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Sjöstedt N, Timmermans RGM, Vieraankivi M, Suominen L, Vellonen KS, Bhattacharya M, Auriola S, Kidron H. Exploring the effect of intracellular loop 1 genetic variants in human ABCG2 on transport activity and protein abundance. Drug Metab Pharmacokinet 2025; 62:101482. [PMID: 40203631 DOI: 10.1016/j.dmpk.2025.101482] [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: 11/12/2024] [Revised: 02/21/2025] [Accepted: 03/13/2025] [Indexed: 04/11/2025]
Abstract
ABCG2 (breast cancer resistance protein, BCRP), can affect drug disposition, and thus, variation in the ABCG2 gene may alter drug exposure. We studied non-synonymous naturally occurring single-nucleotide variants (SNVs) in intracellular loop 1 (ICL1), which contains a coupling helix that transmits conformational changes in the protein. Reference ABCG2, the common SNVs V12M and Q141K, and five SNVs (K453R, I456V, H457R, G462R and G462V) in ICL1 were expressed in HEK293 cells. Additionally, combinations of selected SNVs were expressed to determine if an activating substitution in ICL1 could compensate for an inactivating substitution elsewhere. Transport of Lucifer yellow, estrone sulfate and rosuvastatin was studied using membrane vesicles and the ABCG2 abundance was quantified. While K453R and I456V abundance was similar to the reference ABCG2, abundance was lower for H457R and G462R/V. Apparent transport activities were partially substrate dependent, but excluding G462R/V, the ICL variants transported at least one of the substrates similarly to the reference ABCG2. In double substitutions, I456V had a more consistent effect than H457R on both transport activity and protein abundance. Altogether, SNVs in ICL1 can have both detrimental and beneficial effects on ABCG2 activity. Effects may be hard to predict, especially if more than one SNV is present.
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Affiliation(s)
- Noora Sjöstedt
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Ritchie G M Timmermans
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Marika Vieraankivi
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Laura Suominen
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | | | - Madhushree Bhattacharya
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Seppo Auriola
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
| | - Heidi Kidron
- Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
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Wang Y, Xia B, Cao L, Yang J, Feng C, Jiang F, Li C, Gu L, Yang Y, Tian J, Cheng X, Furuuchi K, Fulmer J, Verdi A, Rybinski K, Soto A, Albone E, Uenaka T, Gong L, Liu T, Qin Q, Wei Z, Zhou Y. Preclinical studies of BB-1701, a HER2-targeting eribulin-containing ADC with potent bystander effect and ICD activity. Antib Ther 2024; 7:221-232. [PMID: 39036069 PMCID: PMC11259758 DOI: 10.1093/abt/tbae019] [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: 01/31/2024] [Revised: 06/03/2024] [Accepted: 06/24/2024] [Indexed: 07/23/2024] Open
Abstract
BACKGROUND Several HER2-targeting antibody-drug conjugates (ADC) have gained market approval for the treatment of HER2-expressing metastasis. Promising responses have been reported with the new generation of ADCs in patients who do not respond well to other HER2-targeting therapeutics. However, these ADCs still face challenges of resistance and/or severe adverse effects associated with their particular payload toxins. Eribulin, a therapeutic agent for the treatment of metastatic breast cancer and liposarcoma, is a new choice of ADC payload with a distinct mechanism of action and safety profile. METHODS We've generated a novel HER2-tageting eribulin-containing ADC, BB-1701. The potency of BB-1701 was tested in vitro and in vivo against cancer cells where HER2-expressing levels vary in a large range. Bystander killing effect and toxin-induced immunogenic cell death (ICD) of BB-1701 were also tested. RESULTS In comparison with HER2-targeting ADCs with DM1 and Dxd payload, eribulin-containing ADC demonstrated higher in vitro cytotoxicity in HER2-low cancer cell lines. BB-1701 also effectively suppressed tumors in models resistant to DM1 or Dxd containing ADCs. Mode of action studies showed that BB-1701 had a significant bystander effect on HER2-null cells adjacent to HER2-high cells. In addition, BB-1701 treatment induced ICD. Repeated doses of BB-1701 in nonhuman primates showed favorable pharmacokinetics and safety profiles at the intended clinical dosage, route of administration, and schedule. CONCLUSIONS The preclinical data support the test of BB-1701 in patients with various HER2-expressing cancers, including those resistant to other HER2-targeting ADCs. A phase I clinical trial of BB-1701 (NCT04257110) in patients is currently underway.
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Affiliation(s)
- Yang Wang
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Bing Xia
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Lixia Cao
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Jianfeng Yang
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Cui Feng
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Fangdun Jiang
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Chen Li
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Lixia Gu
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Yifan Yang
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Jing Tian
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Xin Cheng
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Keiji Furuuchi
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - James Fulmer
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Arielle Verdi
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Katherine Rybinski
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Allis Soto
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Earl Albone
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Toshimitsu Uenaka
- Epochal Precision Anti-Cancer Therapeutics (EPAT), Cell Lineage and Differentiation (CLD) Domain, Eisai Inc., Exton, PA 19341, United States
| | - Likun Gong
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Tingting Liu
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Qiuping Qin
- Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Ziping Wei
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
| | - Yuhong Zhou
- Bliss Biopharmaceutical (Hangzhou) Co., Ltd, Hexiang Technology Center, Hangzhou 310018, China
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Kasten A, Cascorbi I. Understanding the impact of ABCG2 polymorphisms on drug pharmacokinetics: focus on rosuvastatin and allopurinol. Expert Opin Drug Metab Toxicol 2024; 20:519-528. [PMID: 38809523 DOI: 10.1080/17425255.2024.2362184] [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: 03/25/2024] [Accepted: 05/28/2024] [Indexed: 05/30/2024]
Abstract
INTRODUCTION In addition to the well-established understanding of the pharmacogenetics of drug-metabolizing enzymes, there is growing data on the effects of genetic variation in drug transporters, particularly ATP-binding cassette (ABC) transporters. However, the evidence that these genetic variants can be used to predict drug effects and to adjust individual dosing to avoid adverse events is still limited. AREAS COVERED This review presents a summary of the current literature from the PubMed database as of February 2024 regarding the impact of genetic variants on ABCG2 function and their relevance to the clinical use of the HMG-CoA reductase inhibitor rosuvastatin and the xanthine oxidase inhibitor allopurinol. EXPERT OPINION Although there are pharmacogenetic guidelines for the ABCG2 missense variant Q141K, there is still some conflicting data regarding the clinical benefits of these recommendations. Some caution appears to be warranted in homozygous ABCG2 Q141K carriers when rosuvastatin is administered at higher doses and such information is already included in the drug label. The benefit of dose adaption to lower possible side effects needs to be evaluated in prospective clinical studies.
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Affiliation(s)
- Anne Kasten
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany
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Liu Y, Chen Y, Wei B, Li H, Peng Y, Luo Z. Impacts of ABCG2 loss of function variant (p. Gln141Lys, c.421 C > A, rs2231142) on lipid levels and statin efficiency: a systematic review and meta-analysis. BMC Cardiovasc Disord 2024; 24:202. [PMID: 38589776 PMCID: PMC11000409 DOI: 10.1186/s12872-024-03821-2] [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: 09/27/2023] [Accepted: 02/28/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND The latest evidence indicates that ATP-binding cassette superfamily G member 2 (ABCG2) is critical in regulating lipid metabolism and mediating statin or cholesterol efflux. This study investigates whether the function variant loss within ABCG2 (rs2231142) impacts lipid levels and statin efficiency. METHODS PubMed, Cochrane Library, Central, CINAHL, and ClinicalTrials.gov were searched until November 18, 2023. RESULTS Fifteen studies (34,150 individuals) were included in the analysis. The A allele [Glu141Lys amino acid substitution was formed by a transversion from cytosine (C) to adenine (A)] of rs2231142 was linked to lower levels of high-density lipoprotein cholesterol (HDL-C), and higher levels of low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). In addition, the A allele of rs2231142 substantially increased the lipid-lowering efficiency of rosuvastatin in Asian individuals with dyslipidemia. Subgroup analysis indicated that the impacts of rs2231142 on lipid levels and statin response were primarily in Asian individuals. CONCLUSIONS The ABCG2 rs2231142 loss of function variant significantly impacts lipid levels and statin efficiency. Preventive use of rosuvastatin may prevent the onset of coronary artery disease (CAD) in Asian individuals with dyslipidemia.
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Affiliation(s)
- Yang Liu
- Department of Endocrinology, China Resources and WISCO General Hospital, Wuhan, China
| | - Yuan Chen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baozhu Wei
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China.
- Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China.
| | - Hang Li
- Department of Geratology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Yuanyuan Peng
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, China
| | - Zhi Luo
- Department of Cardiology, Suining Central Hospital, Suining, Sichuan, 629000, China.
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Suominen L, Sjöstedt N, Vellonen KS, Gynther M, Auriola S, Kidron H. In vitro identification of decreased function phenotype ABCG2 variants. Eur J Pharm Sci 2023; 188:106527. [PMID: 37451410 DOI: 10.1016/j.ejps.2023.106527] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/18/2023]
Abstract
Reduced activity of efflux transporter ABCG2, caused e.g., by inhibition or decreased function genetic variants, can increase drug absorption and plasma levels. ABCG2 has one clinically significant single nucleotide variant Q141K (c.421C>A), which leads to decreased protein levels and transport activity. In addition to Q141K, ABCG2 has over 500 rare (<1% minor allele frequency) nonsynonymous variants, but their functionality remains unknown. We studied the transport activity and abundance of 30 rare ABCG2 variants. The variants were transiently expressed in HEK293 cells. Transport activity and protein abundance were measured from inside-out crude membrane vesicles. Results were normalised to the reference ABCG2, while Q141K was used to categorise variants into decreased and normal function phenotypes based on their apparent transport activity. Fourteen variants (G80E, D128V, T434M, Q437R, C438R, C438W, C438Y, L479S, P480L, S486N, T512N, S519P, G553D and K647E) had similar or lower apparent transport activity than Q141K and thus were categorised as having a decreased function phenotype. Protein abundance could not explain all of the observed changes in transport activity: Only six variants (D128V, Q437R, C438R, S519P, G553D, and K647E) had similar or lower abundance compared to Q141K. The decreased function variants may increase systemic drug exposure and therefore cause interindividual variability in pharmacokinetics. In the future, in vitro phenotype classification may help to design personalised drug treatments.
