Mechanistic Investigation of Imatinib-Induced Cardiac Toxicity and the Involvement of c-Abl Kinase

Hu, Wenyue; Lu, Shuyan; McAlpine, Indrawan; Jamieson, Joseph; Lee, Dong U.; Marroquin, Lisa D.; Heyen, Jonathan R.; Jessen, Bart

doi:10.1093/toxsci/kfs192

Cited by 34 publications

(27 citation statements)

References 26 publications

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“…Antagonism of miR-34, a negative transcriptional regulator of vinculin, led to improved outcome in mice experiencing pressure overload or myocardial infarction and correlated with vinculin overexpression (40), although vinculin was not specifically implicated as an active component of protection. Posttranslational modification of vinculin may also play a role in the aging process; vinculin localization is regulated by phosphorylation by the kinase Abelson (41), whose chronic inhibition by imatinib is associated with contractile dysfunction (42). …”

Section: Discussionmentioning

confidence: 99%

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

et al. 2015

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The human heart is capable of functioning for decades despite minimal cell turnover or regeneration, suggesting that molecular alterations help sustain heart function with age. However, identification of compensatory remodeling events in the aging heart remains elusive. We present the cardiac proteomes of young and old rhesus monkeys and rats, from which we show that certain age-associated remodeling events within the cardiomyocyte cytoskeleton are highly conserved and beneficial rather than deleterious. Targeted transcriptomic analysis in Drosophila confirmed conservation and implicated vinculin as a unique molecular regulator of cardiac function during aging. Cardiac-restricted vinculin overexpression reinforced the cortical cytoskeleton and enhanced myofilament organization, leading to improved contractility and hemodynamic stress tolerance in healthy and myosin-deficient fly hearts. Moreover, cardiac-specific vinculin overexpression increased median life span by more than 150% in flies. A broad array of potential therapeutic targets and regulators of age-associated modifications, specifically for vinculin, are presented. These findings suggest that the heart has molecular mechanisms to sustain performance and promote longevity, which may be assisted by therapeutic intervention to ameliorate the decline of function in aging patient hearts.

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Section: Discussionmentioning

confidence: 99%

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

et al. 2015

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“…We suggest that ErbB2 regulation of GPx activity may be related to the action of c-Abl and Arg nonreceptor tyrosine kinases, as these kinases and active forms were elevated under ErbB2 expression and are also known to activate both GPx and catalase enzymes (5,6). The importance of c-Abl and Arg in cardiac growth and development (8,52) is highlighted in studies showing that drugs such as imatinib mesylate (Gleevec) that target and inhibit c-Abl/Arg also cause cardiac dysfunction with subsequent reduction of cardiac GPx activity (27,29,33,53). Our findings are in agreement with these previous studies with additional evidence showing that ErbB2 protein upregulates c-Abl/Arg and GPx expression and activity.…”

