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  1. Article ; Online: Cadmium transport by mammalian ATP-binding cassette transporters.

    Thévenod, Frank / Lee, Wing-Kee

    Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine

    2024  

    Abstract: Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ... ...

    Abstract Cellular responses to toxic metals depend on metal accessibility to intracellular targets, reaching interaction sites, and the intracellular metal concentration, which is mainly determined by uptake pathways, binding/sequestration and efflux pathways. ATP-binding cassette (ABC) transporters are ubiquitous in the human body-usually in epithelia-and are responsible for the transfer of indispensable physiological substrates (e.g. lipids and heme), protection against potentially toxic substances, maintenance of fluid composition, and excretion of metabolic waste products. Derailed regulation and gene variants of ABC transporters culminate in a wide array of pathophysiological disease states, such as oncogenic multidrug resistance or cystic fibrosis. Cadmium (Cd) has no known physiological role in mammalians and poses a health risk due to its release into the environment as a result of industrial activities, and eventually passes into the food chain. Epithelial cells, especially within the liver, lungs, gastrointestinal tract and kidneys, are particularly susceptible to the multifaceted effects of Cd because of the plethora of uptake pathways available. Pertinent to their broad substrate spectra, ABC transporters represent a major cellular efflux pathway for Cd and Cd complexes. In this review, we summarize current knowledge concerning transport of Cd and its complexes (mainly Cd bound to glutathione) by the ABC transporters ABCB1 (P-glycoprotein, MDR1), ABCB6, ABCC1 (multidrug resistance related protein 1, MRP1), ABCC7 (cystic fibrosis transmembrane regulator, CFTR), and ABCG2 (breast cancer related protein, BCRP). Potential detoxification strategies underlying ABC transporter-mediated efflux of Cd and Cd complexes are discussed.
    Language English
    Publishing date 2024-02-06
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 1112688-7
    ISSN 1572-8773 ; 0966-0844
    ISSN (online) 1572-8773
    ISSN 0966-0844
    DOI 10.1007/s10534-024-00582-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Iron and Its Role in Cancer Defense: A Double-Edged Sword.

    Thévenod, Frank

    Metal ions in life sciences

    2018  Volume 18

    Abstract: Iron (Fe) is an essential metal, vital for biological functions, including electron transport, DNA synthesis, detoxification, and erythropoiesis that all contribute to metabolism, cell growth, and proliferation. Interactions between Fe and O2 can result ... ...

    Abstract Iron (Fe) is an essential metal, vital for biological functions, including electron transport, DNA synthesis, detoxification, and erythropoiesis that all contribute to metabolism, cell growth, and proliferation. Interactions between Fe and O2 can result in the generation of reactive oxygen species (ROS), which is based on the ability of Fe to redox cycle. Excess Fe may cause oxidative damage with ensuing cell death, but DNA damage may also lead to permanent mutations. Hence Fe is carcinogenic and may initiate tumor formation and growth, and also nurture the tumor microenvironment and metastasis. However, Fe can also contribute to cancer defense. Fe may induce toxic ROS and/or initiate specific forms of cell death, including ferroptosis that will benefit cancer treatment. Furthermore, Fe-binding and Fe-regulatory proteins, such as hepcidin, lipocalin-2/NGAL, heme oxygenase-1, ferritin, and iron-sulfur clusters can display antitumor properties under specific conditions and in particular cancer types. In addition, the milk protein lactoferrin may synergize with other established anticancer agents in the prevention and therapy of cancer. Consequently, drugs that target Fe metabolism in tumors are promising candidates for the prevention and therapy of cancer, but consideration of context specificity (e.g., tumor type; systemic versus tumor microenvironment Fe homeostasis) is mandatory.
    MeSH term(s) Animals ; Antineoplastic Agents/chemistry ; Antineoplastic Agents/pharmacology ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Drug Design ; Homeostasis ; Humans ; Iron/metabolism ; Iron Chelating Agents/chemistry ; Iron Chelating Agents/pharmacology ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Neoplasms/pathology ; Oxidative Stress/drug effects ; Tumor Microenvironment
    Chemical Substances Antineoplastic Agents ; Iron Chelating Agents ; Iron (E1UOL152H7)
    Language English
    Publishing date 2018--05
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ISSN 1559-0836
    ISSN 1559-0836
    DOI 10.1515/9783110470734-021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Distinct concentration-dependent oxidative stress profiles by cadmium in a rat kidney proximal tubule cell line.

