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

Abstract

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.

Keywords

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

Abbreviations

Akt

AKT8 virus oncogene cellular homolog

ASK1

Apoptosis signal-regulating kinase 1

AT2

Angiotensin II receptor type 2

ATP

Adenosine triphosphate

BAD

Bcl-2-associated death promoter

Bcl-2

B-cell lymphoma 2 protein

Bcl-xL

B-cell lymphoma-extra large protein

Bcr-Abl

Fusion protein encoded by the Philadelphia chromosome

c-Kit

Stem cell growth factor receptor

DMSO

Dimethyl sulfoxide

FBS

Fetal bovine serum

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

JNK

Jun N-terminal kinase

LC3

Microtubule-associated protein 1 light chain 3

MST2

Serine/threonine kinase 3 (STK3)

mTORC1

Mammalian target of rapamycin complex 1

PDGFR

Platelet derived growth factor receptor

phospho-Akt/pAkt

Phosphorylated Akt

phospho-BAD/pBAD

Phosphorylated BAD

Phospho-Bcl2/pBcl2

Phosphorylated Bcl-2

phospho-JNK/pJNK

Phosphorylated JNK

PI3K

Phosphoinositide 3 kinase

QSP

Quantitative systems pharmacology

RAF

Rapidly accelerated fibrosarcoma kinase protein

RAF1

v-raf1 murine leukemia viral oncogene homolog 1

ROS

Reactive oxygen species

S6K

Ribosomal protein S6 kinase beta-1

Src

Rous sarcoma oncogene cellular homolog tyrosine kinase protein

TKI

Tyrosine kinase inhibitor

VEGFR

Vascular endothelial growth factor receptor

Notes

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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