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Affiliation(s)
- Laura Suominen
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland
| | - Noora Sjöstedt
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland
| | | | - Mikko Gynther
- School of Pharmacy, University of Eastern Finland, Kuopio FI-70210, Finland
| | - Seppo Auriola
- School of Pharmacy, University of Eastern Finland, Kuopio FI-70210, Finland
| | - Heidi Kidron
- Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Helsinki FI-00014, Finland.
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Özvegy-Laczka C, Ungvári O, Bakos É. Fluorescence-based methods for studying activity and drug-drug interactions of hepatic solute carrier and ATP binding cassette proteins involved in ADME-Tox. Biochem Pharmacol 2023; 209:115448. [PMID: 36758706 DOI: 10.1016/j.bcp.2023.115448] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/11/2023]
Abstract
In humans, approximately 70% of drugs are eliminated through the liver. This process is governed by the concerted action of membrane transporters and metabolic enzymes. Transporters mediating hepatocellular uptake of drugs belong to the SLC (Solute carrier) superfamily of transporters. Drug efflux either toward the portal vein or into the bile is mainly mediated by active transporters of the ABC (ATP Binding Cassette) family. Alteration in the function and/or expression of liver transporters due to mutations, disease conditions, or co-administration of drugs or food components can result in altered pharmacokinetics. On the other hand, drugs or food components interacting with liver transporters may also interfere with liver function (e.g., bile acid homeostasis) and may even cause liver toxicity. Accordingly, certain transporters of the liver should be investigated already at an early stage of drug development. Most frequently radioactive probes are applied in these drug-transporter interaction tests. However, fluorescent probes are cost-effective and sensitive alternatives to radioligands, and are gaining wider application in drug-transporter interaction tests. In our review, we summarize our current understanding about hepatocyte ABC and SLC transporters affected by drug interactions. We provide an update of the available fluorescent and fluorogenic/activable probes applicable in in vitro or in vivo testing of these ABC and SLC transporters, including near-infrared transporter probes especially suitable for in vivo imaging. Furthermore, our review gives a comprehensive overview of the available fluorescence-based methods, not directly relying on the transport of the probe, suitable for the investigation of hepatic ABC or SLC-type drug transporters.
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Affiliation(s)
- Csilla Özvegy-Laczka
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary.
| | - Orsolya Ungvári
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary; Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Éva Bakos
- Institute of Enzymology, RCNS, Eötvös Loránd Research Network, H-1117 Budapest, Magyar tudósok krt. 2., Hungary
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ABCG2 Polymorphisms and Predictive Fluoroquinolone Phototoxicity in Nondomestic Felids. Genes (Basel) 2022; 13:genes13122178. [PMID: 36553444 PMCID: PMC9778035 DOI: 10.3390/genes13122178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 11/14/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022] Open
Abstract
Fluoroquinolones are a widely used class of chemotherapeutics within veterinary medicine, prized for their broad-spectrum bactericidal activity. These drugs present a known risk of retinal phototoxicity in domestic cats (Felis catus); therefore, using lower doses and alternative antibiotic classes is encouraged in this species. This adverse drug effect of fluoroquinolones, and enrofloxacin specifically, has been determined to be species-specific in domestic felids. Four feline-specific missense variants in ABCG2 result in four amino acid changes (E159M, S279L, H283Q, and T644I) that are unique to the domestic cat compared with multiple other nonfeline mammalian species. These changes alter the ABCG2 protein involved with the cellular transmembrane transport of drugs, including fluoroquinolones, making the protein functionally defective in domestic cats. The predisposition to fluoroquinolone-mediated phototoxicity in nondomestic felids was explored in this study. At least eight nondomestic felids share the four ABCG2 missense variants with domestic cats, and eleven other felids shared at least three of the four domestic cat variants. Taken together, these results suggest the genetic potential for nondomestic felids to also experience fluoroquinolone-induced retinal phototoxicity; therefore, cautions similar to those for domestic cats should be followed for these drugs in the entire feline taxon.
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Ghanem CI, Manautou JE. Role and Regulation of Hepatobiliary ATP-Binding Cassette Transporters during Chemical-Induced Liver Injury. Drug Metab Dispos 2022; 50:1376-1388. [PMID: 35914951 PMCID: PMC9513844 DOI: 10.1124/dmd.121.000450] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/20/2022] [Indexed: 11/22/2022] Open
Abstract
Severity of drug-induced liver injury (DILI) ranges from mild, asymptomatic, and transient elevations in liver function tests to irreversible liver damage, often needing transplantation. Traditionally, DILI is classified mechanistically as high-frequency intrinsic DILI, commonly dose dependent or DILI that rarely occurs and is idiosyncratic in nature. This latter form is not dose dependent and has a pattern of histopathological manifestation that is not always uniform. Currently, a third type of DILI called indirect hepatotoxicity has been described that is associated with the pharmacological action of the drug. Historically, DILI was primarily linked to drug metabolism events; however, the impact of transporter-mediated rates of drug uptake and excretion has gained greater prominence in DILI research. This review provides a comprehensive view of the major findings from studies examining the contribution of hepatic ATP-binding cassette transporters as key contributors to DILI and how changes in their expression and function influence the development, severity, and overall toxicity outcome. SIGNIFICANCE STATEMENT: Drug-induced liver injury (DILI) continues to be a focal point in drug development research. ATP-binding cassette (ABC) transporters have emerged as important determinants of drug detoxification, disposition, and safety. This review article provides a comprehensive analysis of the literature addressing: (a) the role of hepatic ABC transporters in DILI, (b) the influence of genetic mutations in ABC transporters on DILI, and (c) new areas of research emphasis, such as the influence of the gut microbiota and epigenetic regulation, on ABC transporters.
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Affiliation(s)
- Carolina I Ghanem
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET) (C.I.G.) and Cátedra de Fisiopatología (C.I.G.), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (J.E.M.)
| | - Jose E Manautou
- Instituto de Investigaciones Farmacológicas (ININFA-UBA-CONICET) (C.I.G.) and Cátedra de Fisiopatología (C.I.G.), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina; and Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut (J.E.M.)
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Selective Fluorescent Probes for High-Throughput Functional Diagnostics of the Human Multidrug Transporter P-Glycoprotein (ABCB1). Int J Mol Sci 2022; 23:ijms231810599. [PMID: 36142507 PMCID: PMC9503576 DOI: 10.3390/ijms231810599] [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: 08/16/2022] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
The multidrug transporter ABCB1 (MDR1, Pgp) plays an important role in the absorption, distribution, metabolism, and elimination of a wide range of pharmaceutical compounds. Functional investigation of the ABCB1 expression is also essential in many diseases, including drug-resistant cancer, inflammatory conditions, or Alzheimer disease. In this study, we examined the potential interaction of the ABCB1 multidrug transporter with a group of commercially available viability dyes that are generally considered not to penetrate into intact cells. Here, we demonstrate that the slow cellular accumulation of TO-PRO™-1 (TP1) or TO-PRO™-3 (TP3) was strongly inhibited by ABCB1-dependent dye extrusion. TP1/3 dye accumulation was not affected by the presence of ABCC1 or ABCG2, while this uptake was increased to the level in the ABCB1-negative cells by a specific P-glycoprotein inhibitor, Tariquidar. We suggest that TP compounds can be used as highly sensitive, selective, non-toxic, and stable dyes to examine the functional expression and properties of the ABCB1 multidrug transporter, especially in microplate-based high-throughput flow cytometry assays. In addition, we demonstrate the applicability of the TP dyes to efficiently select and separate even a very low number of Pgp-expressing intact cells.
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Roncato R, Gerratana L, Palmero L, Gagno S, Poetto AS, Peruzzi E, Zanchetta M, Posocco B, De Mattia E, Canil G, Alberti M, Orleni M, Toffoli G, Puglisi F, Cecchin E. An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer. Front Pharmacol 2022; 13:897951. [PMID: 35942220 PMCID: PMC9356076 DOI: 10.3389/fphar.2022.897951] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug–drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients’ plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.
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Affiliation(s)
- Rossana Roncato
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- *Correspondence: Rossana Roncato, ; Sara Gagno,
| | - Lorenzo Gerratana
- Department of Medical Oncology-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Lorenza Palmero
- Department of Medical Oncology-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Sara Gagno
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- *Correspondence: Rossana Roncato, ; Sara Gagno,
| | - Ariana Soledad Poetto
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Elena Peruzzi
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Martina Zanchetta
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Bianca Posocco
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Elena De Mattia
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Giovanni Canil
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Martina Alberti
- Department of Medical Oncology-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Marco Orleni
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
| | - Fabio Puglisi
- Department of Medical Oncology-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Erika Cecchin
- Experimental and Clinical Pharmacology Unit-CRO Aviano, National Cancer Institute, IRCCS, Aviano, Italy
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Saavedra K, Leal K, Saavedra N, Prado Y, Paez I, Ubilla CG, Rojas G, Salazar LA. MicroRNA-20a-5p Downregulation by Atorvastatin: A Potential Mechanism Involved in Lipid-Lowering Therapy. Int J Mol Sci 2022; 23:ijms23095022. [PMID: 35563413 PMCID: PMC9104095 DOI: 10.3390/ijms23095022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/14/2022] [Accepted: 04/22/2022] [Indexed: 02/05/2023] Open
Abstract
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.
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Affiliation(s)
- Kathleen Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Karla Leal
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Nicolás Saavedra
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
| | - Yalena Prado
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Isis Paez
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Carmen G. Ubilla
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Gabriel Rojas
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
| | - Luis A. Salazar
- Center of Molecular Biology and Pharmacogenetics, Department of Basic Sciences, Faculty of Medicine, Universidad de La Frontera, Temuco 4811230, Chile; (K.S.); (K.L.); (N.S.); (Y.P.); (I.P.); (C.G.U.); (G.R.)
