit hepatic transporters organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, bile salt export pump (BSEP), multidrug resistance-associated protein (MRP) 2, MRP3, or MRP4. Islatravir was neither a substrate nor a significant inhibitor of renal transporters organic anion transporter (OAT) 1, OAT3, OCT2, multidrug and toxin extrusion protein (MATE) 1, or MATE2K. Islatravir did not significantly inhibit P-glycoprotein and breast cancer resistance protein (BCRP); however, it was a substrate of BCRP, which is not expected to be of clinical significance. These findings suggest islatravir is unlikely to be the victim or perpetrator of drug-drug interactions with commonly co-prescribed medications, including statins, diuretics, anti-diabetic drugs, proton pump inhibitors, anticoagulants, benzodiazepines, and selective serotonin reuptake inhibitors.
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Affiliation(s)
| | | | | | | | | | | | | | - Kerry L. Fillgrove
- Merck & Co., Inc., Kenilworth, NJ 07033, USA; (K.B.); (R.H.); (M.H.); (M.L.); (J.G.); (B.L.); (R.I.S.)
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Hao X, Wang B, Chen J, Wang B, Xu J, Pan J, Ma L. Molecular characterization and functional analysis of multidrug resistance-associated genes of Pinewood nematode (Bursaphelenchus xylophilus) for nematicides. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2021; 177:104902. [PMID: 34301363 DOI: 10.1016/j.pestbp.2021.104902] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 05/10/2021] [Accepted: 06/09/2021] [Indexed: 05/02/2023]
Abstract
Bursaphelenchus xylophilus (Pinewood nematode, PWN) is the causative agent of pine wilt disease (PWD) which caused serious threat to pine forests in the world, especially in East Asia and Western Europe. At present, the control of PWD mainly rely on the massive use of pesticide despite the damage to human health and environmental safety. Developing novel drug targets is the optimized strategy for developing new method to control PWN. In this study, four multidrug resistance-associated protein (MRP) genes containing highly conserved MRP-associated domains were cloned from PWN. The expression patterns of the four Bx-mrps under three different nematicides treatments were studied by quantitative reverse transcription PCR (qRT-PCR) and the function of the four genes in multidrug resistance were also validated by RNA interference (RNAi). Results showed that the expression of Bx-mrp1, Bx-mrp2, Bx-mrp3, and Bx-mrp4 were significantly increased when exposed to different nematicides, wherein, Bx-mrp4 exposed by 4.0 mg/mL of matrine own the highest expression level. The mortality rates of Bx-mrps silenced nematodes revealed significant increase(P < 0.05)under matrine, avermectin, and emamectin benzoate exposure. Specially, Bx-mrp4 exposed with 4.0 mg/mL matrine for 24 h own the highest mortality increase by 18.34%. After RNAi of Bx-mrps, feeding ability of the nematodes were also significantly decreased. These results demonstrate that Bx-mrps were linked to the detoxification process and feeding behavior of PWN. Silencing of Bx-mrps can lead to increased sensitivity of PWN to nematicides and decrease its feeding ability. Bx-mrps are potential new PWN control targets in the future.
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Affiliation(s)
- Xin Hao
- School of Forestry, Northeast Forestry University, Harbin 150040, China.
| | - Bowen Wang
- School of Forestry, Northeast Forestry University, Harbin 150040, China
| | - Jie Chen
- School of Forestry, Northeast Forestry University, Harbin 150040, China
| | - Buyong Wang
- School of Agriculture and Bioengineering, Heze University, Heze 274015, China
| | - Jiayao Xu
- School of Forestry, Northeast Forestry University, Harbin 150040, China
| | - Jialiang Pan
- Key laboratory of State Forestry Administration on Forest Pest Monitoring and Warning, General Station of Forest and Grassland Pest Management, General Station of Forest and Grassland Pest Management, National Forestry and Grassland Administration, Shenyang 110034, China..
| | - Ling Ma
- School of Forestry, Northeast Forestry University, Harbin 150040, China.