    Lee, Wing-Kee / Probst, Stephanie / Scharner, Bettina / Deba, Timo / Dahdouh, Faouzi / Thévenod, Frank

    Archives of toxicology

    2024  Volume 98, Issue 4, Page(s) 1043–1059

    Abstract: Levels and chemical species of reactive oxygen/nitrogen species (ROS/RNS) determine oxidative eustress and distress. Abundance of uptake pathways and high oxygen consumption for ATP-dependent transport makes the renal proximal tubule particularly ... ...

    Abstract Levels and chemical species of reactive oxygen/nitrogen species (ROS/RNS) determine oxidative eustress and distress. Abundance of uptake pathways and high oxygen consumption for ATP-dependent transport makes the renal proximal tubule particularly susceptible to cadmium (Cd
    MeSH term(s) Rats ; Animals ; Reactive Oxygen Species/metabolism ; Cadmium/toxicity ; Catalase/metabolism ; Catalase/pharmacology ; Superoxides/metabolism ; Hydrogen Peroxide/metabolism ; alpha-Tocopherol/metabolism ; alpha-Tocopherol/pharmacology ; Superoxide Dismutase-1/metabolism ; Superoxide Dismutase-1/pharmacology ; Oxidative Stress ; Antioxidants/pharmacology ; Antioxidants/metabolism ; Kidney ; Superoxide Dismutase/metabolism ; Cell Line ; Cyclic N-Oxides ; Metalloporphyrins ; Spin Labels
    Chemical Substances Reactive Oxygen Species ; Cadmium (00BH33GNGH) ; Catalase (EC 1.11.1.6) ; tempol (U78ZX2F65X) ; manganese(III)-tetrakis(4-benzoic acid)porphyrin ; Superoxides (11062-77-4) ; Hydrogen Peroxide (BBX060AN9V) ; alpha-Tocopherol (H4N855PNZ1) ; Superoxide Dismutase-1 (EC 1.15.1.1) ; Antioxidants ; Superoxide Dismutase (EC 1.15.1.1) ; Cyclic N-Oxides ; Metalloporphyrins ; Spin Labels
    Language English
    Publishing date 2024-01-30
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-023-03677-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Renal hypoxia-HIF-PHD-EPO signaling in transition metal nephrotoxicity: friend or foe?

    Thévenod, Frank / Schreiber, Timm / Lee, Wing-Kee

    Archives of toxicology

    2022  Volume 96, Issue 6, Page(s) 1573–1607

    Abstract: The kidney is the main organ that senses changes in systemic oxygen tension, but it is also the key detoxification, transit and excretion site of transition metals (TMs). Pivotal to oxygen sensing are prolyl-hydroxylases (PHDs), which hydroxylate ... ...

    Abstract The kidney is the main organ that senses changes in systemic oxygen tension, but it is also the key detoxification, transit and excretion site of transition metals (TMs). Pivotal to oxygen sensing are prolyl-hydroxylases (PHDs), which hydroxylate specific residues in hypoxia-inducible factors (HIFs), key transcription factors that orchestrate responses to hypoxia, such as induction of erythropoietin (EPO). The essential TM ion Fe is a key component and regulator of the hypoxia-PHD-HIF-EPO (HPHE) signaling axis, which governs erythropoiesis, angiogenesis, anaerobic metabolism, adaptation, survival and proliferation, and hence cell and body homeostasis. However, inadequate concentrations of essential TMs or entry of non-essential TMs in organisms cause toxicity and disrupt health. Non-essential TMs are toxic because they enter cells and displace essential TMs by ionic and molecular mimicry, e. g. in metalloproteins. Here, we review the molecular mechanisms of HPHE interactions with TMs (Fe, Co, Ni, Cd, Cr, and Pt) as well as their implications in renal physiology, pathophysiology and toxicology. Some TMs, such as Fe and Co, may activate renal HPHE signaling, which may be beneficial under some circumstances, for example, by mitigating renal injuries from other causes, but may also promote pathologies, such as renal cancer development and metastasis. Yet some other TMs appear to disrupt renal HPHE signaling, contributing to the complex picture of TM (nephro-)toxicity. Strikingly, despite a wealth of literature on the topic, current knowledge lacks a deeper molecular understanding of TM interaction with HPHE signaling, in particular in the kidney. This precludes rationale preventive and therapeutic approaches to TM nephrotoxicity, although recently activators of HPHE signaling have become available for therapy.
    MeSH term(s) Erythropoietin/metabolism ; Humans ; Hypoxia/metabolism ; Hypoxia/pathology ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Kidney/metabolism ; Kidney Diseases/pathology ; Oxygen/metabolism ; Transcription Factors/metabolism
    Chemical Substances Hypoxia-Inducible Factor 1, alpha Subunit ; Transcription Factors ; Erythropoietin (11096-26-7) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2022-04-21
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-022-03285-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Cell organelles as targets of mammalian cadmium toxicity.

