Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.
<h4>Introduction</h4>Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an...
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2016-01-01
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| Online Access: | https://doi.org/10.1371/journal.pone.0145937 |
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| author | Fabian Jacob Amina Y Yonis Friederike Cuello Pradeep Luther Thomas Schulze Alexandra Eder Thomas Streichert Ingra Mannhardt Marc N Hirt Sebastian Schaaf Justus Stenzig Thomas Force Thomas Eschenhagen Arne Hansen |
| author_facet | Fabian Jacob Amina Y Yonis Friederike Cuello Pradeep Luther Thomas Schulze Alexandra Eder Thomas Streichert Ingra Mannhardt Marc N Hirt Sebastian Schaaf Justus Stenzig Thomas Force Thomas Eschenhagen Arne Hansen |
| author_sort | Fabian Jacob |
| collection | DOAJ |
| description | <h4>Introduction</h4>Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism.<h4>Methods and results</h4>We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy).<h4>Conclusion</h4>This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux. |
| format | Article |
| id | doaj-art-4f66960b03bb435d9932d201d933a2ed |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2016-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-4f66960b03bb435d9932d201d933a2ed2025-08-20T02:34:07ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01112e014593710.1371/journal.pone.0145937Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue.Fabian JacobAmina Y YonisFriederike CuelloPradeep LutherThomas SchulzeAlexandra EderThomas StreichertIngra MannhardtMarc N HirtSebastian SchaafJustus StenzigThomas ForceThomas EschenhagenArne Hansen<h4>Introduction</h4>Left ventricular dysfunction is a frequent and potentially severe side effect of many tyrosine kinase inhibitors (TKI). The mode of toxicity is not identified, but may include impairment of mitochondrial or sarcomeric function, autophagy or angiogenesis, either as an on-target or off-target mechanism.<h4>Methods and results</h4>We studied concentration-response curves and time courses for nine TKIs in three-dimensional, force generating engineered heart tissue (EHT) from neonatal rat heart cells. We detected a concentration- and time-dependent decline in contractile force for gefitinib, lapatinib, sunitinib, imatinib, sorafenib, vandetanib and lestaurtinib and no decline in contractile force for erlotinib and dasatinib after 96 hours of incubation. The decline in contractile force was associated with an impairment of autophagy (LC3 Western blot) and appearance of autophagolysosomes (transmission electron microscopy).<h4>Conclusion</h4>This study demonstrates the feasibility to study TKI-mediated force effects in EHTs and identifies an association between a decline in contractility and inhibition of autophagic flux.https://doi.org/10.1371/journal.pone.0145937 |
| spellingShingle | Fabian Jacob Amina Y Yonis Friederike Cuello Pradeep Luther Thomas Schulze Alexandra Eder Thomas Streichert Ingra Mannhardt Marc N Hirt Sebastian Schaaf Justus Stenzig Thomas Force Thomas Eschenhagen Arne Hansen Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. PLoS ONE |
| title | Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. |
| title_full | Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. |
| title_fullStr | Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. |
| title_full_unstemmed | Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. |
| title_short | Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. |
| title_sort | analysis of tyrosine kinase inhibitor mediated decline in contractile force in rat engineered heart tissue |
| url | https://doi.org/10.1371/journal.pone.0145937 |
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