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LncRNA as a multifunctional regulator in cancer multi-drug resistance. Mol Biol Rep 2021; 48:1-15. [PMID: 34333735 DOI: 10.1007/s11033-021-06603-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 07/26/2021] [Indexed: 12/28/2022]
Abstract
BACKGROUND Malignant tumors have become the most dangerous disease in recent years. Chemotherapy is the most effective treatment for this disease; however, the problem of drug resistance has become even more common, which leads to the poor prognosis of patients suffering from cancers. Thus, necessary measures should be taken to address these problems at the earliest. Many studies have demonstrated that drug resistance is closely related to the abnormal expressions of long non-coding RNAs (lncRNAs). METHODS AND RESULTS This review aimed to summarize the molecular mechanisms underlying the association of lncRNAs and the development of drug resistance and to find potential strategies for the clinical diagnosis and treatment of cancer drug resistance. Studies showed that lncRNAs can regulate the expression of genes through chromatin remodeling, transcriptional regulation, and post-transcriptional processing. Furthermore, lncRNAs have been reported to be closely related to the occurrence of malignant tumors. In summary, lncRNAs have gained attention in related fields during recent years. According to previous studies, lncRNAs have a vital role in several different types of cancers owing to their multiple mechanisms of action. Different mechanisms have different functions that could result in different consequences in the same disease. CONCLUSIONS LncRNAs closely participated in cancer drug resistance by regulating miRNA, signaling pathways, proteins, cancer stem cells, pro- and ant-apoptosis, and autophagy. lncRNAs can be used as biomarkers of the possible treatment target in chemotherapy, which could provide solutions to the problem of drug resistance in chemotherapy in the future.
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Jaromi L, Csongei V, Vesel M, Abdelwahab EMM, Soltani A, Torok Z, Smuk G, Sarosi V, Pongracz JE. KRAS and EGFR Mutations Differentially Alter ABC Drug Transporter Expression in Cisplatin-Resistant Non-Small Cell Lung Cancer. Int J Mol Sci 2021; 22:ijms22105384. [PMID: 34065402 PMCID: PMC8160643 DOI: 10.3390/ijms22105384] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 02/06/2023] Open
Abstract
Lung carcinoma is still the most common malignancy worldwide. One of the major subtypes of non-small cell lung cancer (NSCLC) is adenocarcinoma (AC). As driver mutations and hence therapies differ in AC subtypes, we theorized that the expression and function of ABC drug transporters important in multidrug resistance (MDR) would correlate with characteristic driver mutations KRAS or EGFR. Cisplatin resistance (CR) was generated in A549 (KRAS) and PC9 (EGFR) cell lines and gene expression was tested. In three-dimensional (3D) multicellular aggregate cultures, both ABCB1 and ABCG2 transporters, as well as the WNT microenvironment, were investigated. ABCB1 and ABCG2 gene expression levels were different in primary AC samples and correlated with specific driver mutations. The drug transporter expression pattern of parental A549 and PC9, as well as A549-CR and PC9-CR, cell lines differed. Increased mRNA levels of ABCB1 and ABCG2 were detected in A549-CR cells, compared to parental A549, while the trend observed in the case of PC9 cells was different. Dominant alterations were observed in LEF1, RHOU and DACT1 genes of the WNT signalling pathway in a mutation-dependent manner. The study confirmed that, in lung AC-s, KRAS and EGFR driver mutations differentially affect both drug transporter expression and the cisplatin-induced WNT signalling microenvironment.
