TY - JOUR
T1 - Analysis of tyrosine kinase inhibitor-mediated decline in contractile force in rat engineered heart tissue
AU - Jacob, Fabian
AU - Yonis, Amina Y.
AU - Cuello, Friederike
AU - Luther, Pradeep
AU - Schulze, Thomas
AU - Eder, Alexandra
AU - Streichert, Thomas
AU - Mannhardt, Ingra
AU - Hirt, Marc N.
AU - Schaaf, Sebastian
AU - Stenzig, Justus
AU - Force, Thomas
AU - Eschenhagen, Thomas
AU - Hansen, Arne
N1 - Publisher Copyright:
© 2016 Jacob et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - Introduction: 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. Methods and Results: 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). Conclusion: 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.
AB - Introduction: 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. Methods and Results: 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). Conclusion: 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.
UR - http://www.scopus.com/inward/record.url?scp=84959036453&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0145937
DO - 10.1371/journal.pone.0145937
M3 - Journal articles
C2 - 26840448
AN - SCOPUS:84959036453
VL - 11
JO - PLoS ONE
JF - PLoS ONE
IS - 2
M1 - e0145937
ER -