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile
- Correspondence:
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The Association between ABCG2 421C>A (rs2231142) Polymorphism and Rosuvastatin Pharmacokinetics: A Systematic Review and Meta-Analysis. Pharmaceutics 2022; 14:pharmaceutics14030501. [PMID: 35335877 PMCID: PMC8954661 DOI: 10.3390/pharmaceutics14030501] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/22/2022] [Accepted: 02/23/2022] [Indexed: 02/04/2023] Open
Abstract
Although several studies have revealed the association between rosuvastatin pharmacokinetics and the ABCG2 421C>A (rs2231142) polymorphism, most studies were conducted with small sample sizes, making it challenging to apply the findings clinically. Therefore, the purpose of this study is to perform a meta-analysis of the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. We searched three electronic databases, EMBASE, PubMed, and Web of Science, using search terms related to ABCG2 gene polymorphisms and rosuvastatin. In addition, we reviewed studies published before 12 August 2021, to examine the relationship between the ABCG2 421C>A polymorphism and rosuvastatin pharmacokinetics. To examine the magnitude of the association, the log geometric mean difference (lnGM) and 95% confidence intervals (CIs) were calculated and interpreted as the antilogarithm of a natural logarithm (elnGM). The meta-analysis was performed using Review Manager (version 5.4) and R Studio (version 4.0.2). Subgroup analysis was performed according to race and the types of mean values. Among the 318 identified studies, a total of 8 studies involving 423 patients is included in this meta-analysis. The A allele carriers of ABCG2 421C>A showed 1.5 times higher in both AUC0-∞ (lnGM = 0.43; 95% CI = 0.35−0.50; p < 0.00001) and Cmax (lnGM = 0.42; 95% CI = 0.33−0.51; p < 0.00001) than non-carriers, while there was no significant difference in Tmax and half-life. There was no significance in the pharmacokinetic parameters of the subgroups using either ethnicity or mean values. This meta-analysis demonstrates that subjects carrying the A allele of ABCG2 421C>A show significantly increased AUC0-∞ and Cmax values compared to subjects with the CC genotype. Therefore, information about ABCG2 genotypes might be useful for individualized rosuvastatin therapy.
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Interaction of Alcohol Consumption and ABCG2 rs2231142 Variant Contributes to Hyperuricemia in a Taiwanese Population. J Pers Med 2021; 11:jpm11111158. [PMID: 34834509 PMCID: PMC8618280 DOI: 10.3390/jpm11111158] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/29/2021] [Accepted: 11/04/2021] [Indexed: 12/22/2022] Open
Abstract
Background: ABCG2 rs2231142 is an important genetic factor that contributes to the development of gout and hyperuricemia (HUA). Epidemiologic studies have demonstrated that lifestyle risk factors of HUA (e.g., alcohol consumption) and genetic predisposition (e.g., ABCG2 gene) together, contribute to enhanced serum uric acid levels. However, the interaction between ABCG2 rs2231142, alcohol consumption, and HUA in the Taiwanese population is still unclear. Therefore, this study investigated whether the risk of HUA is associated with ABCG2 rs2231142 variants and how this is affected by alcohol consumption. Method: study subjects were selected from the participants of the Taiwan Biobank database. Overall, 114,540 participants aged 30 to 70 years were enrolled in this study. The interaction between ABCG2 rs2231142, alcohol consumption, and serum uric acid (sUA) levels was analyzed by multiple logistic regression models. Results: the prevalence of HUA was 32.7% and 4.4 % in the male and female populations, respectively. In the whole study population, the minor T allele of ABCG2 rs2231142 was significantly associated with HUA risk, and the occurrence of HUA was high in TT genotype and TG genotype. The risk of HUA was significantly increased by the combined association of ABCG2 rs2231142 and alcohol consumption for TG/TT genotype compared to the GG genotype (wild-type genotype), especially among women. Conclusion: the ABCG2 rs2231142 is a crucial genetic locus for sUA levels in the Taiwanese population and our findings revealed that alcohol consumption combined with the ABCG2 rs2231142 risk allele contributes to increased HUA risk.
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Jin Y, Li X, Jiang C, Zhao J, Liu G, Li H, Jin G, Li Q. An Update in Our Understanding of the Relationships Between Gene Polymorphisms and Chemotherapy-Induced Nausea and Vomiting. Int J Gen Med 2021; 14:5879-5892. [PMID: 34566427 PMCID: PMC8458022 DOI: 10.2147/ijgm.s329257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/01/2021] [Indexed: 11/23/2022] Open
Abstract
The occurrence and severity of chemotherapy-induced nausea and vomiting (CINV) are influenced by many factors; this includes therapeutic factors, such as the dose, administration mode, and chemotherapeutic agent emetogenicity, as well as patient-related risk factors, such as the gender, age, alcohol consumption history, and anxiety level. However, these factors cannot fully explain the individual CINV differences. In recent years, the correlation between gene polymorphism and CINV has been a hot research topic; the present paper reviews current research on CINV-related gene polymorphisms, and the results indicate that the use of gene polymorphism for the optimization of CINV efficacy is of important clinical significance.
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Affiliation(s)
- Yilan Jin
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Xiaorong Li
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Caihong Jiang
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Jun Zhao
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Guang Liu
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Hui Li
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Gaowa Jin
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
| | - Quanfu Li
- Department of Medical Oncology, Ordos Central Hospital, Ordos, 017000, People's Republic of China
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Wen X, Kozlosky D, Zhang R, Doherty C, Buckley B, Barrett E, Aleksunes LM. BCRP/ ABCG2 Transporter Regulates Accumulation of Cadmium in Kidney Cells: Role of the Q141K Variant in Modulating Nephrotoxicity. Drug Metab Dispos 2021; 49:629-637. [PMID: 34074729 PMCID: PMC8382159 DOI: 10.1124/dmd.121.000446] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/03/2021] [Indexed: 12/18/2022] Open
Abstract
Exposure to the environmental pollutant cadmium is ubiquitous, as it is present in cigarette smoke and the food supply. Over time, cadmium enters and accumulates in the kidneys, where it causes tubular injury. The breast cancer resistance protein (BCRP, ATP-Binding Cassette G2 ABCG2) is an efflux transporter that mediates the urinary secretion of pharmaceuticals and toxins. The ABCG2 genetic variant Q141K exhibits altered membrane trafficking that results in reduced efflux of BCRP substrates. Here, we sought to 1) evaluate the in vitro and in vivo ability of BCRP to transport cadmium and protect kidney cells from toxicity and 2) determine whether this protection is impaired by the Q141K variant. Cadmium concentrations, cellular stress, and toxicity were quantified in human embryonic kidney 293 cells expressing an empty vector (EV), BCRP wild-type (WT), or variant (Q141K) gene. Treatment with CdCl2 resulted in greater accumulation of cadmium and apoptosis in EV cells relative to WT cells. Exposure to CdCl2 induced expression of stress-related genes and proteins including MT-1A/MT-2A, NAD(P)H quinone dehydrogenase 1, and heme oxygenase-1 to a higher extent in EV cells compared with WT cells. Notably, the Q141K variant protected against CdCl2-induced activation of stress genes and cytotoxicity, but this protection was to a lesser magnitude than observed with WT BCRP. Lastly, concentrations of cadmium in the kidneys of Bcrp knockout mice were 40% higher than in WT mice, confirming that cadmium is an in vivo substrate of BCRP. In conclusion, BCRP prevents the accumulation of cadmium and protects against toxicity, a response that is impaired by the Q141K variant. SIGNIFICANCE STATEMENT: The breast cancer resistance protein transporter lowers cellular accumulation of the toxic heavy metal cadmium. This protective function is partially attenuated by the Q141K genetic variant in the ABCG2 gene.
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Affiliation(s)
- Xia Wen
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Danielle Kozlosky
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Ranran Zhang
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Cathleen Doherty
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Brian Buckley
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Emily Barrett
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
| | - Lauren M Aleksunes
- Department of Pharmacology and Toxicology, Rutgers University Ernest Mario School of Pharmacy, Piscataway, New Jersey (X.W., D.K., L.M.A.); Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, New Jersey (X.W., R.Z., C.D., B.B., E.B., L.M.A.); and Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey (R.Z., E.B.)
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Medically Important Alterations in Transport Function and Trafficking of ABCG2. Int J Mol Sci 2021; 22:ijms22062786. [PMID: 33801813 PMCID: PMC8001156 DOI: 10.3390/ijms22062786] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 02/06/2023] Open
Abstract
Several polymorphisms and mutations in the human ABCG2 multidrug transporter result in reduced plasma membrane expression and/or diminished transport function. Since ABCG2 plays a pivotal role in uric acid clearance, its malfunction may lead to hyperuricemia and gout. On the other hand, ABCG2 residing in various barrier tissues is involved in the innate defense mechanisms of the body; thus, genetic alterations in ABCG2 may modify the absorption, distribution, excretion of potentially toxic endo- and exogenous substances. In turn, this can lead either to altered therapy responses or to drug-related toxic reactions. This paper reviews the various types of mutations and polymorphisms in ABCG2, as well as the ways how altered cellular processing, trafficking, and transport activity of the protein can contribute to phenotypic manifestations. In addition, the various methods used for the identification of the impairments in ABCG2 variants and the different approaches to correct these defects are overviewed.
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Bruckmueller H, Cascorbi I. ABCB1, ABCG2, ABCC1, ABCC2, and ABCC3 drug transporter polymorphisms and their impact on drug bioavailability: what is our current understanding? Expert Opin Drug Metab Toxicol 2021; 17:369-396. [PMID: 33459081 DOI: 10.1080/17425255.2021.1876661] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Interindividual differences in drug response are a frequent clinical challenge partly due to variation in pharmacokinetics. ATP-binding cassette (ABC) transporters are crucial determinants of drug disposition. They are subject of gene regulation and drug-interaction; however, it is still under debate to which extend genetic variants in these transporters contribute to interindividual variability of a wide range of drugs. AREAS COVERED This review discusses the current literature on the impact of genetic variants in ABCB1, ABCG2 as well as ABCC1, ABCC2, and ABCC3 on pharmacokinetics and drug response. The aim was to evaluate if results from recent studies would increase the evidence for potential clinically relevant pharmacogenetic effects. EXPERT OPINION Although enormous efforts have been made to investigate effects of ABC transporter genotypes on drug pharmacokinetics and response, the majority of studies showed only weak if any associations. Despite few unique results, studies mostly failed to confirm earlier findings or still remained inconsistent. The impact of genetic variants on drug bioavailability is only minor and other factors regulating the transporter expression and function seem to be more critical. In our opinion, the findings on the so far investigated genetic variants in ABC efflux transporters are not suitable as predictive biomarkers.
