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  1. Article ; Online: Regulated cell death pathways in doxorubicin-induced cardiotoxicity.

    Christidi, Effimia / Brunham, Liam R

    Cell death & disease

    2021  Volume 12, Issue 4, Page(s) 339

    Abstract: Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has ... ...

    Abstract Doxorubicin is a chemotherapeutic drug used for the treatment of various malignancies; however, patients can experience cardiotoxic effects and this has limited the use of this potent drug. The mechanisms by which doxorubicin kills cardiomyocytes has been elusive and despite extensive research the exact mechanisms remain unknown. This review focuses on recent advances in our understanding of doxorubicin induced regulated cardiomyocyte death pathways including autophagy, ferroptosis, necroptosis, pyroptosis and apoptosis. Understanding the mechanisms by which doxorubicin leads to cardiomyocyte death may help identify novel therapeutic agents and lead to more targeted approaches to cardiotoxicity testing.
    MeSH term(s) Animals ; Apoptosis/drug effects ; Autophagy/drug effects ; Cardiotoxicity/metabolism ; Doxorubicin/pharmacology ; Humans ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/metabolism ; Necroptosis/drug effects
    Chemical Substances Doxorubicin (80168379AG)
    Language English
    Publishing date 2021-04-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-021-03614-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: RARG S427L attenuates the DNA repair response to doxorubicin in induced pluripotent stem cell-derived cardiomyocytes.

    Huang, Haojun / Christidi, Effimia / Shafaattalab, Sanam / Davis, Margot K / Tibbits, Glen F / Brunham, Liam R

    Stem cell reports

    2022  Volume 17, Issue 4, Page(s) 756–765

    Abstract: Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma ( ... ...

    Abstract Doxorubicin is a commonly used chemotherapeutic drug, but its use is limited by doxorubicin-induced cardiotoxicity (DIC), which can lead to irreversible heart failure and death. A missense variant rs2229774 (p.S427L) in the retinoic acid receptor gamma (RARG) gene is associated with increased susceptibility to DIC, but the precise mechanism underlying this association is incompletely understood. We performed molecular dynamic simulations to determine the effect of this variant on RARG structure and then validated these predictions using CRISPR-Cas9-genome-edited, induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). We found that this variant leads to reduced activation of its target genes in response to doxorubicin, including gene pathways involved in DNA repair and consequently an inability to mediate DNA repair after exposure to doxorubicin. Our findings establish a role of RARG p.S427L in attenuating DNA repair in DIC and provide insight into the pathogenesis of this cardiotoxic effect.
    MeSH term(s) Antibiotics, Antineoplastic/pharmacology ; Cardiotoxicity ; DNA Repair ; Doxorubicin/pharmacology ; Humans ; Induced Pluripotent Stem Cells ; Myocytes, Cardiac/metabolism
    Chemical Substances Antibiotics, Antineoplastic ; Doxorubicin (80168379AG)
    Language English
    Publishing date 2022-03-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2022.03.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: CRISPR/Cas9-mediated genome editing in human stem cell-derived cardiomyocytes: Applications for cardiovascular disease modelling and cardiotoxicity screening.

    Christidi, Effimia / Huang, Haojun Margaret / Brunham, Liam R

    Drug discovery today. Technologies

    2018  Volume 28, Page(s) 13–21

    Abstract: Cardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug- ...

    Abstract Cardiovascular diseases (CVDs) are leading causes of death worldwide, and drug-induced cardiotoxicity is among the most common cause of drug withdrawal from the market. Improved models of cardiac tissue are needed to study the mechanisms of CVDs and drug-induced cardiotoxicity. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CM) have provided a major advance to our ability to study these conditions. Combined with efficient genome editing technologies, such as CRISPR/Cas9, we now have the ability to study with greater resolution the genetic causes and underlying mechanisms of inherited and drug-induced cardiotoxicity, and to investigate new treatments. Here, we review recent advances in the use of hPSC-CMs and CRISPR/Cas9-mediated genome editing to study cardiotoxicity and model CVD.
    MeSH term(s) Animals ; CRISPR-Cas Systems ; Cardiotoxicity/genetics ; Cardiotoxicity/therapy ; Cardiovascular Diseases/genetics ; Cardiovascular Diseases/therapy ; Cell Differentiation/genetics ; Gene Editing ; Genome, Human ; Humans ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/physiology ; Stem Cells/cytology ; Stem Cells/physiology
    Language English
    Publishing date 2018-06-25
    Publishing country England
    Document type Journal Article ; Review
    ISSN 1740-6749
    ISSN (online) 1740-6749
    DOI 10.1016/j.ddtec.2018.06.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Variation in RARG increases susceptibility to doxorubicin-induced cardiotoxicity in patient specific induced pluripotent stem cell-derived cardiomyocytes.

    Christidi, Effimia / Huang, Haojun / Shafaattalab, Sanam / Maillet, Agnes / Lin, Eric / Huang, Kate / Laksman, Zachary / Davis, Margot K / Tibbits, Glen F / Brunham, Liam R

    Scientific reports

    2020  Volume 10, Issue 1, Page(s) 10363

    Abstract: Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC ... ...