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Affiliation(s)
- Luca Jaromi
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Veronika Csongei
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Monika Vesel
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - ElHusseiny Mohamed Mahmud Abdelwahab
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Amina Soltani
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
| | - Zsofia Torok
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
- Department of Pulmonology, Internal Medicine, The Medical School and Clinical Centre, University of Pecs, 12 Szigeti Str, H-7624 Pecs, Hungary;
| | - Gabor Smuk
- Department of Pathology, The Medical School and Clinical Centre, University of Pecs, 12 Szigeti Str, H-7624 Pecs, Hungary;
| | - Veronika Sarosi
- Department of Pulmonology, Internal Medicine, The Medical School and Clinical Centre, University of Pecs, 12 Szigeti Str, H-7624 Pecs, Hungary;
| | - Judit Erzsebet Pongracz
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, University of Pecs, 2 Rokus Str, H-7624 Pecs, Hungary; (L.J.); (V.C.); (M.V.); (E.M.M.A.); (A.S.); (Z.T.)
- Wnt-Signalling and Biotechnology Research Group, Szentagothai Research Centre, University of Pecs, 20 Ifjusag Str, H-7624 Pecs, Hungary
- Correspondence: ; Tel.: +36-72-536-000 (ext. 29250) or +36-30-435-7944
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Namasivayam V, Silbermann K, Pahnke J, Wiese M, Stefan SM. Scaffold fragmentation and substructure hopping reveal potential, robustness, and limits of computer-aided pattern analysis (C@PA). Comput Struct Biotechnol J 2021; 19:3269-3283. [PMID: 34141145 PMCID: PMC8193046 DOI: 10.1016/j.csbj.2021.05.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 05/03/2021] [Accepted: 05/08/2021] [Indexed: 02/07/2023] Open
Abstract
Computer-aided pattern analysis (C@PA) was recently presented as a powerful tool to predict multitarget ABC transporter inhibitors. The backbone of this computational methodology was the statistical analysis of frequently occurring molecular features amongst a fixed set of reported small-molecules that had been evaluated toward ABCB1, ABCC1, and ABCG2. As a result, negative and positive patterns were elucidated, and secondary positive substructures could be suggested that complemented the multitarget fingerprints. Elevating C@PA to a non-statistical and exploratory level, the concluded secondary positive patterns were extended with potential positive substructures to improve C@PA's prediction capabilities and to explore its robustness. A small-set compound library of known ABCC1 inhibitors with a known hit rate for triple ABCB1, ABCC1, and ABCG2 inhibition was taken to virtually screen for the extended positive patterns. In total, 846 potential broad-spectrum ABCB1, ABCC1, and ABCG2 inhibitors resulted, from which 10 have been purchased and biologically evaluated. Our approach revealed 4 novel multitarget ABCB1, ABCC1, and ABCG2 inhibitors with a biological hit rate of 40%, but with a slightly lower inhibitory power than derived from the original C@PA. This is the very first report about discovering novel broad-spectrum inhibitors against the most prominent ABC transporters by improving C@PA.
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Key Words
- ABC transporter, ATP-binding cassette transporter
- ABCB1 (P-gp)
- ABCC1 (MRP1)
- ABCG2 (BCRP)
- ATP, adenosine-triphosphate
- Alzheimer's disease (AD)
- BCRP, breast cancer resistance protein (ABCG2)
- C@PA, computer-aided pattern analysis
- F1–5, pharmacophore features 1–5
- IC50, half-maximal inhibition concentration
- MDR, multidrug resistance
- MOE, molecular operating environment
- MRP1, multidrug resistance-associated protein 1 (ABCC1)
- Multidrug resistance (MDR)
- Multitarget fingerprints
- P-gp, P-glycoprotein (ABCB1)
- Pan-ABC inhibition / antagonism / blockage (PANABC)
- Pattern analysis (C@PA)
- SEM, standard error of the mean
- SMILES, simplified molecular input line entry specification
- Tc, Tanimotto coefficient
- Triple / multitarget / broad-spectrum / promiscuous inhibitor / antagonist
- Under-studied ABC transporters (e.g., ABCA7)
- Well-studied ABC transporters
- calcein AM, calcein acetoxymethyl
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Affiliation(s)
- Vigneshwaran Namasivayam
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Katja Silbermann
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Jens Pahnke
- Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
- LIED, University of Lübeck, Ratzenburger Allee 160, 23538 Lübeck, Germany