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Affiliation(s)
- Henrike Bruckmueller
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Ingolf Cascorbi
- Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
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Shu H, Yuan B, Huang Y, Wang L, He B, Sun Q, Sun L. High expression of ABCG2 is associated with chemotherapy resistance of osteosarcoma. J Orthop Surg Res 2021; 16:85. [PMID: 33509236 PMCID: PMC7842061 DOI: 10.1186/s13018-021-02204-z] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/04/2021] [Indexed: 12/18/2022] Open
Abstract
Objectives Previous studies showed overexpression of ABCG2 in a variety of tumor tissues, which could potentially indicate the probability of chemotherapy resistance. This study aimed to reveal the role of ABCG2 in the development of chemotherapy resistance and the prognosis of osteosarcoma (OS). Methods Sixty-eight OS patients were included in this study. Tumor tissues were collected for each patient during surgery. DOX-resistant OS cell lines were induced by consecutive exposure of gradually increasing concentration of DOX to the parental cell lines. Lentivirus was used for the knockdown of ABCG2 in OS cells. Cells were treated with the gradient concentration of DOX, and the viability was assessed by CCK8 assay. Total RNA was isolated from the tumor tissues or tumor cells, and the expression of ABCG2 was analyzed by qPCR. The relationship between ABCG2 expression and clinicopathological characteristics of the patients was analyzed using Student’s t test or the Chi-square test. The overall survival time was calculated by the Kaplan-Meier method and analyzed by the log-rank test. p < 0.05 was considered statistically significant. Results DOX-resistant OS cells were successfully established through continuous exposure to DOX. Forty-eight hours after DOX exposure, the IC 50 value of DOX-resistant HOS cells and DOX-resistant U2OS was 3.5 μM and 3.25 μM, respectively. By contrast, those of the untreated HOS and U2OS cells were 1.15 μM and 0.93 μM, respectively (p < 0.01). The mRNA expression level of ABCG2 was significantly increased in DOX-resistant cell lines. The CCK-8 assay showed that the DOX-resistant HOS cells and DOX-resistant U2OS cells transfected with ShABCG2 were more sensitive to the DOX treatment than those transfected with ShCtrl. Analysis of gene expression in OS tissues showed remarkably higher expression of ABCG2 as compared with adjacent normal tissues (p < 0.01). Patients with high expression level of ABCG2 had obviously decreased overall survival time than the patients with normal expression (p < 0.01). Conclusions ABCG2 expression level was significantly associated with the resistance to chemotherapy and the overall survival of OS patients. ABCG2 may be a promising therapeutic target for OS patients. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-021-02204-z.
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Affiliation(s)
- Hao Shu
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China
| | - Bin Yuan
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China
| | - Yao Huang
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China
| | - Lei Wang
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China
| | - Bing He
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China
| | - Qi Sun
- Department of Pathology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China
| | - Luning Sun
- Department of Orthopedics, Sports Medicine Center, Affiliated Hospital of Nanjing University of Chinese Medicine, Hanzhong Road 115, Nanjing, 210029, China.
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Gao S, Bell EC, Zhang Y, Liang D. Racial Disparity in Drug Disposition in the Digestive Tract. Int J Mol Sci 2021; 22:1038. [PMID: 33494365 PMCID: PMC7865938 DOI: 10.3390/ijms22031038] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/17/2021] [Accepted: 01/18/2021] [Indexed: 12/13/2022] Open
Abstract
The major determinants of drug or, al bioavailability are absorption and metabolism in the digestive tract. Genetic variations can cause significant differences in transporter and enzyme protein expression and function. The racial distribution of selected efflux transporter (i.e., Pgp, BCRP, MRP2) and metabolism enzyme (i.e., UGT1A1, UGT1A8) single nucleotide polymorphisms (SNPs) that are highly expressed in the digestive tract are reviewed in this paper with emphasis on the allele frequency and the impact on drug absorption, metabolism, and in vivo drug exposure. Additionally, preclinical and clinical models used to study the impact of transporter/enzyme SNPs on protein expression and function are also reviewed. The results showed that allele frequency of the major drug efflux transporters and the major intestinal metabolic enzymes are highly different in different races, leading to different drug disposition and exposure. The conclusion is that genetic polymorphism is frequently observed in different races and the related protein expression and drug absorption/metabolism function and drug in vivo exposure can be significantly affected, resulting in variations in drug response. Basic research on race-dependent drug absorption/metabolism is expected, and FDA regulations of drug dosing adjustment based on racial disparity are suggested.
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Affiliation(s)
- Song Gao
- Department of Pharmaceutical Science, College of Pharmacy and Health Sciences, Texas Southern University, 3100 Cleburne Street, Houston, TX 77004, USA; (E.C.B.); (Y.Z.); (D.L.)
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20
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Ahangari N, Doosti M, Ghayour Mobarhan M, Sahebkar A, Ferns GA, Pasdar A. Personalised medicine in hypercholesterolaemia: the role of pharmacogenetics in statin therapy. Ann Med 2020; 52:462-470. [PMID: 32735150 PMCID: PMC7877934 DOI: 10.1080/07853890.2020.1800074] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Statins are the first-line choice in Lipid-lowering therapy to reduce cardiovascular risk. In a continuous attempt to optimise treatment success, there is a need for additional research on genes and related molecular pathways that can determine the efficacy and toxicity of lipid-lowering drugs. Several variations within genes associated with lipid metabolism, including those involved in uptake, distribution and metabolism of statins have been reported. The purpose of this study was to evaluate the effect of genetic variations in the key genes responsible for statins' metabolism and their role in personalised medicine and pharmacogenetic testing (PGx) in patients treated with such drugs. Genetic assessment for specific known SNPs within the most known genes such as ABCG2, SLCO1B1, CYP3A4, and HMGCR, appears likely to predict the efficacy of statin therapy and prevent their side effects but does not necessarily reduce the risk of cardiovascular events. Key Messages Hypercholesterolaemia patients show different response to statin therapy. Several variations within genes associated with statin metabolism have been investigated. Genetic assessment for specific known SNPs within the most known genes may improve the efficacy of statins treatment and prevent their side effects.
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Affiliation(s)
- Najmeh Ahangari
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Doosti
- Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
| | - Majid Ghayour Mobarhan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton and Sussex Medical School, Brighton, UK
| | - Alireza Pasdar
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Division of Applied Medicine, Medical School, University of Aberdeen, Aberdeen, UK.,Bioinformatics Research Group, Mashhad University of Medical Sciences, Mashhad, Iran
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Chen KG, Duran GE, Mogul MJ, Wang YC, Ross KL, Jaffrézou JP, Huff LM, Johnson KR, Fojo T, Lacayo NJ, Sikic BI. Genomic stability at the coding regions of the multidrug transporter gene ABCB1: insights into the development of alternative drug resistance mechanisms in human leukemia cells. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3:959-979. [PMID: 34541464 PMCID: PMC8445225 DOI: 10.20517/cdr.2020.51] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/19/2020] [Accepted: 10/09/2020] [Indexed: 01/12/2023]
Abstract
AIM Despite considerable efforts to reverse clinical multidrug resistance (MDR), targeting the predominant multidrug transporter ABCB1/P-glycoprotein (P-gp) using small molecule inhibitors has been unsuccessful, possibly due to the emergence of alternative drug resistance mechanisms. However, the non-specific P-gp inhibitor cyclosporine (CsA) showed significant clinical benefits in patients with acute myeloid leukemia (AML), which likely represents the only proof-of-principle clinical trial using several generations of MDR inhibitors. Nevertheless, the mutational mechanisms that may underlie unsuccessful MDR modulation by CsA are not elucidated because of the absence of CsA-relevant cellular models. In this study, our aims were to establish CsA-resistant leukemia models and to examine the presence or absence of ABCB1 exonic mutations in these models as well as in diverse types of human cancer samples including AMLs. METHODS Drug-resistant lines were established by stepwise drug co-selection and characterized by drug sensitivity assay, rhodamine-123 accumulation, [3H]-labeled drug export, ABCB1 cDNA sequencing, and RNase protection assay. The genomic stability of the ABCB1 coding regions was evaluated by exome sequencing analysis of variant allele frequencies in human populations. Moreover, the mutational spectrum of ABCB1 was further assessed in diverse types of cancer samples including AMLs in the Cancer Genome Atlas (TCGA) at the National Cancer Institute. RESULTS We report the development of two erythroleukemia variants, RVC and RDC, which were derived by stepwise co-selection of K562/R7 drug-resistant leukemia cells with the etoposide-CsA and doxorubicin-CsA drug combinations, respectively. Interestingly, both RVC and RDC cell lines, which retained P-gp expression, showed altered multidrug-resistant phenotypes that were resistant to CsA modulation. Strikingly, no mutations were found in the ABCB1 coding regions in these variant cells even under long-term stringent drug selection. Genomically, ABCB1 displayed relatively low variant allele frequencies in human populations when compared with several ABC superfamily members. Moreover, ABCB1 also exhibited a very low mutational frequency in AMLs compared with all types of human cancer. In addition, we found that CsA played a role in undermining the selection of highly drug-resistant cells via induction of low-level and unstable drug resistance. CONCLUSION Our data indicate that ABCB1 coding regions are genomically stable and relatively resistant to drug-induced mutations. Non-ABCB1 mutational mechanisms are responsible for the drug-resistant phenotypes in both RVC and RDC cell lines, which are also prevalent in clinical AML patients. Accordingly, we propose several relevant models that account for the development of alternative drug resistance mechanisms in the absence of ABCB1 mutations.
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Affiliation(s)
- Kevin G. Chen
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Current Address: NIH Stem Cell Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - George E. Duran
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mark J. Mogul
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Current Address: Medical Affairs U.S., Servier Pharmaceuticals, Boston, MA 02210, USA
| | - Yan C. Wang
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Kevin L. Ross
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Current Address: Ross BioPharm Group, Rocky Point, NY 11778, USA
| | - Jean-Pierre Jaffrézou
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Current Address: French National Centre for Scientific Research, Paris 75016, France
| | - Lyn M. Huff
- Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Current Address, Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kory R. Johnson
- Intramural IT and Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tito Fojo
- Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
- Current Address: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center/New York-Presbyterian Hospital, New York, NY 10032, USA
| | - Norman J. Lacayo
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
- Division of Pediatric Hematology-Oncology-Stem Cell Transplantation and Cancer Biology, Stanford University School of Medicine and Stanford Cancer Institute, Palo Alto, CA 94305, USA
| | - Branimir I. Sikic
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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22
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Sarkadi B, Homolya L, Hegedűs T. The ABCG2/BCRP transporter and its variants - from structure to pathology. FEBS Lett 2020; 594:4012-4034. [PMID: 33015850 DOI: 10.1002/1873-3468.13947] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/27/2020] [Accepted: 09/21/2020] [Indexed: 12/13/2022]
Abstract
The ABCG2 protein has a key role in the transport of a wide range of structurally dissimilar endo- and xenobiotics in the human body, especially in the tissue barriers and the metabolizing or secreting organs. The human ABCG2 gene harbors a high number of polymorphisms and mutations, which may significantly modulate its expression and function. Recent high-resolution structural data, complemented with molecular dynamic simulations, may significantly help to understand intramolecular movements and substrate handling, as well as the effects of mutations on the membrane transporter function of ABCG2. As reviewed here, structural alterations may result not only in direct alterations in drug binding and transporter activity, but also in improper folding or problems in the carefully regulated process of trafficking, including vesicular transport, endocytosis, recycling, and degradation. Here, we also review the clinical importance of altered ABCG2 expression and function in general drug metabolism, cancer multidrug resistance, and impaired uric acid excretion, leading to gout.
