Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue
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Analysis of Tyrosine Kinase Inhibitor-Mediated Decline in Contractile Force in Rat Engineered Heart Tissue. / Jacob, Fabian; Yonis, Amina Y; Cuello, Friederike; Luther, Pradeep; Schulze, Thomas; Eder, Alexandra; Streichert, Thomas; Mannhardt, Ingra; Hirt, Marc N; Schaaf, Sebastian; Stenzig, Justus; Force, Thomas; Eschenhagen, Thomas; Hansen, Arne.
In: PLOS ONE, Vol. 11, No. 2, 2016, p. e0145937.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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
PY - 2016
Y1 - 2016
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.
U2 - 10.1371/journal.pone.0145937
DO - 10.1371/journal.pone.0145937
M3 - SCORING: Journal article
C2 - 26840448
VL - 11
SP - e0145937
JO - PLOS ONE
JF - PLOS ONE
SN - 1932-6203
IS - 2
ER -