    Lee, Wing-Kee / Thévenod, Frank

    Archives of toxicology

    2020  Volume 94, Issue 4, Page(s) 1017–1049

    Abstract: Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal and human cadmium exposure ranges from ingestion of ... ...

    Abstract Ever increasing environmental presence of cadmium as a consequence of industrial activities is considered a health hazard and is closely linked to deteriorating global health status. General animal and human cadmium exposure ranges from ingestion of foodstuffs sourced from heavily polluted hotspots and cigarette smoke to widespread contamination of air and water, including cadmium-containing microplastics found in household water. Cadmium is promiscuous in its effects and exerts numerous cellular perturbations based on direct interactions with macromolecules and its capacity to mimic or displace essential physiological ions, such as iron and zinc. Cell organelles use lipid membranes to form complex tightly-regulated, compartmentalized networks with specialized functions, which are fundamental to life. Interorganellar communication is crucial for orchestrating correct cell behavior, such as adaptive stress responses, and can be mediated by the release of signaling molecules, exchange of organelle contents, mechanical force generated through organelle shape changes or direct membrane contact sites. In this review, cadmium effects on organellar structure and function will be critically discussed with particular consideration to disruption of organelle physiology in vertebrates.
    MeSH term(s) Animals ; Cadmium/toxicity ; Environmental Pollutants/toxicity ; Humans ; Mammals ; Organelles/drug effects ; Organelles/physiology ; Plastics ; Signal Transduction
    Chemical Substances Environmental Pollutants ; Plastics ; Cadmium (00BH33GNGH)
    Language English
    Publishing date 2020-03-23
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 124992-7
    ISSN 1432-0738 ; 0340-5761
    ISSN (online) 1432-0738
    ISSN 0340-5761
    DOI 10.1007/s00204-020-02692-8
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Corrigendum: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications.

    Thévenod, Frank / Lee, Wing-Kee / Garrick, Michael D

    Frontiers in cell and developmental biology

    2021  Volume 9, Page(s) 687810

    Abstract: This corrects the article DOI: 10.3389/fcell.2020.00848.]. ...

    Abstract [This corrects the article DOI: 10.3389/fcell.2020.00848.].
    Language English
    Publishing date 2021-04-19
    Publishing country Switzerland
    Document type Published Erratum
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2021.687810
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Teaching an old dog new tricks: reactivated developmental signaling pathways regulate ABCB1 and chemoresistance in cancer.

    Lee, Wing-Kee / Frank, Thévenod

    Cancer drug resistance (Alhambra, Calif.)

    2021  Volume 4, Issue 2, Page(s) 424–452

    Abstract: Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not ...

    Abstract Oncogenic multidrug resistance (MDR) is a multifactorial phenotype intimately linked to deregulated expression of detoxification transporters. Drug efflux transporters, particularly the MDR P-glycoprotein ABCB1, represent a central mechanism by which not only chemotherapeutic drugs are extruded or sequestered to prevent drug delivery to their intracellular targets, but also for inhibiting apoptotic cell death cues, such as removal of proapoptotic signals. Several cell populations exhibiting the MDR phenotype co-exist within a tumor, such as cells forming the bulk tumor cell mass, cancer stem cells, and cancer persister cells. The key to regulation of ABCB1 expression is the cellular transcriptional machinery. Developmental signaling pathways (e.g, Hedgehog, Notch, Wnt/β-catenin, TGFβ, PITX2) are pivotal in governing cell proliferation, survival, differentiation and guiding cell migration during embryogenesis, and their reactivation during carcinogenesis, which is of particular significance for tumor initiation, progression, and metastasis, also leads to the upregulation of ABCB1. These pathways also drive and maintain cancer cell stemness, for which ABCB1 is used as a marker. In this review, the contribution of canonical and non-canonical developmental signaling pathways in transcriptional regulation of ABCB1 to confer MDR in cancer is delineated.
    Language English
    Publishing date 2021-06-19
    Publishing country United States
    Document type Journal Article ; Review
    ISSN 2578-532X
    ISSN (online) 2578-532X
    DOI 10.20517/cdr.2020.114
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: Oncogenic PITX2 facilitates tumor cell drug resistance by inverse regulation of hOCT3/SLC22A3 and ABC drug transporters in colon and kidney cancers.

    Lee, Wing-Kee / Thévenod, Frank

    Cancer letters

    2019  Volume 449, Page(s) 237–251

    Abstract: Oncogenic pituitary homeobox 2 (PITX2), a de facto master regulator of developmental organ asymmetry, previously upregulated multidrug resistance (MDR) P-glycoprotein ABCB1 in A498 renal cell carcinoma (RCC) cells. The role of PITX2 isoforms in MDR ... ...