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Affiliation(s)
- Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.,Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary
| | - Tamás Hegedűs
- Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
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23
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Khunweeraphong N, Mitchell-White J, Szöllősi D, Hussein T, Kuchler K, Kerr ID, Stockner T, Lee JY. Picky ABCG5/G8 and promiscuous ABCG2 - a tale of fatty diets and drug toxicity. FEBS Lett 2020; 594:4035-4058. [PMID: 32978801 PMCID: PMC7756502 DOI: 10.1002/1873-3468.13938] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 09/03/2020] [Indexed: 12/20/2022]
Abstract
Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily G ATP‐binding cassette (ABCG) transporters and disclose putative substrate‐binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane‐embedded polar relay, the re‐entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transports only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol‐binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters.
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Affiliation(s)
- Narakorn Khunweeraphong
- Max Perutz Labs Vienna, Campus Vienna Biocenter, Center for Medical Biochemistry, Medical University of Vienna, Vienna, Austria.,CCRI-St. Anna Children's Cancer Research Institute, Vienna, Austria
| | - James Mitchell-White
- School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Dániel Szöllősi
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Toka Hussein
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Karl Kuchler
- Max Perutz Labs Vienna, Campus Vienna Biocenter, Center for Medical Biochemistry, Medical University of Vienna, Vienna, Austria
| | - Ian D Kerr
- School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Thomas Stockner
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Jyh-Yeuan Lee
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
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24
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Gagno S, Bartoletti M, Romualdi C, Poletto E, Scalone S, Sorio R, Zanchetta M, De Mattia E, Roncato R, Cecchin E, Giorda G, Toffoli G. Pharmacogenetic score predicts overall survival, progression-free survival and platinum sensitivity in ovarian cancer. Pharmacogenomics 2020; 21:995-1010. [PMID: 32894980 DOI: 10.2217/pgs-2020-0049] [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
Aim: To define the impact of polymorphisms in genes involved in platinum-taxane and estrogen activity in the outcome of platinum-based treated ovarian cancer patients (OCP). Patients & Methods: Two hundred and thirty OCP were analyzed for 124 germ-line polymorphisms to generate a prognostic score for overall survival (OS), progression-free survival (PFS) and platinum-free interval (PFI). Results: ABCG2 rs3219191D>I, UGT1A rs10929302G>A and UGT1A rs2741045T>C polymorphisms were significantly associated with all three parameters (OS, PFS and PFI) and were used to generate a score. Patients in high-risk group had a poorer OS (hazard ratio [HR]: 1.8; 95% CI: 1.3-2.7; p = 0.0019), PFS (HR: 2.0; 95% CI: 1.4-2.9; p < 0.0001) and PFI (HR: 1.9; 95% CI: 1.4-2.8; p = 0.0002) compared with those in low-risk group. Conclusion: The prognostic-score including polymorphisms involved in drug and estrogen pathways stratifies OCP according to OS, PFS and PFI.
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Affiliation(s)
- Sara Gagno
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Michele Bartoletti
- Department of Medicine (DAME), University of Udine, Via Palladio 8, 33100, Udine, Italy.,Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Chiara Romualdi
- Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35122, Padova, Italy
| | - Elena Poletto
- Department of Oncology, ASUI Udine University Hospital, Via Pozzuolo 330, 33100, Udine, Italy
| | - Simona Scalone
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Roberto Sorio
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Martina Zanchetta
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Elena De Mattia
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Rossana Roncato
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Erika Cecchin
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Giorgio Giorda
- Gynaecological Oncology Unit, Centro di Riferimento Oncologico (CRO) di Aviano, IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
| | - Giuseppe Toffoli
- Experimental & Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Via Franco Gallini 2, 33081, Aviano, Italy
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25
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Future avenues for Alzheimer's disease detection and therapy: liquid biopsy, intracellular signaling modulation, systems pharmacology drug discovery. Neuropharmacology 2020; 185:108081. [PMID: 32407924 DOI: 10.1016/j.neuropharm.2020.108081] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/01/2020] [Accepted: 03/30/2020] [Indexed: 12/20/2022]
Abstract
When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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26
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Horsey AJ, Briggs DA, Holliday ND, Briddon SJ, Kerr ID. Application of fluorescence correlation spectroscopy to study substrate binding in styrene maleic acid lipid copolymer encapsulated ABCG2. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1862:183218. [PMID: 32057756 PMCID: PMC7156912 DOI: 10.1016/j.bbamem.2020.183218] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 01/28/2020] [Accepted: 01/30/2020] [Indexed: 12/16/2022]
Abstract
ABCG2 is one of a trio of human ATP binding cassette transporters that have the ability to bind and transport a diverse array of chemical substrates out of cells. This so-called "multidrug" transport has numerous physiological consequences including effects on how drugs are absorbed into and eliminated from the body. Understanding how ABCG2 is able to interact with multiple drug substrates remains an important goal in transporter biology. Most drugs are believed to interact with ABCG2 through the hydrophobic lipid bilayer and experimental systems for ABCG2 study need to incorporate this. We have exploited styrene maleic acid to solubilise ABCG2 from HEK293T cells overexpressing the transporter, and confirmed by dynamic light scattering and fluorescence correlation spectroscopy (FCS) that this results in the extraction of SMA lipid copolymer (SMALP) particles that are uniform in size and contain a dimer of ABCG2, which is the predominant physiological state. FCS was further employed to measure the diffusion of a fluorescent ABCG2 substrate (BODIPY-prazosin) in the presence and absence of SMALP particles of purified ABCG2. Autocorrelation analysis of FCS traces enabled the mathematical separation of free BODIPY-prazosin from drug bound to ABCG2 and allowed us to show that combining SMALP extraction with FCS can be used to study specific drug: transporter interactions.
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Affiliation(s)
- Aaron J Horsey
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Deborah A Briggs
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Nicholas D Holliday
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Stephen J Briddon
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, University of Birmingham and University of Nottingham, The Midlands, UK.
| | - Ian D Kerr
- School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
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27
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Zámbó B, Mózner O, Bartos Z, Török G, Várady G, Telbisz Á, Homolya L, Orbán TI, Sarkadi B. Cellular expression and function of naturally occurring variants of the human ABCG2 multidrug transporter. Cell Mol Life Sci 2020; 77:365-378. [PMID: 31254042 PMCID: PMC6971004 DOI: 10.1007/s00018-019-03186-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/29/2019] [Accepted: 06/06/2019] [Indexed: 12/20/2022]
Abstract
The human ABCG2 multidrug transporter plays a crucial role in the absorption and excretion of xeno- and endobiotics; thus the relatively frequent polymorphic and mutant ABCG2 variants in the population may significantly alter disease conditions and pharmacological effects. Low-level or non-functional ABCG2 expression may increase individual drug toxicity, reduce cancer drug resistance, and result in hyperuricemia and gout. In the present work we have studied the cellular expression, trafficking, and function of nine naturally occurring polymorphic and mutant variants of ABCG2. A comprehensive analysis of the membrane localization, transport, and ATPase activity, as well as retention and degradation in intracellular compartments was performed. Among the examined variants, R147W and R383C showed expression and/or protein folding defects, indicating that they could indeed contribute to ABCG2 functional deficiency. These studies and the applied methods should significantly promote the exploration of the medical effects of these personal variants, promote potential therapies, and help to elucidate the specific role of the affected regions in the folding and function of the ABCG2 protein.
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Affiliation(s)
- Boglárka Zámbó
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - Orsolya Mózner
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - Zsuzsa Bartos
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - György Török
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - György Várady
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - Ágnes Telbisz
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - Tamás I Orbán
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary
| | - Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudosok krt. 2, Budapest, 1117, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tuzolto u. 37-47, Budapest, 1094, Hungary.
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28
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Khot MI, Downey CL, Armstrong G, Svavarsdottir HS, Jarral F, Andrew H, Jayne DG. The role of ABCG2 in modulating responses to anti-cancer photodynamic therapy. Photodiagnosis Photodyn Ther 2019; 29:101579. [PMID: 31639455 DOI: 10.1016/j.pdpdt.2019.10.014] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Revised: 10/03/2019] [Accepted: 10/11/2019] [Indexed: 01/10/2023]
Abstract
The ATP-binding cassette (ABC) superfamily G member 2 (ABCG2) transmembrane protein transporter is known for conferring resistance to treatment in cancers. Photodynamic therapy (PDT) is a promising anti-cancer method involving the use of light-activated photosensitisers to precisely induce oxidative stress and cell death in cancers. ABCG2 can efflux photosensitisers from out of cells, reducing the capacity of PDT and limiting the efficacy of treatment. Many studies have attempted to elucidate the relationship between the expression of ABCG2 in cancers, its effect on the cellular retention of photosensitisers and its impact on PDT. This review looks at the studies which investigate the effect of ABCG2 on a range of different photosensitisers in different pre-clinical models of cancer. This work also evaluates the approaches that are being investigated to address the role of ABCG2 in PDT with an outlook on potential clinical validation.
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Affiliation(s)
- M Ibrahim Khot
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK.
| | - Candice L Downey
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - Gemma Armstrong
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | | | - Fazain Jarral
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - Helen Andrew
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
| | - David G Jayne
- School of Medicine, St James's University Hospital, University of Leeds, Leeds, UK
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29
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Mózner O, Bartos Z, Zámbó B, Homolya L, Hegedűs T, Sarkadi B. Cellular Processing of the ABCG2 Transporter-Potential Effects on Gout and Drug Metabolism. Cells 2019; 8:E1215. [PMID: 31597297 PMCID: PMC6830335 DOI: 10.3390/cells8101215] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/04/2019] [Accepted: 10/05/2019] [Indexed: 02/07/2023] Open
Abstract
The human ABCG2 is an important plasma membrane multidrug transporter, involved in uric acid secretion, modulation of absorption of drugs, and in drug resistance of cancer cells. Variants of the ABCG2 transporter, affecting cellular processing and trafficking, have been shown to cause gout and increased drug toxicity. In this paper, we overview the key cellular pathways involved in the processing and trafficking of large membrane proteins, focusing on ABC transporters. We discuss the information available for disease-causing polymorphic variants and selected mutations of ABCG2, causing increased degradation and impaired travelling of the transporter to the plasma membrane. In addition, we provide a detailed in silico analysis of an as yet unrecognized loop region of the ABCG2 protein, in which a recently discovered mutation may actually promote ABCG2 membrane expression. We suggest that post-translational modifications in this unstructured loop at the cytoplasmic surface of the protein may have special influence on ABCG2 processing and trafficking.
