Updates in Anthracycline-Mediated Cardiotoxicity

Cardiotoxicity is one of the main adverse effects of chemotheraphy, affecting the completion of cancer therapies and the short- and long-term quality of life. Anthracyclines are currently used to treat many cancers, including the various forms of leukemia, lymphoma, melanoma, uterine, breast, and gastric cancers. World Health Organization registered anthracyclines in the list of essential medicines. However, anthracyclines display a major cardiotoxicity that can ultimately culminate in congestive heart failure. Taking into account the growing rate of cancer survivorship, the clinical significance of anthracycline cardiotoxicity is an emerging medical issue. In this review, we focus on the key progenitor cells and cardiac cells (cardiomyocytes, fibroblasts, and vascular cells), focusing on the signaling pathways involved in cellular damage, and the clinical biomarkers in anthracycline-mediated cardiotoxicity

Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection

Abstract Background High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest. Objectives This study investigated how different concentrations of doxorubicin (DOX) can affect the function of the cardiac cells. This study also examined whether activation of prokineticin receptor-1 (PKR1) by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models. Methods We used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EPDCs) for in vitro, assays and tumor-bearing and acute and chronic toxicity mouse models for in vivo assays. Results Brief exposure to cardiomyocytes with high-dose DOX increases the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic NRF2. Prolonged exposure to medium-dose DOX induces apoptosis in cardiomyocytes, ECs, and EPDCs. However, low-dose DOX promotes functional defects without inducing apoptosis in EPDCs and ECs. IS20 alleviates detrimental effects of DOX in cardiac cells via activating AKT or mitogen-activated protein kinase pathways. Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20. In a chronic mouse model of DOX cardiotoxicity, IS20 normalizes an elevated serum marker of cardiotoxicity and vascular and EPDC deficits, attenuates apoptosis and fibrosis, and improves the survival rate and cardiac function. IS20 does not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer but attenuates the decreases in LV diastolic volume induced by acute DOX treatment. Conclusions This study identifies the molecular and cellular signature of dose-dependent DOX-mediated cardiotoxicity and provides evidence that PKR1 is a promising target to combat cardiotoxicity of cancer treatments

Flavaglines Alleviate Doxorubicin Cardiotoxicity: Implication of Hsp27

Background: Despite its effectiveness in the treatment of various cancers, the use of doxorubicin is limited by a potentially fatal cardiomyopathy. Prevention of this cardiotoxicity remains a critical issue in clinical oncology. We hypothesized that flavaglines, a family of natural compounds that display potent neuroprotective effects, may also alleviate doxorubicininduced cardiotoxicity. Methodology/Principal Findings: Our in vitro data established that a pretreatment with flavaglines significantly increased viability of doxorubicin-injured H9c2 cardiomyocytes as demonstrated by annexin V, TUNEL and active caspase-3 assays. We demonstrated also that phosphorylation of the small heat shock protein Hsp27 is involved in the mechanism by which flavaglines display their cardioprotective effect. Furthermore, knocking-down Hsp27 in H9c2 cardiomyocytes completely reversed this cardioprotection. Administration of our lead compound (FL3) to mice attenuated cardiomyocyte apoptosis and cardiac fibrosis, as reflected by a 50 % decrease of mortality. Conclusions/Significance: These results suggest a prophylactic potential of flavaglines to prevent doxorubicin-induce

Prokineticin Is a New Linker between Obesity and Cardiovascular Diseases

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The role of GPCR signaling in cardiac Epithelial to Mesenchymal Transformation (EMT)

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Functional consequence of serotonin/5-HT2B receptor signaling in heart: role of mitochondria in transition between hypertrophy and heart failure?

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Prokineticin signaling in heart-brain developmental axis: Therapeutic options for heart and brain injuries

International audienceHeart and brain development occur simultaneously during the embryogenesis, and both organ development and injuries are interconnected. Early neuronal and cardiac injuries share mutual cellular events, such as angiogenesis and plasticity that could either delay disease progression or, in the long run, result in detrimental health effects. For this reason, the common mechanisms provide a new and previously undervalued window of opportunity for intervention. Because angiogenesis, cardiogenesis and neurogenesis are essential for the development and regeneration of the heart and brain, we discuss therein the role of prokineticin as an angiogenic neuropeptide in heart-brain development and injuries. We focus on the role of prokineticin signaling and the effect of drugs targeting prokineticin receptors in neuroprotection and cardioprotection, with a special emphasis on heart failure, neurodegenerativParkinson's disease and ischemic heart and brain injuries. Indeed, prokineticin triggers common pro-survival signaling pathway in heart and brain. Our review aims at stimulating researchers and clinicians in neurocardiology to focus on the role of prokineticin signaling in the reciprocal interaction between heart and brain. We hope to facilitate the discovery of new treatment strategies, acting in both heart and brain degenerative diseases