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

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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.

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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

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Authors and Affiliations

  1. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, 6550 Sanger Road, Office: 469, Orlando, FL, 32827, USA

    Tanaya Vaidya, Jeff Kamta, Maher Chaar, Anusha Ande & Sihem Ait-Oudhia

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  1. Tanaya Vaidya
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  2. Jeff Kamta
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Correspondence to Sihem Ait-Oudhia.

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Vaidya, T., Kamta, J., Chaar, M. et al. Systems pharmacological analysis of mitochondrial cardiotoxicity induced by selected tyrosine kinase inhibitors. J Pharmacokinet Pharmacodyn 45, 401–418 (2018). https://doi.org/10.1007/s10928-018-9578-9

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