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Affiliation(s)
- Orsolya Mózner
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Zsuzsa Bartos
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Boglárka Zámbó
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Tamás Hegedűs
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
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30
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Pan G. Roles of Hepatic Drug Transporters in Drug Disposition and Liver Toxicity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1141:293-340. [PMID: 31571168 DOI: 10.1007/978-981-13-7647-4_6] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatic drug transporters are mainly distributed in parenchymal liver cells (hepatocytes), contributing to drug's liver disposition and elimination. According to their functions, hepatic transporters can be roughly divided into influx and efflux transporters, translocating specific molecules from blood into hepatic cytosol and mediating the excretion of drugs and metabolites from hepatic cytosol to blood or bile, respectively. The function of hepatic transport systems can be affected by interspecies differences and inter-individual variability (polymorphism). In addition, some drugs and disease can redistribute transporters from the cell surface to the intracellular compartments, leading to the changes in the expression and function of transporters. Hepatic drug transporters have been associated with the hepatic toxicity of drugs. Gene polymorphism of transporters and altered transporter expressions and functions due to diseases are found to be susceptible factors for drug-induced liver injury (DILI). In this chapter, the localization of hepatic drug transporters, their regulatory factors, physiological roles, and their roles in drug's liver disposition and DILI are reviewed.
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Affiliation(s)
- Guoyu Pan
- Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, Shanghai, China.
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31
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Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:63-70. [PMID: 31416579 DOI: 10.1016/j.mrrev.2019.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/04/2019] [Accepted: 04/08/2019] [Indexed: 01/11/2023]
Abstract
EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.
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Malfará BN, Benzi JRDL, de Oliveira Filgueira GC, Zanelli CF, Duarte G, de Carvalho Cavalli R, de Moraes NV. ABCG2 c.421C>A polymorphism alters nifedipine transport to breast milk in hypertensive breastfeeding women. Reprod Toxicol 2019; 85:1-5. [PMID: 30659932 DOI: 10.1016/j.reprotox.2019.01.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Revised: 11/30/2018] [Accepted: 01/15/2019] [Indexed: 01/16/2023]
Abstract
Nifedipine, a known substrate to breast cancer resistance protein (ABCG2/BCRP), is used for the treatment of hypertension during breastfeeding. This study aimed to evaluate the effect of ABCG2 c.421C>A on nifedipine transfer to breast milk (BM) in hypertensive women. Nineteen hypertensive breastfeeding women treated with 20 mg nifedipine every 12 hours were investigated. Blood and BM samples were collected simultaneously 15-30 days after delivery and at least 15 days after drug treatment. Patients genotyped as ABCG2 c.421CC showed nifedipine plasma and BM concentrations ranging from 8.32-178.1 ng/mL and 4.8-58.5 ng/mL, respectively. ABCG2 c.421C>A showed a trend towards significance (p = 0.0793) on nifedipine in BM, with concentrations approximately 3 times higher in the heterozygous 421 CA (29 ng/mL) in comparison to 421 CC (10.5 ng/mL). Nifedipine BM/plasma ratio was significantly lower in 421CC when compared to 421CA (p = 0.01). In conclusion, ABCG2 c.421C>A polymorphism is associated with higher transfer of nifedipine to BM.
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Affiliation(s)
- Bianca Nayra Malfará
- Department of Natural Products and Toxicology, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil
| | | | | | - Cleslei Fernando Zanelli
- Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil
| | - Geraldo Duarte
- Department of Gynecology and Obstetrics, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Ricardo de Carvalho Cavalli
- Department of Gynecology and Obstetrics, School of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil
| | - Natália Valadares de Moraes
- Department of Natural Products and Toxicology, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, Brazil.
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Abstract
The transport of specific molecules across lipid membranes is an essential function of all living organisms. The processes are usually mediated by specific transporters. One of the largest transporter families is the ATP-binding cassette (ABC) family. More than 40 ABC transporters have been identified in human, which are divided into 7 subfamilies (ABCA to ABCG) based on their gene structure, amino acid sequence, domain organization, and phylogenetic analysis. Of them, at least 11 ABC transporters including P-glycoprotein (P-GP/ABCB1), multidrug resistance-associated proteins (MRPs/ABCCs), and breast cancer resistance protein (BCRP/ABCG2) are involved in multidrug resistance (MDR) development. These ABC transporters are expressed in various tissues such as the liver, intestine, kidney, and brain, playing important roles in absorption, distribution, and excretion of drugs. Some ABC transporters are also involved in diverse cellular processes such as maintenance of osmotic homeostasis, antigen processing, cell division, immunity, cholesterol, and lipid trafficking. Several human diseases such as cystic fibrosis, sitosterolemia, Tangier disease, intrahepatic cholestasis, and retinal degeneration are associated with mutations in corresponding transporters. This chapter will describe function and expression of several ABC transporters (such as P-GP, BCRP, and MRPs), their substrates and inhibitors, as well as their clinical significance.
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Affiliation(s)
- Xiaodong Liu
- China Pharmaceutical University, Nanjing, China.
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Heyes N, Kapoor P, Kerr ID. Polymorphisms of the Multidrug Pump ABCG2: A Systematic Review of Their Effect on Protein Expression, Function, and Drug Pharmacokinetics. Drug Metab Dispos 2018; 46:1886-1899. [PMID: 30266733 DOI: 10.1124/dmd.118.083030] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 09/20/2018] [Indexed: 12/11/2022] Open
Abstract
The widespread expression and polyspecificity of the multidrug ABCG2 efflux transporter make it an important determinant of the pharmacokinetics of a variety of substrate drugs. Null ABCG2 expression has been linked to the Junior blood group. Polymorphisms affecting the expression or function of ABCG2 may have clinically important roles in drug disposition and efficacy. The most well-studied single nucleotide polymorphism (SNP), Q141K (421C>A), is shown to decrease ABCG2 expression and activity, resulting in increased total drug exposure and decreased resistance to various substrates. The effect of Q141K can be rationalized by inspection of the ABCG2 structure, and the effects of this SNP on protein processing may make it a target for pharmacological intervention. The V12M SNP (34G>A) appears to improve outcomes in cancer patients treated with tyrosine kinase inhibitors, but the reasons for this are yet to be established, and this residue's role in the mechanism of the protein is unexplored by current biochemical and structural approaches. Research into the less-common polymorphisms is confined to in vitro studies, with several polymorphisms shown to decrease resistance to anticancer agents such as SN-38 and mitoxantrone. In this review, we present a systematic analysis of the effects of ABCG2 polymorphisms on ABCG2 function and drug pharmacokinetics. Where possible, we use recent structural advances to present a molecular interpretation of the effects of SNPs and indicate where we need further in vitro experiments to fully resolve how SNPs impact ABCG2 function.
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Affiliation(s)
- Niall Heyes
- School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Parth Kapoor
- School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
| | - Ian D Kerr
- School of Life Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, United Kingdom
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Polymorphisms of ABCG2 and its impact on clinical relevance. Biochem Biophys Res Commun 2018; 503:408-413. [PMID: 29964015 DOI: 10.1016/j.bbrc.2018.06.157] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 12/11/2022]
Abstract
Human ABCG2 is one of the most important ATP-binding cassette (ABC) transporters. This protein functions as a xenobiotic transporter of large, hydrophobic, positively or negatively charged molecules, a wide variety anticancer drugs, fluorescent dyes, and different toxic compounds found in normal food. SNPs in ABCG2 may affect absorption and distribution of these substrates, altering the accumulation, effectiveness and toxicity of compounds or drugs in large populations. Its transport properties have been implicated clinically and ABCG2 expression is linked with different disease states. We reviewed the SNPs of ABCG2 in clinical relevance about gout, acute myeloid leukemia, solid tumors, and other diseases.
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Robey RW, Pluchino KM, Hall MD, Fojo AT, Bates SE, Gottesman MM. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat Rev Cancer 2018; 18:452-464. [PMID: 29643473 PMCID: PMC6622180 DOI: 10.1038/s41568-018-0005-8] [Citation(s) in RCA: 1237] [Impact Index Per Article: 176.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Most patients who die of cancer have disseminated disease that has become resistant to multiple therapeutic modalities. Ample evidence suggests that the expression of ATP-binding cassette (ABC) transporters, especially the multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), which is encoded by ABC subfamily B member 1 (ABCB1), can confer resistance to cytotoxic and targeted chemotherapy. However, the development of MDR1 as a therapeutic target has been unsuccessful. At the time of its discovery, appropriate tools for the characterization and clinical development of MDR1 as a therapeutic target were lacking. Thirty years after the initial cloning and characterization of MDR1 and the implication of two additional ABC transporters, the multidrug resistance-associated protein 1 (MRP1; encoded by ABCC1)), and ABCG2, in multidrug resistance, interest in investigating these transporters as therapeutic targets has waned. However, with the emergence of new data and advanced techniques, we propose to re-evaluate whether these transporters play a clinical role in multidrug resistance. With this Opinion article, we present recent evidence indicating that it is time to revisit the investigation into the role of ABC transporters in efficient drug delivery in various cancer types and at the blood-brain barrier.
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Affiliation(s)
- Robert W Robey
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Kristen M Pluchino
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Matthew D Hall
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA
| | - Antonio T Fojo
- Division of Hematology/Oncology, Department of Medicine, Columbia University/New York Presbyterian Hospital, Manhattan, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
| | - Susan E Bates
- Division of Hematology/Oncology, Department of Medicine, Columbia University/New York Presbyterian Hospital, Manhattan, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
| | - Michael M Gottesman
- Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Rocha KCE, Pereira BMV, Rodrigues AC. An update on efflux and uptake transporters as determinants of statin response. Expert Opin Drug Metab Toxicol 2018; 14:613-624. [PMID: 29842801 DOI: 10.1080/17425255.2018.1482276] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Statins are used in the treatment of dyslipidemia promoting primary and secondary prevention against detrimental cardiovascular events. ATP-binding cassette (ABC) and solute carrier (SLC) membrane transporters transport statins across the cell membrane. Differences in drug transporter tissue expression and activity contribute to variability in statin pharmacokinetics (PK) and response. Areas covered: The purpose of this review is to discuss factors impacting transporter expression and the effect this has on statin efficacy and safety. Previous studies have demonstrated that genetic polymorphisms, drug-drug interactions (DDI), nuclear receptors, and microRNAs affect statin PK and pharmacodynamics. Expert opinion: Genetic variants of ABCG2 and SLCO1B1 transporters affect statin PK and, as a result, the intended lipid-lowering response. However, the effect size is small, limiting its applicability in clinical practice. Furthermore, genetic variants do not totally explain the observed intervariability in statin response. Thus, it is likely that transcriptional and post-transcriptional regulation of drug transporters are also highly involved. Further studies are required to understand the contribution of each of these new factors in statin disposition and toxicity.