    Abstract Oncogenic pituitary homeobox 2 (PITX2), a de facto master regulator of developmental organ asymmetry, previously upregulated multidrug resistance (MDR) P-glycoprotein ABCB1 in A498 renal cell carcinoma (RCC) cells. The role of PITX2 isoforms in MDR cancers was investigated. Data mining correlated elevated PITX2 in >30% of cancers analyzed, maximally in colon (4.4-fold), confirmed in co-immunostaining of colon and renal cancer microarrays wherein ABCB1 concomitantly increased in RCC. Drug-resistant colorectal adenocarcinoma Colo320DM cells exhibited increased nuclear PITX2 (40-fold), PITX2 promoter activity (27-fold) and ABCB1 (8000-fold) compared to drug-sensitive Colo205. ABCB1 inhibitor PSC833/valspodar or PITX2 siRNA reversed doxorubicin resistance. Nuclei from Colo320DM and A498 cells harbored PITX2A/B1 and PITX2A/B1/B2/Cα/Cβ, respectively. ChIP-qPCR evidenced PITX2 promoter binding in drug exporters ABCB1, ABCC1, ABCG2 and importer hOCT3/SLC22A3. In A498, 786-O, Caki-1, Colo320DM, and Caco2 cells, PITX2 siRNA diminished exporters, increased hOCT3/SLC22A3 expression and activity, and reverted vincristine resistance. Heterologous PITX2 expression induced ABCB1, repressed hOCT3/SLC22A3, enhanced vincristine resistance and diminished proliferation inhibition wherein PITX2A and PITX2C were most effective. Furthermore, PITX2 activity and MDR depended on phosphorylation by GSK3 in A498 cells. Conclusively, oncogenic PITX2 limits sensitizing drug uptake and potentiates cytoprotective drug efflux, contributing to MDR phenotype.
    MeSH term(s) ATP Binding Cassette Transporter 1/genetics ; ATP Binding Cassette Transporter 1/metabolism ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics ; ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism ; Antineoplastic Agents/pharmacology ; Caco-2 Cells ; Cell Proliferation/drug effects ; Colonic Neoplasms/drug therapy ; Colonic Neoplasms/genetics ; Colonic Neoplasms/metabolism ; Doxorubicin/pharmacology ; Drug Resistance, Multiple/genetics ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Neoplastic ; Glycogen Synthase Kinase 3/metabolism ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Humans ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/genetics ; Kidney Neoplasms/metabolism ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Organic Cation Transport Proteins/genetics ; Organic Cation Transport Proteins/metabolism ; Phosphorylation ; Signal Transduction ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Vincristine/pharmacology ; Homeobox Protein PITX2
    Chemical Substances ABCA1 protein, human ; ABCG2 protein, human ; ATP Binding Cassette Transporter 1 ; ATP Binding Cassette Transporter, Subfamily G, Member 2 ; Antineoplastic Agents ; Homeodomain Proteins ; Neoplasm Proteins ; Organic Cation Transport Proteins ; Transcription Factors ; solute carrier family 22 (organic cation transporter), member 3 ; Vincristine (5J49Q6B70F) ; Doxorubicin (80168379AG) ; Glycogen Synthase Kinase 3 (EC 2.7.11.26)
    Language English
    Publishing date 2019-02-10
    Publishing country Ireland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 195674-7
    ISSN 1872-7980 ; 0304-3835
    ISSN (online) 1872-7980
    ISSN 0304-3835
    DOI 10.1016/j.canlet.2019.01.044
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article: Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications.

    Thévenod, Frank / Lee, Wing-Kee / Garrick, Michael D

    Frontiers in cell and developmental biology

    2020  Volume 8, Page(s) 848

    Abstract: Regulation of body fluid homeostasis is a major renal function, occurring largely through epithelial solute transport in various nephron segments driven by ... ...

    Abstract Regulation of body fluid homeostasis is a major renal function, occurring largely through epithelial solute transport in various nephron segments driven by Na
    Language English
    Publishing date 2020-09-02
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2737824-X
    ISSN 2296-634X
    ISSN 2296-634X
    DOI 10.3389/fcell.2020.00848
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Corrigendum

    Frank Thévenod / Wing-Kee Lee / Michael D. Garrick

    Frontiers in Cell and Developmental Biology, Vol

    Iron and Cadmium Entry Into Renal Mitochondria: Physiological and Toxicological Implications

    2021  Volume 9

    Keywords reactive oxygen species ; divalent metal transporter 1 ; ionic mimicry ; manganese ; copper ; nephrotoxicity ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher Frontiers Media S.A.
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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