Ageing is a risk factor in imatinib mesylate cardiotoxicity

Abstract

AimsChemotherapy-induced heart failure is increasingly recognized as a major clinical challenge. Cardiotoxicity of imatinib mesylate, a highly selective and effective anticancer drug belonging to the new class of tyrosine kinase inhibitors, is being reported in patients, some progressing to congestive heart failure. This represents an unanticipated challenge that could limit effective drug use. Understanding the mechanisms and risk factors of imatinib mesylate cardiotoxicity is crucial for prevention of cardiovascular complications in cancer patients.Methods and resultsWe used genetically engineered mice and primary rat neonatal cardiomyocytes to analyse the action of imatinib on the heart. We found that treatment with imatinib (200 mg/kg/day for 5 weeks) leads to mitochondrial-dependent myocyte loss and cardiac dysfunction, as confirmed by electron microscopy, RNA analysis, and echocardiography. Imatinib cardiotoxicity was more severe in older mice, in part due to an age-dependent increase in oxidative stress. Mechanistically, depletion of the transcription factor GATA4 resulting in decreased levels of its prosurvival targets Bcl-2 and Bcl-XL was an underlying cause of imatinib toxicity. Consistent with this, GATA4 haploinsufficient mice were more susceptible to imatinib, and myocyte-specific up-regulation of GATA4 or Bcl-2 protected against drug-induced cardiotoxicity.ConclusionThe results indicate that imatinib action on the heart targets cardiomyocytes and involves mitochondrial impairment and cell death that can be further aggravated by oxidative stress. This in turn offers a possible explanation for the current conflicting data regarding imatinib cardiotoxicity in cancer patients and suggests that cardiac monitoring of older patients receiving imatinib therapy may be especially warranted.

From embryogenesis to adulthood: Critical role for GATA factors in heart development and function

“…These observations were mirrored in primary cardiomyocytes where GATA4 overexpression increased cardiomyocyte survival while reduced GATA4 levels potentiated DOX‐induced cell death . The role of GATA4 in cardiomyocyte survival has now been shown in other models of cardiac injury and heart failure (pressure overload, myocardial infarction, other anticancer drugs, hyperglycemia) . Mechanistically, GATA4's prosurvival effect has been linked to its activation of the proteins B‐Cell Lymphoma 2 and X (BCL2 and BCLX) but also more recently to the erythropoietin receptor .…”

“…68 The role of GATA4 in cardiomyocyte survival has now been shown in other models of cardiac injury and heart failure (pressure overload, myocardial infarction, other anticancer drugs, hyperglycemia). 25,[69][70][71] Mechanistically, GATA4's prosurvival effect has been linked to its activation of the proteins B-Cell Lymphoma 2 and X (BCL2 and BCLX) but also more recently to the erythropoietin receptor. 68,72 Similarly, the mechanisms that reduce GATA4 expression in response to cardiotoxic stimuli involve both transcriptional and post-translational mechanisms.…”

SIRT6 as a transcriptional coactivator of GATA4 prevents doxorubicin cardiotoxicity independently of its deacylase activity

“…Cardiomyocyte apoptosis is the leading cause of heart failure (3). Transcription factor GATA4 is indispensable for postnatal cardiomyocyte survival against DOX (3,(10)(11)(12), by directly targeting on the promoter regions of anti-apoptotic genes, such as Bcl-2 and Bcl-xL. Likewise, SIRT6 protects cardiomyocytes against hypoxic stress partially by upregulating Bcl-2 proteins by an unknown mechanism (35).…”

“…As an early-responsive event to DOX, GATA4 is rapidly and dramatically downregulated in transcript and protein levels (3,(7)(8)(9). GATA4 activates anti-apoptotic gene transcription, such as Bcl-2 and Bcl-xL, against DOX-induced myocyte death (3,(10)(11)(12). Genetically or pharmaceutically restoring GATA4 has been proposed as an accessible approach to prevent against DOX-induced cardiotoxicity (3,10,13).…”

Delivery as nanoparticles reduces imatinib mesylate-induced cardiotoxicity and improves anticancer activity

“…10 In this context, employing a tyrosine kinase inhibitor like imatinib mesylate to treat cancer has been reported to cause unanticipated cardiotoxicity. [11][12][13][14] For instance, imatinib mesylate-treated male spontaneously hypertensive rats are reported to present cardiac lesions, characterized by cytoplasmic vacuolization and myofibrillar loss, suggesting a correlation between hypertension and imatinib mesylate-induced cardiotoxicity. 12 More recently, the deleterious effect of imatinib mesylate on the heart was shown to be dose-, time-, and age-dependent.…”