Liposomal doxorubicin attenuates cardiotoxicity via induction of interferon-related DNA damage resistance

Abstract

Aims The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. Methods and results We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. Conclusions All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression

“…Doxorubicin (Dox) belongs to anthracyclines, one of the most frequently used chemotherapeutics for a wide range of malignancies, such as breast cancer and haematologic cancer 1 . However, the clinical application of Dox is limited by its lethal cardiomyopathy, which is characterized by decrease in left ventricular ejection fraction (LVEF) or even heart failure 1 , 2 , 3 , 4 .…”

Increased Serum Procollagen Type I C-terminal Propeptide Levels are Associated with Subclinical Left Ventricular Dysfunction in Patients with Breast Cancer Treated with Anthracycline-Based Cancer Chemotherapy

“…Although several studies have reported pro brotic effects of anthracyclines, cyclophosphamide, paclitaxel and trastuzumab in the myocardium of experimental models of cardiotoxicity [8][9][10][11][12][13][14], and in rodent cardiac broblasts [9,11], the role of these agents in HCFs has not been characterized. In this regard, we describe that doxorubicin, cyclophosphamide and trastuzumab stimulated the differentiation to a myo broblast collagen-synthesizing phenotype, including enhanced presence of PICP in the extracellular medium.…”

“…Traditionally, cardiotoxicity due to breast cancer treatment, particularly anthracycline-based cancer chemotherapy (ACC), has been attributed to cardiomyocyte damage and death, with amino-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponins (hs-Tn) as the most commonly used biomarkers to detect cardiac damage in these patients [5,6]. However, it has been suggested that myocardial interstitial brosis (MIF) is an additional important mechanism contributing to left ventricular dysfunction (LVD) and adverse clinical evolution in ACC-treated patients [6,7], as well as in patients treated with other oncologic drugs such as cyclophosphamide, taxane agents and anti-HER2 therapies [8][9][10][11][12][13][14]. As cumulative evidence suggest that the detrimental impact of MIF on LV function is related to both an excess in collagen type-I ber cross-linking and deposition [15], these characteristics of the collagen ber should be evaluated in the myocardium of patients receiving ACC.…”

Genome‑wide prioritization reveals novel gene signatures associated with cardiotoxic effects of tyrosine kinase inhibitors

“…Left ventricular dysfunction and heart failure (HF), which are typically described as cardiotoxicity, are the most concerning cardiovascular complications of anticancer chemotherapies, which cause an increase in morbidity and mortality (1). Based on previous studies of anthracycline cardiotoxicity, increasing attention has focused on tyrosine kinase inhibitors (TKIs), a type of pharmaceutical drug inhibiting tyrosine kinases by competitively binding to and inhibiting their ATP binding pocket (2)(3)(4)(5). TKIs are characterized by being multi-targeted anticancer agents that lack sufficient specificity, which markedly increases the risk of cardiotoxicity (5).…”