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Mechanisms of the Cardiac Myocyte-Damaging Effects of Dasatinib

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Abstract

The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.

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Abbreviations

ABC:

ATP-binding-cassette

CML:

Chronic myeloid leukemia

DCF:

2′,7′-Dichlorofluorescin

DF-x :

Dulbecco's modified eagle medium/Ham's F-12 Medium 1:1 where x is % (v/v) serum

ERK:

Extracellular signal-regulated kinase

GAPDH:

Glyceraldehyde 3-phosphate dehydrogenase

K d :

Kinase binding dissociation constant

LDH:

Lactate dehydrogenase

PBS:

Dulbecco’s phosphate buffered saline (pH 7.4)

λEx and λEm :

Excitation and emission wavelengths, respectively

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Acknowledgements

This research was supported by grants from the Canadian Institutes of Health Research [Grant MOP13748], the Canada Research Chairs Program, and a Canada Research Chair in Drug Development to Brian Hasinoff.

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  1. College of Pharmacy, Apotex Centre, University of Manitoba, 750 McDermot Avenue, Winnipeg, MB, R3E 0T5, Canada

    Brian B. Hasinoff & Daywin Patel

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Correspondence to Brian B. Hasinoff.

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The authors declare no competing financial interests. The funding sources had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.

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The animal protocol was approved by the University of Manitoba Animal Care Committee.

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Hasinoff, B.B., Patel, D. Mechanisms of the Cardiac Myocyte-Damaging Effects of Dasatinib. Cardiovasc Toxicol 20, 380–389 (2020). https://doi.org/10.1007/s12012-020-09565-7

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