- Department of Pharmacology, Faculty of Medicine, University of Latvia, Jelgavas iela 1, 1004 Rīga, Latvia
- Department of Bioorganic Chemistry, Leibniz-Institute of Plant Biochemistry, Weinberg 3, 06120 Halle, Germany
| | - Michael Wiese
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Sven Marcel Stefan
- Department of Pharmaceutical and Cellbiological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
- Department of Neuro-/Pathology, University of Oslo and Oslo University Hospital, Sognsvannsveien 20, 0372 Oslo, Norway
- Cancer Drug Resistance and Stem Cell Program, University of Sydney, Kolling Builging, 10 Westbourne Street, Sydney, New South Wales 2065, Australia
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Angelis I, Moussis V, Tsoukatos DC, Tsikaris V. Multidrug Resistance Protein 4 (MRP4/ABCC4): A Suspected Efflux Transporter for Human's Platelet Activation. Protein Pept Lett 2021; 28:983-995. [PMID: 33964863 DOI: 10.2174/0929866528666210505120659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 03/10/2021] [Accepted: 03/16/2021] [Indexed: 11/22/2022]
Abstract
The main role of platelets is to contribute to hemostasis. However, under pathophysiological conditions, platelet activation may lead to thrombotic events of cardiovascular diseases. Thus, anti-thrombotic treatment is important in patients with cardiovascular disease. This review focuses on a platelet receptor, a transmembrane protein, the Multidrug Resistance Protein 4, MRP4, which contributes to platelet activation by extruding endogenous molecules responsible for their activation and accumulation. The regulation of the intracellular concentration levels of these molecules by MRP4 turned to make the protein suspicious and, at the same time, an interesting regulatory factor of normal platelet function. Especially, the possible role of MRP4 in the excretion of xenobiotic and antiplatelet drugs such as aspirin is discussed, thus imparting platelet aspirin tolerance and correlating the protein with the ineffectiveness of aspirin antiplatelet therapy. Based on the above, this review finally underlines that the development of a highly selective and targeted strategy for platelet MRP4 inhibition will also lead to inhibition of platelet activation and accumulation.
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Affiliation(s)
- Ioannis Angelis
- Department of Chemistry, Organic Chemistry & Biochemistry, University of Ioannina, Ioannina. Greece
| | - Vassilios Moussis
- Department of Chemistry, Organic Chemistry & Biochemistry, University of Ioannina, Ioannina. Greece
| | - Demokritos C Tsoukatos
- Department of Chemistry, Organic Chemistry & Biochemistry, University of Ioannina, Ioannina. Greece
| | - Vassilios Tsikaris
- Department of Chemistry, Organic Chemistry & Biochemistry, University of Ioannina, Ioannina. Greece
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Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue. Int J Mol Sci 2021; 22:ijms22094673. [PMID: 33925129 PMCID: PMC8125767 DOI: 10.3390/ijms22094673] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer, specifically metastatic breast, is a leading cause of morbidity and mortality in women. This is mainly due to relapse and reoccurrence of tumor. The primary reason for cancer relapse is the development of multidrug resistance (MDR) hampering the treatment and prognosis. MDR can occur due to a multitude of molecular events, including increased expression of efflux transporters such as P-gp, BCRP, or MRP1; epithelial to mesenchymal transition; and resistance development in breast cancer stem cells. Excessive dose dumping in chemotherapy can cause intrinsic anti-cancer MDR to appear prior to chemotherapy and after the treatment. Hence, novel targeted nanomedicines encapsulating chemotherapeutics and gene therapy products may assist to overcome cancer drug resistance. Targeted nanomedicines offer innovative strategies to overcome the limitations of conventional chemotherapy while permitting enhanced selectivity to cancer cells. Targeted nanotheranostics permit targeted drug release, precise breast cancer diagnosis, and importantly, the ability to overcome MDR. The article discusses various nanomedicines designed to selectively target breast cancer, triple negative breast cancer, and breast cancer stem cells. In addition, the review discusses recent approaches, including combination nanoparticles (NPs), theranostic NPs, and stimuli sensitive or “smart” NPs. Recent innovations in microRNA NPs and personalized medicine NPs are also discussed. Future perspective research for complex targeted and multi-stage responsive nanomedicines for metastatic breast cancer is discussed.
