Editorial: The Challenge of New Therapeutic Approaches for Unmet Therapeutic Needs

Molecular mechanisms of carfilzomib-induced cardiotoxicity in mice and the emerging cardioprotective role of metformin

AbstractCarfilzomib (Cfz), an irreversible proteasome inhibitor licensed for relapsed/refractory myeloma, is associated with cardiotoxicity in humans. We sought to establish the optimal protocol of Cfz-induced cardiac dysfunction, to investigate the underlying molecular-signaling and, based on the findings, to evaluate the cardioprotective potency of metformin (Met). Mice were randomized into protocols 1 and 2 (control and Cfz for 1 and 2 consecutive days, respectively); protocols 3 and 4 (control and alternate doses of Cfz for 6 and 14 days, respectively); protocols 5A and 5B (control and Cfz, intermittent doses on days 0, 1 [5A] and 0, 1, 7, and 8 [5B] for 13 days); protocols 6A and 6B (p…

Nitroglycerin-induced cardioprotection is endothelial nitric oxide synthase- dependent

Purpose We sought to evaluate the contribution of the endogenous NO pathway to the cardioprotective action of nitroglycerin (NTG). Methods and Results Anesthetized rabbits were subjected to 30-min myocardial ischemia (isc) and 3-h reperfusion (rep) and randomized into: Control group (no further intervention); PostC group (application of 8 cycles 30-sec isc/rep) and NTG treated group (2 μg/kg-1/min-1 IV bolus) for 65 min starting 10 min prior to rep. In additional groups, pharmacological inhibitors of NOS, nNOS, iNOS, PI3K, adenosine receptors and PKG were administrated with or without NTG. The infarcted (I) to risk (R) ratio was estimated. In a second experimental series tissue samples were…

Metformin Restores AMPK Alpha-Mediated Autophagy and Prevents Carfilzomib-Induced Cardiotoxicity In Vivo

Abstract Introduction: Carfilzomib (Cfz) significantly prolongs progression-free survival in relapsed or refractory multiple myeloma patients, as highlighted in the ENDEAVOR trial. However, Cfz has high incidences of cardiotoxicity and heart failure, leading to treatment cessation. Thus, there is an imperative need for preventive therapies. The study aimed to i) establish an in vivo Cfz cardiotoxicity protocol, ii) investigate the molecular mechanism, identify molecular targets and iii) based on initial results, investigate the potential protective effect and mechanism of Metformin (Met). Methods: Male, C57BL/6 mice, were randomized in groups as following: Acute protocol (6 days): Control (…

P3488Mechanistic insight on the cardioprotective effect of levosimendan against doxorubicin induced cardiomyopathy: Pivotal role of PKA signaling

Abstract Background Levosimendan (LEVO) an inodilator indicated for the treatment of heart failure exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains elusive. We have previously shown that LEVO exerts cardioprotection against DXR-induced cardiomyopathy in a rat in vivo model, in a PKA/PKG-dependent manner. Purpose We sought to elucidate the mechanism of LEVO's induced cardioprotection and clarify the contribution of PKG and PKA pathways converging onto phospholamban (PLN). Methods As previously observed, LEVO at a dose of 24μg/kg protects against DXR cardiotoxicity, with protein kinase B (A…

Levosimendan prevents doxorubicin-induced cardiotoxicity in time- and dose-dependent manner: implications for inotropy.

Abstract Aims Levosimendan (LEVO) a clinically-used inodilator, exerts multifaceted cardioprotective effects. Case-studies indicate protection against doxorubicin (DXR)-induced cardiotoxicity, but this effect remains obscure. We investigated the effect and mechanism of different regimens of levosimendan on sub-chronic and chronic doxorubicin cardiotoxicity. Methods and results Based on preliminary in vivo experiments, rats serving as a sub-chronic model of doxorubicin-cardiotoxicity and were divided into: Control (N/S-0.9%), DXR (18 mg/kg-cumulative), DXR+LEVO (LEVO, 24 μg/kg-cumulative), and DXR+LEVO (acute) (LEVO, 24 μg/kg-bolus) for 14 days. Protein kinase-B (Akt), endothelial nitric oxi…

Investigating the Vascular Toxicity Outcomes of the Irreversible Proteasome Inhibitor Carfilzomib

Background: Carfilzomib&rsquo

Corrigendum to “European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)” [Redox Biol. 13 (2017) 94–162]

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics b…

Synergistic Effect of Carfilzomib and Metformin in Vascular Plasticity; The Emerging Role of Autophagy

Introduction: Carfilzomib (Cfz) correlates with a risk of reversible cardiotoxicity in 5-10% of multiple myeloma (MM) patients. We have recently shown that metformin (Met) has a prophylactic role against the Cfz-induced cardiotoxicity in vivo, through activation of AMPKα signaling (Blood 2019;133:710-23). However, the impact of Cfz on vascular function is obscure. Therefore, we sought to investigate: i) the acute, ii) the sub-chronic effect of Cfz on the vascular reactivity, iii) the effect of metformin co-administration on the vascular phenotype and iv) the impact of Cfz and Met co-administration on aged Human Aortic Smooth Muscle Cells (HAoSMCs). Methods: Forty male C57Bl/6 mice were assi…

The role of mitochondrial reactive oxygen species, NO and H2S in ischaemia/reperfusion injury and cardioprotection

Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed a…

Investigating and re-evaluating the role of glycogen synthase kinase 3 beta kinase as a molecular target for cardioprotection by using novel pharmacological inhibitors

Aims Glycogen synthase kinase 3 beta (GSK3β) link with the mitochondrial Permeability Transition Pore (mPTP) in cardioprotection is debated. We investigated the role of GSK3β in ischaemia (I)/reperfusion (R) injury using pharmacological tools. Methods and results Infarct size using the GSK3β inhibitor BIO (6-bromoindirubin-3'-oxime) and several novel analogues (MLS2776-MLS2779) was determined in anaesthetized rabbits and mice. In myocardial tissue GSK3β inhibition and the specificity of the compounds was tested. The mechanism of protection focused on autophagy-related proteins. GSK3β localization was determined in subsarcolemmal (SSM) and interfibrillar mitochondria (IFM) isolated from Lang…

European contribution to the study of ROS : A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

WOS: 000410470000009