Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production

Riccio, Gennaro; Antonucci, Salvatore; Coppola, Carmela; D’Avino, Chiara; Piscopo, Giovanna; Fiore, Danilo; Maurea, C; Russo, Michele; Rea, Domenica; Arra, Claudio; Condorelli, Gerolama; Lisa, Fabio Di; Tocchetti, Carlo G.; Lorenzo, Claudia De; Maurea, Nicola

doi:10.3389/fphys.2018.00038

Cited by 41 publications

(35 citation statements)

References 61 publications

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“…We observed that a single dose of 20 mg/kg trastuzumab for 3 weeks induced severe LV systolic dysfunction, as LVIDs and ESV were significantly increased and EF and FS were remarkably decreased compared to baseline. Although our results were compatible with several in vivo experiments [14,17,25,26] and clinical data [27,28], controversial observations regarding the correlation of trastuzumab treatment and cardiac dysfunction have been reported. Jassal et al demonstrated that 5 days treatment with 10mg/kg trastuzumab did not change the EF or FS in C57Bl/6 mice [29].…”

Section: Discussionsupporting

confidence: 92%

“…The beta-blockers cardioprotective effect against trastuzumab has been reported, but the molecular mechanism of this action has not been fully explained [21][22][23]. Inhibition of cardiac Erbb2 and Akt by trastuzumab may make cardiac injuries [14,26,33]. It has been reported that carvedilol could improve cardiac function by up-regulation of AKt expression, down-regulation of cytochrome c-induced apoptosis pathway and inhibition of mitochondrial damage [34][35][36].…”

Section: Discussionmentioning

confidence: 99%

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In Vivo Evaluation of Carvedilol Cardiac Protection Against Trastuzumab Cardiotoxicity

et al. 2020

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Cardiac dysfunction is a major side effect of trastuzumab therapy for patients with HER2-positive breast cancer. Beta blockers, such as carvedilol, have been used for protection of trastuzumab cardiotoxicity but there is no definitive conclusive clinical report on their efficacy. In the present study, the preservability effects of carvedilol on trastuzumab-induced left ventricular (LV) dysfunction and the reversibility of trastuzumab-induced cardiotoxicity were evaluated in Wistar rats by echocardiography method. We showed that trastuzumab treatment of rats could induce the LV dysfunction through increasing the LV internal systolic diameter (LVIDs), increasing the end-systolic volume (ESV), decreasing the ejection fraction (EF), and decreasing the fractional shortening (FS). These parameters were not reversed after 14 days of stopping trastuzumab administration. Interestingly, carvedilol improved LVIDs, ESV, EF, and FS. Collectively, the results of this study have verified clinical observations which simultaneously administration of carvedilol may be considered as a possible therapeutic strategy to prevent trastuzumab-mediated LV dysfunction.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

In Vivo Evaluation of Carvedilol Cardiac Protection Against Trastuzumab Cardiotoxicity

et al. 2020

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“…Cancer patients subjected to therapies with TMZ or anti‐EGFR drugs have a high risk of cardiovascular diseases, reducing their overall survival (Maurea et al, ;Riccio et al, ). Interestingly, several clinical and preclinical studies are focused on the use of cardioprotective agents during chemotherapy, such as Ranolazine (having antioxidant properties), nutraceuticals, and other anti‐inflammatory bioactive compounds (Quagliariello et al, ; Riccio et al, ).…”

Section: Discussionmentioning

confidence: 99%

Boswellic acid has anti‐inflammatory effects and enhances the anticancer activities of Temozolomide and Afatinib, an irreversible ErbB family blocker, in human glioblastoma cells

Barbarisi

Sena

et al. 2019

Phytotherapy Research

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Glioblastoma multiforme (GBM) is the most aggressive brain tumor. Current therapeutic strategies are based on the use of Temozolomide (TMZ) and antihuman epidermal growth factor receptor (EGFR) drugs, such as Afatinib. However, clinically relevant drug‐resistance events are still present and closely related to a proinflammatory cancer brain microenvironment. The primary aim of this study is the association of Boswellic acid (BA), a molecule derived from Boswellia Serrata, with TMZ and Afatinibin different human GBM cells. We performed cell viability studies evaluating its antioxidant and anti‐inflammatory effects analyzing p65/NF‐κB and Leukotriene B4 expression and production of interleukins and growth factors (IL‐8, IL‐6, vascular endothelial growth factor, CXCL‐12, and MMP‐9). Considering the cardiotoxicity of TMZ and anti‐EGFR drugs, we evaluated the putative cardioprotective effects of BA in adult cardiomyocytes. BA significantly increased the anticancer activities of TMZ and Afatinib. These effects are related to its anti‐inflammatory and antioxidant effects, based on the inhibition of growth factors and proinflammatory interleukins. Notably, BA exerts also cardioprotective effects in combination to both drugs. This study provides evidences of anti‐inflammatory, cardioprotective, and chemo sensitizing effects of BA in glioblastoma cells giving a rationale for new translational studies based on the use of this natural molecule during conventional therapies.

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“…We also further investigated the protective effects, both in vitro and in vivo, of ranolazine, a drug in clinical use to treat chronic angina and ischemia, acting as an inhibitor of the late Na + ion current in cardiac cells, 14 which has already shown cardioprotective effects for doxorubicin and trastuzumab treatment by reducing the effects of oxidative stress. 18 , 19 Here, we tested whether it could also be used to revert the cardiotoxic effects of the novel approved drugs. We found that ranolazine attenuated not only the cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments on all the cardiac cell lines used in our study.…”

Section: Discussionmentioning

confidence: 99%

“…As previously described, ranolazine is able to protect the cardiac function from both doxorubicin- and trastuzumab-related cardiotoxicity by reducing the effects of oxidative stress. 18 , 19 …”

Section: Introductionmentioning

confidence: 99%

Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine

Lorenzo¹,

Paciello²,

Riccio³

et al. 2018

OTT

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PurposePertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody–drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity.MethodsThe cardiotoxic effects were tested in vitro on rat cardiomyoblasts, human fetal cardiomyocytes, adult-like cardiomyocytes, and in vivo on a mouse model.ResultsAll the treated cardiac cell lines were significantly affected by treatment with the tested drugs. Surprisingly, TDM1 showed stronger inhibitory effects on cardiac cells with respect to trastuzumab and pertuzumab by more significantly reducing the cell viability and by changing the morphology of these cells. TDM1 also affected the beating phenotype of adult-like cardiomyocytes in vitro and reduced fractional shortening and ejection fraction in vivo in a mouse model. We also found that ranolazine attenuated not only the cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments both in vitro and in vivo, as demonstrated by the recovery of fractional shortening and ejection fraction values in mice pretreated with TDM1.ConclusionWe demonstrated that it is possible to predict the eventual cardiotoxic effects of novel approved anticancer drugs early by using in vitro and in vivo approaches, which can also be useful to screen in advance the cardioprotective agents, so as to avoid the onset of unwanted cardiotoxic side effects.

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Ranolazine Attenuates Trastuzumab-Induced Heart Dysfunction by Modulating ROS Production

Cited by 41 publications

References 61 publications

In Vivo Evaluation of Carvedilol Cardiac Protection Against Trastuzumab Cardiotoxicity

In Vivo Evaluation of Carvedilol Cardiac Protection Against Trastuzumab Cardiotoxicity

Boswellic acid has anti‐inflammatory effects and enhances the anticancer activities of Temozolomide and Afatinib, an irreversible ErbB family blocker, in human glioblastoma cells

Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine

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