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Affiliation(s)
- Karina Cunha E Rocha
- a Department of Pharmacology , Institute of Biomedical Sciences, University of Sao Paulo , Sao Paulo , SP , Brazil
| | - Beatriz Maria Veloso Pereira
- a Department of Pharmacology , Institute of Biomedical Sciences, University of Sao Paulo , Sao Paulo , SP , Brazil
| | - Alice Cristina Rodrigues
- a Department of Pharmacology , Institute of Biomedical Sciences, University of Sao Paulo , Sao Paulo , SP , Brazil
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Futatsugi A, Toshimoto K, Yoshikado T, Sugiyama Y, Kato Y. Evaluation of Alteration in Hepatic and Intestinal BCRP Function In Vivo from ABCG2 c.421C>A Polymorphism Based on PBPK Analysis of Rosuvastatin. Drug Metab Dispos 2018; 46:749-757. [PMID: 29440178 DOI: 10.1124/dmd.117.078816] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 02/08/2018] [Indexed: 01/06/2023] Open
Abstract
Polymorphism c.421C>A in the ABCG2 gene is thought to reduce the activity of breast cancer resistance protein (BCRP), a xenobiotic transporter, although it is not clear which organ(s) contributes to the polymorphism-associated pharmacokinetic change. The aim of the present study was to estimate quantitatively the influence of c.421C>A on intestinal and hepatic BCRP activity using a physiologically based pharmacokinetic (PBPK) model of rosuvastatin developed from clinical data and several in vitro studies. Simultaneous fitting of clinical data for orally and intravenously administered rosuvastatin, obtained in human subjects without genotype information, was first performed with the PBPK model to estimate intrinsic clearance for hepatic elementary process. The fraction of BCRP activity in 421CA and 421AA (fca and faa values, respectively) with respect to that in 421CC subjects was then estimated based on extended clearance concepts and simultaneous fitting to oral administration data for the three genotypes (421CC, 421CA, and 421AA). On the assumption that c.421C>A affects both intestinal and hepatic BCRP, clinical data in each genotype were well reproduced by the model, and the estimated terminal half-life was compatible with the observed values. The assumption that c.421C>A affects only either intestinal or hepatic BCRP gave poorer agreement with observed values. The faa values obtained on the former assumption were 0.48-0.54. Thus, PBPK model analysis enabled quantitative evaluation of alteration in BCRP activity owing to c.421C>A, and BCRP activity in 421AA was estimated as half that in 421CC.
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Affiliation(s)
- Azusa Futatsugi
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN (A.F., K.T., T.Y., Y.S.), and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (A.F., Y.K.), Kanazawa, Japan
| | - Kota Toshimoto
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN (A.F., K.T., T.Y., Y.S.), and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (A.F., Y.K.), Kanazawa, Japan
| | - Takashi Yoshikado
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN (A.F., K.T., T.Y., Y.S.), and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (A.F., Y.K.), Kanazawa, Japan
| | - Yuichi Sugiyama
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN (A.F., K.T., T.Y., Y.S.), and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (A.F., Y.K.), Kanazawa, Japan
| | - Yukio Kato
- Sugiyama Laboratory, RIKEN Innovation Center, RIKEN Cluster for Industry Partnerships, RIKEN (A.F., K.T., T.Y., Y.S.), and Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (A.F., Y.K.), Kanazawa, Japan
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A new fluorescent dye accumulation assay for parallel measurements of the ABCG2, ABCB1 and ABCC1 multidrug transporter functions. PLoS One 2018; 13:e0190629. [PMID: 29342177 PMCID: PMC5771559 DOI: 10.1371/journal.pone.0190629] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 12/18/2017] [Indexed: 01/01/2023] Open
Abstract
ABC multidrug transporters are key players in cancer multidrug resistance and in general xenobiotic elimination, thus their functional assays provide important tools for research and diagnostic applications. In this study we have examined the potential interactions of three key human ABC multidrug transporters with PhenGreen diacetate (PGD), a cell permeable fluorescent metal ion indicator. The non-fluorescent, hydrophobic PGD rapidly enters the cells and, after cleavage by cellular esterases, in the absence of quenching metal ions, PhenGreen (PG) becomes highly fluorescent. We found that in cells expressing functional ABCG2, ABCB1, or ABCC1 transporters, cellular PG fluorescence is strongly reduced. This fluorescence signal in the presence of specific transporter inhibitors is increased to the fluorescence levels in the control cells. Thus the PG accumulation assay is a new, unique tool for the parallel determination of the function of the ABCG2, ABCB1, and ABCC1 multidrug transporters. Since PG has very low cellular toxicity, the PG accumulation assay also allows the selection, separation and culturing of selected cell populations expressing either of these transporters.
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A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting. Crit Rev Oncol Hematol 2017; 121:51-61. [PMID: 29279099 DOI: 10.1016/j.critrevonc.2017.11.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 10/25/2017] [Accepted: 11/16/2017] [Indexed: 02/07/2023] Open
Abstract
Despite current advances in antiemetic treatments, between 30% to and 60% of oncology patients experience chemotherapy-induced nausea (CIN) and 13% to 33% report chemotherapy-induced vomiting (CIV). Inter-individual differences are observed in the occurrence and severity of chemotherapy-induced nausea and vomiting (CINV). This review summarizes and critiques studies on associations between occurrence and severity of CINV and polymorphisms in serotonin receptor, drug metabolism, and drug transport pathway genes. Sixteen studies evaluated the associations between the occurrence and/or severity of CINV and single nucleotide polymorphisms (SNPs). Across these studies, three SNPs in 5-hydroxytryptamine receptor (5-HT3R) genes, two alleles of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, and three SNPs in ATP binding cassette subfamily B member 1 (ABCB1) gene were associated with the occurrence and severity of CINV. Given the limited number of polymorphisms evaluated, additional research is warranted to identify new mechanisms to develop more targeted therapies.
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Khunweeraphong N, Stockner T, Kuchler K. The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion. Sci Rep 2017; 7:13767. [PMID: 29061978 PMCID: PMC5653816 DOI: 10.1038/s41598-017-11794-w] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 08/31/2017] [Indexed: 12/13/2022] Open
Abstract
The human ABC transporter ABCG2 (Breast Cancer Resistance Protein, BCRP) is implicated in anticancer resistance, in detoxification across barriers and linked to gout. Here, we generate a novel atomic model of ABCG2 using the crystal structure of ABCG5/G8. Extensive mutagenesis verifies the structure, disclosing hitherto unrecognized essential residues and domains in the homodimeric ABCG2 transporter. The elbow helix, the first intracellular loop (ICL1) and the nucleotide-binding domain (NBD) constitute pivotal elements of the architecture building the transmission interface that borders a central cavity which acts as a drug trap. The transmission interface is stabilized by salt-bridge interactions between the elbow helix and ICL1, as well as within ICL1, which is essential to control the conformational switch of ABCG2 to the outward-open drug-releasing conformation. Importantly, we propose that ICL1 operates like a molecular spring that holds the NBD dimer close to the membrane, thereby enabling efficient coupling of ATP hydrolysis during the catalytic cycle. These novel mechanistic data open new opportunities to therapeutically target ABCG2 in the context of related diseases.
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Affiliation(s)
- Narakorn Khunweeraphong
- Center for Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Campus Vienna Biocenter, Dr. Bohr-Gasse 9/2, A-1030, Vienna, Austria
| | - Thomas Stockner
- Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University Vienna, Währingerstrasse 13A, A-1090, Vienna, Austria
| | - Karl Kuchler
- Center for Medical Biochemistry, Max F. Perutz Laboratories, Medical University of Vienna, Campus Vienna Biocenter, Dr. Bohr-Gasse 9/2, A-1030, Vienna, Austria.
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Simvastatin intolerance genetic determinants: some features in ethnic Uzbek patients with coronary artery disease. ACTA ACUST UNITED AC 2017; 2:e68-e75. [PMID: 29242847 PMCID: PMC5728073 DOI: 10.5114/amsad.2017.70597] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 09/03/2017] [Indexed: 11/17/2022]
Abstract
Introduction The objective is to study the influence of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) gene polymorphisms on the development of simvastatin intolerance in ethnic Uzbek patients with coronary artery disease (CAD). Material and methods The case group contained 50 patients with clinical simvastatin-induced intolerance symptoms; the control group contained 50 patients without side-effects. Genotyping was performed by means of the PCR-RFLP method. Results Among 37 patients with simvastatin-induced liver symptoms the *3/*3 genotype of the CYP3A5 gene (p = 0.0001) and variant genotype of the CA BCRP gene were observed more frequently than in the control group (p = 0.0001). However, when the 13 patients who had statin-associated muscle symptoms (SAMS) were compared with the control group (n = 50), it was found that in the case group the 3*/3* genotype of the CYP3A5 gene (OR = 8.6; 95% CI: 2.1-34.1; p = 0.003) and C allele carriers of the gene polymorphism SLCO1B1 (OR = 3.54; 95% CI: 1.35-9.27; Χ2 = 5.7; p = 0.017) were predominant. Conclusions The *3/*3 genotype of the CYP3A5 (6986A>G) gene and CA genotype of the BCRP (ABCG2, 421C>A) gene were associated with simvastatin-induced liver symptoms in ethnic Uzbek CAD patients, whereas in patients with simvastatin-associated muscle symptoms (SAMS), the combination of *3/*3 genotype of CYP3A5 (6986A> G) and carriage of the C allele of the SLCO1B1 gene polymorphism was predominant.