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Silva V, Gil-Martins E, Silva B, Rocha-Pereira C, Sousa ME, Remião F, Silva R. Xanthones as P-glycoprotein modulators and their impact on drug bioavailability. Expert Opin Drug Metab Toxicol 2021; 17:441-482. [PMID: 33283552 DOI: 10.1080/17425255.2021.1861247] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: P-glycoprotein (P-gp) is an important efflux pump responsible for the extruding of many endogenous and exogenous substances out of the cells. P-gp can be modulated by different molecules - including xanthone derivatives - to surpass the multidrug resistance (MDR) phenomenon through P-gp inhibition, or to serve as an antidotal strategy in intoxication scenarios through P-gp induction/activation.Areas covered: This review provides a perspective on P-gp modulators, with particular focus on xanthonic derivatives, highlighting their ability to modulate P-gp expression and/or activity, and the potential impact of these effects on the pharmacokinetics, pharmacodynamics and toxicity of P-gp substrates.Expert opinion: Xanthones, of natural or synthetic origin, are able to modulate P-gp, interfering with its protein synthesis or with its mechanism of action, by decreasing or increasing its efflux capacity. These modulatory effects make the xanthonic scaffold a promising source of new derivatives with therapeutic potential. However, the mechanisms beyond the xanthones-mediated P-gp modulation and the chemical characteristics that make them more potent P-gp inhibitors or inducers/activators are still understudied. Furthermore, a new window of opportunity exists in the neuropathologies field, where xanthonic derivatives with potential to modulate P-gp should be further explored to optimize the prevention/treatment of brain pathologies.
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Affiliation(s)
- Vera Silva
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Eva Gil-Martins
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Bárbara Silva
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Carolina Rocha-Pereira
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Maria Emília Sousa
- CIIMAR - Centro Interdisciplinar de Investigação Marinha e Ambiental, Terminal de Cruzeiros do Porto de Leixões, Matosinhos, Portugal.,Laboratório de Química Orgânica e Farmacêutica, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Fernando Remião
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Renata Silva
- UCIBIO-REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
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Xiao H, Zheng Y, Ma L, Tian L, Sun Q. Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance. Front Pharmacol 2021; 12:648407. [PMID: 33953682 PMCID: PMC8089384 DOI: 10.3389/fphar.2021.648407] [Citation(s) in RCA: 128] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 03/16/2021] [Indexed: 02/04/2023] Open
Abstract
Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.