    Abstract Doxorubicin is a potent anticancer drug used to treat a variety of cancer types. However, its use is limited by doxorubicin-induced cardiotoxicity (DIC). A missense variant in the RARG gene (S427L; rs2229774) has been implicated in susceptibility to DIC in a genome wide association study. The goal of this study was to investigate the functional role of this RARG variant in DIC. We used induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) from patients treated with doxorubicin. iPSC-CMs from individuals who experienced DIC (cases) showed significantly greater sensitivity to doxorubicin compared to iPSC-CMs from doxorubicin-treated individuals who did not develop DIC (controls) in cell viability and optical mapping experiments. Using CRISPR/Cas9, we generated isogenic cell lines that differed only at the RARG locus. Genetic correction of RARG-S427L to wild type resulted in reduced doxorubicin-induced double stranded DNA breaks, reactive oxygen species production, and cell death. Conversely, introduction of RARG-S427L increased susceptibility to doxorubicin. Finally, genetic disruption of the RARG gene resulted in protection from cell death due to doxorubicin treatment. Our findings suggest that the presence of RARG-S427L increases sensitivity to DIC, establishing a direct, causal role for this variant in DIC.
    MeSH term(s) Adult ; Aged ; Aged, 80 and over ; Antibiotics, Antineoplastic/adverse effects ; CRISPR-Cas Systems ; Cardiotoxicity/etiology ; Cardiotoxicity/metabolism ; Cardiotoxicity/pathology ; Case-Control Studies ; Doxorubicin/adverse effects ; Female ; Follow-Up Studies ; Humans ; Induced Pluripotent Stem Cells/drug effects ; Induced Pluripotent Stem Cells/pathology ; Male ; Middle Aged ; Mutation ; Myocytes, Cardiac/drug effects ; Myocytes, Cardiac/pathology ; Neoplasms/drug therapy ; Neoplasms/pathology ; Receptors, Retinoic Acid/antagonists & inhibitors ; Receptors, Retinoic Acid/genetics ; Receptors, Retinoic Acid/metabolism ; Tumor Cells, Cultured ; Retinoic Acid Receptor gamma
    Chemical Substances Antibiotics, Antineoplastic ; Receptors, Retinoic Acid ; Doxorubicin (80168379AG)
    Language English
    Publishing date 2020-06-25
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2615211-3
    ISSN 2045-2322 ; 2045-2322
    ISSN (online) 2045-2322
    ISSN 2045-2322
    DOI 10.1038/s41598-020-65979-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Ibrutinib Displays Atrial-Specific Toxicity in Human Stem Cell-Derived Cardiomyocytes.

    Shafaattalab, Sanam / Lin, Eric / Christidi, Effimia / Huang, Haojun / Nartiss, Yulia / Garcia, Analucia / Lee, Jeehon / Protze, Stephanie / Keller, Gordon / Brunham, Liam / Tibbits, Glen F / Laksman, Zachary

    Stem cell reports

    2019  Volume 12, Issue 5, Page(s) 996–1006

    Abstract: Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical ... ...

    Abstract Ibrutinib (IB) is an oral Bruton's tyrosine kinase (BTK) inhibitor that has demonstrated benefit in B cell cancers, but is associated with a dramatic increase in atrial fibrillation (AF). We employed cell-specific differentiation protocols and optical mapping to investigate the effects of IB and other tyrosine kinase inhibitors (TKIs) on the voltage and calcium transients of atrial and ventricular human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs). IB demonstrated direct cell-specific effects on atrial hPSC-CMs that would be predicted to predispose to AF. Second-generation BTK inhibitors did not have the same effect. Furthermore, IB exposure was associated with differential chamber-specific regulation of a number of regulatory pathways including the receptor tyrosine kinase pathway, which may be implicated in the pathogenesis of AF. Our study is the first to demonstrate cell-type-specific toxicity in hPSC-derived atrial and ventricular cardiomyocytes, which reliably reproduces the clinical cardiotoxicity observed.
    MeSH term(s) Atrial Fibrillation/diagnosis ; Atrial Fibrillation/physiopathology ; Cardiotoxicity/diagnosis ; Cardiotoxicity/physiopathology ; Cell Differentiation ; Cells, Cultured ; Heart/drug effects ; Heart/physiopathology ; Heart Atria/cytology ; Heart Atria/drug effects ; Heart Atria/physiopathology ; Heart Ventricles/cytology ; Heart Ventricles/drug effects ; Heart Ventricles/physiopathology ; Humans ; Myocardium/cytology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/drug effects ; Organ Specificity ; Pluripotent Stem Cells/cytology ; Pluripotent Stem Cells/drug effects ; Protein Kinase Inhibitors/pharmacology ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology
    Chemical Substances Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines ; ibrutinib (1X70OSD4VX)
    Language English
    Publishing date 2019-04-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2019.03.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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