Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors

  • Tanaya Vaidya
  • Jeff Kamta
  • Maher Chaar
  • Anusha Ande
  • Sihem Ait-Oudhia
Original Paper


Tyrosine kinase inhibitors (TKIs) are targeted therapies rapidly becoming favored over conventional cytotoxic chemotherapeutics. Our study investigates two FDA approved TKIs, Dasatinib; indicated for Imatinib-refractory chronic myeloid leukemia, and Sorafenib; indicated for hepatocellular carcinoma and advanced renal cell carcinoma. Limited but crucial evidence suggests that these agents can have cardiotoxic side effects ranging from hypertension to heart failure. A greater understanding of the underlying mechanisms of this cardiotoxicity are needed as concerns grow and the capacity to anticipate them is lacking. The objective of this study was to explore the mitochondrial-mediated cardiotoxic mechanisms of the two selected TKIs. This was achieved experimentally using immortalized human cardiomyocytes, AC16 cells, to investigate dose- and time-dependent cell killing, along with measurements of temporal changes in key signaling proteins involved in the intrinsic apoptotic and autophagy pathways upon exposure to these agents. Quantitative systems pharmacology (QSP) models were developed to capture the toxicological response in AC16 cells using protein dynamic data. The developed QSP models captured well all the various trends in protein signaling and cellular responses with good precision on the parameter estimates, and were successfully qualified using external data sets. An interplay between the apoptotic and autophagic pathways was identified to play a major role in determining toxicity associated with the investigated TKIs. The established modeling platform showed utility in elucidating the mechanisms of cardiotoxicity of Sorafenib and Dasatinib. It may be useful for other small molecule targeted therapies demonstrating cardiac toxicities, and may aid in informing alternate dosing strategies to alleviate cardiotoxicity associated with these therapies.


Cardiotoxicity Tyrosine kinase inhibitors (TKIs) Dasatinib Sorafenib Quantitative systems pharmacology (QSP) models 



AKT8 virus oncogene cellular homolog


Apoptosis signal-regulating kinase 1


Angiotensin II receptor type 2


Adenosine triphosphate


Bcl-2-associated death promoter


B-cell lymphoma 2 protein


B-cell lymphoma-extra large protein


Fusion protein encoded by the Philadelphia chromosome


Stem cell growth factor receptor


Dimethyl sulfoxide


Fetal bovine serum


Glyceraldehyde 3-phosphate dehydrogenase


Jun N-terminal kinase


Microtubule-associated protein 1 light chain 3


Serine/threonine kinase 3 (STK3)


Mammalian target of rapamycin complex 1


Platelet derived growth factor receptor


Phosphorylated Akt


Phosphorylated BAD


Phosphorylated Bcl-2


Phosphorylated JNK


Phosphoinositide 3 kinase


Quantitative systems pharmacology


Rapidly accelerated fibrosarcoma kinase protein


v-raf1 murine leukemia viral oncogene homolog 1


Reactive oxygen species


Ribosomal protein S6 kinase beta-1


Rous sarcoma oncogene cellular homolog tyrosine kinase protein


Tyrosine kinase inhibitor


Vascular endothelial growth factor receptor


Compliance with ethical standards

Conflict of interest

The authors declare that there is no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of PharmacyUniversity of FloridaOrlandoUSA

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