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Affiliation(s)
- Huan Xiao
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Yongcheng Zheng
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Lingling Ma
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Lili Tian
- Department of Anesthesiology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qiu Sun
- State Key Laboratory of Biotherapy, Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, China
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Wang Y, Wang Y, Qin Z, Cai S, Yu L, Hu H, Zeng S. The role of non-coding RNAs in ABC transporters regulation and their clinical implications of multidrug resistance in cancer. Expert Opin Drug Metab Toxicol 2021; 17:291-306. [PMID: 33544643 DOI: 10.1080/17425255.2021.1887139] [Citation(s) in RCA: 88] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Multi-drug resistance (MDR) is a hindrance toward the successful treatment of cancers. The primary mechanism that gives rise to acquired chemoresistance is the overexpression of adenosine triphosphate-binding cassette (ABC) transporters. The dysregulation of non-coding RNAs (ncRNAs) is a widely concerned reason contributing to this phenotype. AREAS COVERED In this review, we describe the role of intracellular and exosomal ncRNAs including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) in ABC transporters-induced tumor MDR. Meanwhile, we will introduce the potential therapeutic strategies which reverse MDR in terms of reducing the expression of ABC transporters via targeting ncRNAs, like nucleic acid delivery with nanoparticles as well as miRNAs-targeted small molecular compounds. EXPERT OPINION The dysregulated ncRNAs-mediated overexpression of ABC transporters in chemo-resistant cancer is not negligible. Finding out the underlying mechanism may provide a theoretical basis for clinical therapy of cancer MDR, and the emergence of new approaches for gene therapy targeting ncRNAs to suppress ABC transporters makes reversing cancer MDR possible despite its clinical application requires further investigations. Also, the discovered ncRNAs regulating ABC transporters in chemo-resistant cancers are just a tip of the iceberg of the genetic transcripts, especially for circRNAs, which justify more concern.Abbreviations: MDR, multi-drug resistance; ABC, adenosine triphosphate-binding cassette; NcRNAs, non-coding RNAs; MiRNAs, microRNAs; LncRNAs, long non-coding RNAs; CircRNAs, circular RNAs; CeRNAs, competing endogenous RNAs; 3'UTR, 3'-untranslated regions; SLC, solute carrier; ABCB1/MDR1, ABC subfamily B member 1; ABCG2/BCRP, ABC subfamily G member 2; ABCCs/MRPs, ABC subfamily C 1 to 12; DLL1: Delta-like protein 1; DTX, docetaxel; DOX/ADM/ADR, doxorubicin/adriamycin; PTX, paclitaxel; VBL, vinblastine; VCR, vincristine; MTX, methotrexate; CDDP/DDP, cisplatin/cis-diaminedichloroplatinum; OXA/L-OHP, oxaliplatin; TMZ, temozolomide; 5-FU, 5-fluorouracil; MTA, pemetrexed; NSCLC, non-small cell lung carcinoma; HCC, hepatocellular carcinoma; CRC, colorectal carcinoma; RB, retinoblastoma; RCC, renal cell carcinoma; OS, osteosarcoma; PDAC, pancreatic ductal adenocarcinoma; TNBC, triple-negative breast cancer.
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Affiliation(s)
- Yu Wang
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yingying Wang
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhiyuan Qin
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Sheng Cai
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Lushan Yu
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Haihong Hu
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Su Zeng
- Institution of Drug Metabolism and Pharmaceutical Analysis, Cancer Center of Zhejiang University,Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Organic Cation Transporters in the Lung-Current and Emerging (Patho)Physiological and Pharmacological Concepts. Int J Mol Sci 2020; 21:ijms21239168. [PMID: 33271927 PMCID: PMC7730617 DOI: 10.3390/ijms21239168] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
Organic cation transporters (OCT) 1, 2 and 3 and novel organic cation transporters (OCTN) 1 and 2 of the solute carrier 22 (SLC22) family are involved in the cellular transport of endogenous compounds such as neurotransmitters, l-carnitine and ergothioneine. OCT/Ns have also been implicated in the transport of xenobiotics across various biological barriers, for example biguanides and histamine receptor antagonists. In addition, several drugs used in the treatment of respiratory disorders are cations at physiological pH and potential substrates of OCT/Ns. OCT/Ns may also be associated with the development of chronic lung diseases such as allergic asthma and chronic obstructive pulmonary disease (COPD) and, thus, are possible new drug targets. As part of the Special Issue "Physiology, Biochemistry and Pharmacology of Transporters for Organic Cations", this review provides an overview of recent findings on the (patho)physiological and pharmacological functions of organic cation transporters in the lung.