Section: Discussionmentioning

confidence: 99%

ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity

Belmonte

Das

Sysa‐Shah

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

101

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bergen C, Gabrielson K. ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity. Am J Physiol Heart Circ Physiol 309: H1271-H1280, 2015. First published August 14, 2015; doi:10.1152/ajpheart.00517.2014.-Levels of the HER2/ErbB2 protein in the heart are upregulated in some women during breast cancer therapy, and these women are at high risk for developing heart dysfunction after sequential treatment with anti-ErbB2/trastuzumab or doxorubicin. Doxorubicin is known to increase oxidative stress in the heart, and thus we considered the possibility that ErbB2 protein influences the status of cardiac antioxidant defenses in cardiomyocytes. In this study, we measured reactive oxygen species (ROS) in cardiac mitochondria and whole hearts from mice with cardiacspecific overexpression of ErbB2 (ErbB2 tg ) and found that, compared with control mice, high levels of ErbB2 in myocardium result in lower levels of ROS in mitochondria (P ϭ 0.0075) and whole hearts (P ϭ 0.0381). Neonatal cardiomyocytes isolated from ErbB2 tg hearts have lower ROS levels and less cellular death (P Ͻ 0.0001) following doxorubicin treatment. Analyzing antioxidant enzyme levels and activities, we found that ErbB2 tg hearts have increased levels of glutathione peroxidase 1 (GPx1) protein (P Ͻ 0.0001) and GPx activity (P ϭ 0.0031) in addition to increased levels of two known GPx activators, c-Abl (P ϭ 0.0284) and Arg (P Ͻ 0.0001). Interestingly, although mitochondrial ROS emission is reduced in the ErbB2 tg hearts, oxygen consumption rates and complex I activity are similar to control littermates. Compared with these in vivo studies, H9c2 cells transfected with ErbB2 showed less cellular toxicity and produced less ROS (P Ͻ 0.0001) after doxorubicin treatment but upregulated GR activity (P ϭ 0.0237) instead of GPx. Our study shows that ErbB2-dependent signaling contributes to antioxidant defenses and suggests a novel mechanism by which anticancer therapies involving ErbB2 antagonists can harm myocardial structure and function.ErbB2; glutathione peroxidase; reactive oxygen species; nRTK; mitochondria NEW & NOTEWORTHY This is the first study on ErbB2 overexpression in the heart that identifies cardioprotection after doxorubicin treatment. Our findings suggest that an adverse effect on redox signaling pathways necessary for maintaining mitochondrial antioxidant defenses may be an important mechanism of cardiac toxicity induced by drugs that target ErbB2 and Abl kinases.THE ERBB2 RECEPTOR TYROSINE kinase is a member of the epidermal growth factor receptor (EGFR) family and has an essential role in cardiac function and development (9,39,47,50). ErbB2 is also important in cancer biology, and dysregulated ErbB2 signaling is implicated in various types of cancer, most notably in breast and ovarian cancer (30, 49). The clinical link between ErbB2 and heart function was discovered when 27% of ErbB2-overexpressing breast cancer patients treated with doxorubicin and anti-...

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“…For example, imatinib has been associated with congestive heart failure: although the incidence in clinical trials was low and typically occurred in patients with a pre-existing history of heart disease, patients with severe congestive heart failure have been reported while receiving imatinib (Kerkela et al, 2006). Imatinib-induced cardiac toxicity, observed in rodents and mechanistically linked to the physicochemical properties of imatinib, was described to be caused by efficient lysosomal sequestration of imatinib leading to lysosomal dysfunction and autophagy perturbation in cardiomyocytes (Herman et al, 2011;Hu et al, 2012). It may well be that other rare, or more frequently encountered, imatinib-related side effects are a direct consequence of a lysosomal impairment caused by the lysosomal accumulation of imatinib in healthy cells.…”

Section: Discussionmentioning

confidence: 99%

Lysosomal Sequestration Determines Intracellular Imatinib Levels

et al. 2015

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The intracellular uptake and retention (IUR) of imatinib is reported to be controlled by the influx transporter SLC22A1 (organic cation transporter 1). We recently hypothesized that alternative uptake and/or retention mechanisms exist that determine intracellular imatinib levels. Here, we systematically investigate the nature of these mechanisms. Imatinib uptake in cells was quantitatively determined by liquid chromatography-tandem mass spectrometry. Fluorescent microscopy was used to establish subcellular localization of imatinib. Immunoblotting, cell cycle analyses, and apoptosis assays were performed to evaluate functional consequences of imatinib sequestration. Uptake experiments revealed high intracellular imatinib concentrations in HEK293, the leukemic cell lines K562 and SD-1, and a gastrointestinal stromal tumor cell line GIST-T1. We demonstrated that imatinib IUR is time-, dose-, temperature-, and energy-dependent and provide evidence that SLC22A1 and other potential imatinib transporters do not substantially contribute to the IUR of imatinib. Prazosin, amantadine, NH 4 Cl, and the vacuolar ATPase inhibitor bafilomycin A1 significantly decreased the IUR of imatinib and likely interfere with lysosomal retention and accumulation of imatinib. Costaining experiments with LysoTracker Red confirmed lysosomal sequestration of imatinib. Inhibition of the lysosomal sequestration had no effect on the inhibition of c-Kit signaling and imatinib-mediated cell cycle arrest but significantly increased apoptosis in imatinib-sensitive GIST-T1 cells. We conclude that intracellular imatinib levels are primarily determined by lysosomal sequestration and do not depend on SLC22A1 expression.

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Mechanistic Investigation of Imatinib-Induced Cardiac Toxicity and the Involvement of c-Abl Kinase

Cited by 34 publications

References 26 publications

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

ErbB2 overexpression upregulates antioxidant enzymes, reduces basal levels of reactive oxygen species, and protects against doxorubicin cardiotoxicity

Lysosomal Sequestration Determines Intracellular Imatinib Levels

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