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How gene polymorphisms can influence clinical response and toxicity following R-CHOP therapy in patients with diffuse large B cell lymphoma. Blood Rev 2017; 31:235-249. [DOI: 10.1016/j.blre.2017.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Revised: 12/07/2016] [Accepted: 02/03/2017] [Indexed: 12/20/2022]
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Yokoyama S, Tamaru S, Tamaki S, Nakanishi D, Mori A, Yamakawa T, Ao T, Sakata Y, Mizuno T, Iwamoto T, Watanabe K, Simomura M, Kawakami K, Konishi N, Kageyama S, Ohtani S, Yamada T, Ban S, Ooi K. Genetic Risk Factors Associated With Antiemetic Efficacy of Palonosetron, Aprepitant, and Dexamethasone in Japanese Breast Cancer Patients Treated With Anthracycline-based Chemotherapy. Clin Breast Cancer 2017; 18:e157-e165. [PMID: 28735677 DOI: 10.1016/j.clbc.2017.05.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Revised: 04/23/2017] [Accepted: 05/22/2017] [Indexed: 10/19/2022]
Abstract
INTRODUCTION Breast cancer patients often receive anthracycline-based chemotherapy, and chemotherapy-induced nausea and vomiting (CINV) remains one of the most uncomfortable and distressing adverse reactions. Poor control of CINV reduces the relative dose intensity of chemotherapy agents, which has been associated with poor clinical outcomes and shorter survival. The aim of the present study was to identify genetic risk factors associated with anthracycline-based CINV. PATIENTS AND METHODS We evaluated CINV attributable to anthracycline-based chemotherapy in Japanese breast cancer patients treated with an antiemetic regimen that included palonosetron, aprepitant, and dexamethasone. Furthermore, we investigated the associations between CINV and single nucleotide polymorphisms in 6 candidate genes. RESULTS Emesis episodes were rarely observed in the 125 patients included in the present survey (7.2%; n = 9); however, significant nausea occurred in more than one half of the patients (52.8%; n = 66). In particular, acute significant nausea was not effectively controlled. Multivariate logistic regression analysis revealed that the ABCG2 (rs2231142) AA genotype is significantly associated with acute significant nausea (odds ratio, 4.87; 95% confidence interval, 1.01-23.60; P = .049). CONCLUSION The findings of the present study provide significant insights for developing personalized antiemetic strategies for breast cancer patients receiving anthracycline-based chemotherapy.
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Affiliation(s)
- Satoshi Yokoyama
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan.
| | - Satoshi Tamaru
- Clinical Research Support Center, Mie University Hospital Hematology and Oncology, Mie University Hospital, Tsu, Japan
| | - Shinya Tamaki
- Department of Pharmacy, Hokkaido Cancer Center, Sapporo, Japan
| | | | - Akiya Mori
- Department of Pharmacy, Suzuka General Hospital, Suzuka, Japan
| | - Tomokazu Yamakawa
- Department of Pharmacy, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Takaaki Ao
- Division of Pharmacy, Suzuka Kaisei Hospital, Suzuka, Japan
| | - Yasuhiko Sakata
- Department of Pharmacy, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Toshiro Mizuno
- Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan
| | - Takuya Iwamoto
- Department of Pharmacy, Mie University Hospital, Tsu, Japan
| | - Kenichi Watanabe
- Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan
| | - Makoto Simomura
- Department of Surgery, Matsusaka City Hospital, Matsusaka, Japan
| | - Keiki Kawakami
- Division of Hematology/Oncology, Suzuka General Hospital, Suzuka, Japan
| | - Naomi Konishi
- Department of Surgery, Mie Prefectural General Medical Center, Yokkaichi, Japan
| | - Shinichi Kageyama
- Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Tsu, Japan
| | - Shoichiro Ohtani
- Department of Breast Surgery, Hiroshima City Hiroshima Citizens Hospital, Hiroshima, Japan
| | - Tomomi Yamada
- Department of Medical Innovation, Osaka University Hospital, Suita, Japan
| | - Susumu Ban
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
| | - Kazuya Ooi
- Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan
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Sobek KM, Cummings JL, Bacich DJ, O'Keefe DS. Contrasting roles of the ABCG2 Q141K variant in prostate cancer. Exp Cell Res 2017; 354:40-47. [PMID: 28300564 PMCID: PMC5424544 DOI: 10.1016/j.yexcr.2017.03.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/09/2017] [Accepted: 03/10/2017] [Indexed: 01/24/2023]
Abstract
ABCG2 is a membrane transport protein that effluxes growth-promoting molecules, such as folates and dihydrotestosterone, as well as chemotherapeutic agents. Therefore it is important to determine how variants of ABCG2 affect the transporter function in order to determine whether modified treatment regimens may be necessary for patients harboring ABCG2 variants. Previous studies have demonstrated an association between the ABCG2 Q141K variant and overall survival after a prostate cancer diagnosis. We report here that in patients with recurrent prostate cancer, those who carry the ABCG2 Q141K variant had a significantly shorter time to PSA recurrence post-prostatectomy than patients homozygous for wild-type ABCG2 (P=0.01). Transport studies showed that wild-type ABCG2 was able to efflux more folic acid than the Q141K variant (P<0.002), suggesting that retained tumoral folate contributes to the decreased time to PSA recurrence in the Q141K variant patients. In a seemingly conflicting study, it was previously reported that docetaxel-treated Q141K variant prostate cancer patients have a longer survival time. We found this may be due to less efficient docetaxel efflux in cells with the Q141K variant versus wild-type ABCG2. In human prostate cancer tissues, confocal microscopy revealed that all genotypes had a mixture of cytoplasmic and plasma membrane staining, with noticeably less staining in the two homozygous KK patients. In conclusion, the Q141K variant plays contrasting roles in prostate cancer: 1) by decreasing folate efflux, increased intracellular folate levels result in enhanced tumor cell proliferation and therefore time to recurrence decreases; and 2) in patients treated with docetaxel, by decreasing its efflux, intratumoral docetaxel levels and tumor cell drug sensitivity increase and therefore patient survival time increases. Taken together, these data suggest that a patient's ABCG2 genotype may be important when determining a personalized treatment plan.
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Affiliation(s)
- Kathryn M Sobek
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jessica L Cummings
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Dean J Bacich
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, University of Texas Health Science Center, San Antonio, TX, USA
| | - Denise S O'Keefe
- Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Urology, University of Texas Health Science Center, San Antonio, TX, USA.
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Cleophas MC, Joosten LA, Stamp LK, Dalbeth N, Woodward OM, Merriman TR. ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2017; 10:129-142. [PMID: 28461764 PMCID: PMC5404803 DOI: 10.2147/pgpm.s105854] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.
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Affiliation(s)
- M C Cleophas
- Department of Internal Medicine.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
| | - L A Joosten
- Department of Internal Medicine.,Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.,Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - L K Stamp
- Department of Medicine, University of Otago Christchurch, Christchurch
| | - N Dalbeth
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - O M Woodward
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Tony R Merriman
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
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Bugde P, Biswas R, Merien F, Lu J, Liu DX, Chen M, Zhou S, Li Y. The therapeutic potential of targeting ABC transporters to combat multi-drug resistance. Expert Opin Ther Targets 2017; 21:511-530. [DOI: 10.1080/14728222.2017.1310841] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Piyush Bugde
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Riya Biswas
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Fabrice Merien
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Science, AUT Roche Diagnostic Laboratory, Auckland University of Technology, Auckland, New Zealand
| | - Jun Lu
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
| | - Dong-Xu Liu
- School of Science, Auckland University of Technology, Auckland, New Zealand
| | - Mingwei Chen
- Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shufeng Zhou
- Department of Biotechnology and Bioengineering, College of Chemical Engineering, Huaqiao University, Xiamen, China
| | - Yan Li
- School of Science, Auckland University of Technology, Auckland, New Zealand
- School of Interprofessional Health Studies, Auckland University of Technology, Auckland, New Zealand
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Caetano-Pinto P, Jansen J, Assaraf YG, Masereeuw R. The importance of breast cancer resistance protein to the kidneys excretory function and chemotherapeutic resistance. Drug Resist Updat 2017; 30:15-27. [DOI: 10.1016/j.drup.2017.01.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 01/03/2017] [Accepted: 01/05/2017] [Indexed: 12/15/2022]
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László L, Sarkadi B, Hegedűs T. Jump into a New Fold-A Homology Based Model for the ABCG2/BCRP Multidrug Transporter. PLoS One 2016; 11:e0164426. [PMID: 27741279 PMCID: PMC5065228 DOI: 10.1371/journal.pone.0164426] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 09/23/2016] [Indexed: 12/03/2022] Open
Abstract
ABCG2/BCRP is a membrane protein, involved in xenobiotic and endobiotic transport in key pharmacological barriers and drug metabolizing organs, in the protection of stem cells, and in multidrug resistance of cancer. Pharmacogenetic studies implicated the role of ABCG2 in response to widely used medicines and anticancer agents, as well as in gout. Its Q141K variant exhibits decreased functional expression thus increased drug accumulation and decreased urate secretion. Still, there has been no reliable molecular model available for this protein, as the published structures of other ABC transporters could not be properly fitted to the ABCG2 topology and experimental data. The recently published high resolution structure of a close homologue, the ABCG5-ABCG8 heterodimer, revealed a new ABC transporter fold, unique for ABCG proteins. Here we present a structural model of the ABCG2 homodimer based on this fold and detail the experimental results supporting this model. In order to describe the effect of mutations on structure and dynamics, and characterize substrate recognition and cholesterol regulation we performed molecular dynamics simulations using full length ABCG2 protein embedded in a membrane bilayer and in silico docking simulations. Our results show that in the Q141K variant the introduced positive charge diminishes the interaction between the nucleotide binding and transmembrane domains and the R482G variation alters the orientation of transmembrane helices. Moreover, the R482 position, which plays a role the substrate specificity of the transporter, is located in one of the substrate binding pockets identified by the in silico docking calculations. In summary, the ABCG2 model and in silico simulations presented here may have significant impact on understanding drug distribution and toxicity, as well as drug development against cancer chemotherapy resistance or gout.
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Affiliation(s)
- Laura László
- Molecular Biophysics Research Group and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
| | - Balázs Sarkadi
- Molecular Biophysics Research Group and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
- Research Centre for Natural Sciences, Institute of Enzymology, Hungarian Academy of Sciences, Budapest, Hungary
| | - Tamás Hegedűs
- Molecular Biophysics Research Group and Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary
- * E-mail:
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Varatharajan S, Panetta JC, Abraham A, Karathedath S, Mohanan E, Lakshmi KM, Arthur N, Srivastava VM, Nemani S, George B, Srivastava A, Mathews V, Balasubramanian P. Population pharmacokinetics of Daunorubicin in adult patients with acute myeloid leukemia. Cancer Chemother Pharmacol 2016; 78:1051-1058. [PMID: 27738808 DOI: 10.1007/s00280-016-3166-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 10/06/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML. METHODS In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters. RESULTS The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR. CONCLUSION Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.
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Affiliation(s)
- Savitha Varatharajan
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - John C Panetta
- Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Ajay Abraham
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Sreeja Karathedath
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Ezhilpavai Mohanan
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Kavitha M Lakshmi
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Nancy Arthur
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Vivi M Srivastava
- Cytogenetics Unit, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Sandeep Nemani
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Biju George
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Alok Srivastava
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
| | - Vikram Mathews
- Department of Haematology, Christian Medical College, Vellore, Tamilnadu, 632004, India
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