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Ogihara T, Mizoi K, Kamioka H, Yano K. Physiological Roles of ERM Proteins and Transcriptional Regulators in Supporting Membrane Expression of Efflux Transporters as Factors of Drug Resistance in Cancer. Cancers (Basel) 2020; 12:E3352. [PMID: 33198344 PMCID: PMC7696277 DOI: 10.3390/cancers12113352] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 11/06/2020] [Accepted: 11/10/2020] [Indexed: 12/23/2022] Open
Abstract
One factor contributing to the malignancy of cancer cells is the acquisition of drug resistance during chemotherapy via increased expression of efflux transporters, such as P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and breast cancer resistance protein (BCRP). These transporters operate at the cell membrane, and are anchored in place by the scaffold proteins ezrin (Ezr), radixin (Rdx), and moesin (Msn) (ERM proteins), which regulate their functional activity. The identity of the regulatory scaffold protein(s) differs depending upon the transporter, and also upon the tissue in which it is expressed, even for the same transporter. Another factor contributing to malignancy is metastatic ability. Epithelial-mesenchymal transition (EMT) is the first step in the conversion of primary epithelial cells into mesenchymal cells that can be transported to other organs via the blood. The SNAI family of transcriptional regulators triggers EMT, and SNAI expression is used is an indicator of malignancy. Furthermore, EMT has been suggested to be involved in drug resistance, since drug excretion from cancer cells is promoted during EMT. We showed recently that ERM proteins are induced by a member of the SNAI family, Snail. Here, we first review recent progress in research on the relationship between efflux transporters and scaffold proteins, including the question of tissue specificity. In the second part, we review the relationship between ERM scaffold proteins and the transcriptional regulatory factors that induce their expression.
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Affiliation(s)
- Takuo Ogihara
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, 60, Nakaorui-machi, Takasaki, Gunma 370-0033, Japan;
| | - Kenta Mizoi
- Faculty of Pharmacy, Takasaki University of Health and Welfare, 60, Nakaorui-machi, Takasaki, Gunma 370-0033, Japan; (K.M.); (K.Y.)
| | - Hiroki Kamioka
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare, 60, Nakaorui-machi, Takasaki, Gunma 370-0033, Japan;
| | - Kentaro Yano
- Faculty of Pharmacy, Takasaki University of Health and Welfare, 60, Nakaorui-machi, Takasaki, Gunma 370-0033, Japan; (K.M.); (K.Y.)
- Laboratory of Drug Metabolism and Pharmacokinetics, Yokohama University of Pharmacy, 601, Matano-cho, Totsuka-ku, Yokohama, Kanagawa 245-0066, Japan
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Sri Laasya T, Thakur S, Poduri R, Joshi G. Current insights toward kidney injury: Decrypting the dual role and mechanism involved of herbal drugs in inducing kidney injury and its treatment. CURRENT RESEARCH IN BIOTECHNOLOGY 2020. [DOI: 10.1016/j.crbiot.2020.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Najafzadeh B, Asadzadeh Z, Motafakker Azad R, Mokhtarzadeh A, Baghbanzadeh A, Alemohammad H, Abdoli Shadbad M, Vasefifar P, Najafi S, Baradaran B. The oncogenic potential of NANOG: An important cancer induction mediator. J Cell Physiol 2020; 236:2443-2458. [PMID: 32960465 DOI: 10.1002/jcp.30063] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/02/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs) are a unique population in the tumor, but they only comprise 2%-5% of the tumor bulk. Although CSCs share several features with embryonic stem cells, CSCs can give rise to the tumor cells. CSCs overexpress embryonic transcription factor NANOG, which is downregulated in differentiated tissues. This transcription factor confers CSC's stemness, unlimited self-renewal, metastasis, invasiveness, angiogenesis, and drug-resistance with the assistance of WNT, OCT4, SOX2, Hedgehog, BMI-1, and other complexes. NANOG facilitates CSCs development via multiple pathways, like angiogenesis and lessening E-cadherin expression levels, which paves the road for metastasis. Moreover, NANOG represses apoptosis and leads to drug-resistance. This review aims to highlight the pivotal role of NANOG and the pertained pathways in CSCs. Also, this current study intends to demonstrate that targeting NANOG can dimmish the CSCs, sensitize the tumor to chemotherapy, and eradicate the cancer cells.
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Affiliation(s)
- Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Zahra Asadzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | | | - Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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