Ranolazine in the prevention of anthracycline cardiotoxicity

Corradi, Francesco; Paolini, Luca; Caterina, Raffaele De

doi:10.1016/j.phrs.2013.11.001

Cited by 27 publications

(18 citation statements)

References 140 publications

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“…In diastolic dysfunction, characterized by the presence of ROS, RNS and hypoxia, the hyperactivation of late I Na is constantly reported as well. A similar scenario can occur in the heart exposed to doxorubicin, where the continuous formation of ROS/RNS together with increased cytoplasmic Ca 2+ may lead to activation of late I Na (Minotti, 2013;Corradi et al, 2014). In our study, high levels of oxidative stress together with significant alterations in Ca 2+ handling proteins (SERCA2 and NCX1) were detected at the end of doxorubicin treatment.…”

Section: Discussionsupporting

confidence: 82%

“…Doxorubicin exposure increased myocardial Na v 1.5 channel (Erickson et al, 2011;Sag et al, 2011;Coppini et al, 2013b;Kreusser and Backs, 2014 (Wagner et al, 2006;Erickson et al, 2008;Wagner et al, 2011;Coppini et al, 2013a). Therefore, the use of ranolazine may be beneficial in diastolic dysfunction and chemotherapeutic cardiotoxicity, due to its capacity to reduce late I Na and cytosolic Na + , and consequently to counteract intracellular Ca 2+ accumulation (Minotti, 2013;Corradi et al, 2014;Mihos et al, 2016;Banerjee et al, 2017). In a previous study in mice, ranolazine was shown to act as an antioxidant when co-administered with doxorubicin (Tocchetti et al, 2014).…”

Section: Discussionmentioning

confidence: 98%

“…mitigate the lifetime risk of cardiotoxicity or to alleviate doxorubicin-induced LV diastolic dysfunction in cancer patients is gaining interest (Minotti, 2013;Corradi et al, 2014), but several compelling arguments are still not validated by experimental evidence. The INTERACT study (www.clinicaltrialsregister.eu: EudraCT n. 2009-016930-29) is a Phase IIB clinical trial conducted on patients who have completed standard dose chemotherapy for the treatment of non-Hodgkin lymphoma or the adjuvant treatment of breast cancer or colorectal cancer.…”

Section: Ranolazinementioning

confidence: 99%

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Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Cappetta

Esposito

Coppini

et al. 2017

British J Pharmacology

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Doxorubicin is a highly effective anticancer drug, but its clinical application is hampered by cardiotoxicity. Asymptomatic diastolic dysfunction can be the earliest manifestation of doxorubicin cardiotoxicity. Therefore, a search for therapeutic intervention that can interfere with early manifestations and possibly prevent later development of cardiotoxicity is warranted. Increased doxorubicin-dependent ROS may explain, in part, Ca 2+ and Na + overload that contributes to diastolic dysfunction and development of heart failure. Therefore, we tested whether the administration of ranolazine, a selective blocker of late Na + current, immediately after completing doxorubicin therapy, could affect diastolic dysfunction and interfere with the progression of functional decline. EXPERIMENTAL APPROACHFischer 344 rats received a cumulative dose of doxorubicin of 15 mg·kg À1 over a period of 2 weeks. After the assessment of diastolic dysfunction, the animals were treated with ranolazine (80 mg·kg À1 , daily) for the following 4 weeks. KEY RESULTSWhile diastolic and systolic function progressively deteriorated in doxorubicin-treated animals, treatment with ranolazine relieved diastolic dysfunction and prevented worsening of systolic function, decreasing mortality. Ranolazine lowered myocardial NADPH oxidase 2 expression and oxidative/nitrative stress. Expression of the Na + /Ca 2+ exchanger 1 and Na v 1.5 channels was reduced and of the sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase 2 protein was increased. In addition, ranolazine lowered doxorubicin-induced hyper-phosphorylation and oxidation of Ca 2+ /calmodulin-dependent protein kinase II, and decreased myocardial fibrosis. CONCLUSIONS AND IMPLICATIONSRanolazine, by the increased Na + influx, induced by doxorubicin, altered cardiac Ca 2+ and Na + handling and attenuated diastolic dysfunction induced by doxorubicin, thus preventing the progression of cardiomyopathy. LINKED ARTICLES

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 98%

Section: Ranolazinementioning

confidence: 99%

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Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Cappetta

Esposito

Coppini

et al. 2017

British J Pharmacology

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“…The myriad of studies aiming to explore cellular and molecular phenomena that may be clinically relevant has been focused on a cardiomyocyte and were extensively reviewed elsewhere [40,41]. However, although cardiomyocyte has been considered a classical cellular target, other cell types such as cardiac fibroblasts, endothelial cells and vascular smooth muscle cells are also present (and are numerically prevalent) within the myocardium.…”

Section: Cellular Targetsmentioning

confidence: 99%

Doxorubicin cardiotoxicity and target cells: a broader perspective

et al. 2016

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The cardiotoxicity of doxorubicin is becoming an interdisciplinary point of interest given a growing population of cancer survivors. The complex and not completely understood pathogenesis of this complication makes difficult to design successful preventive or curative measures. Although cardiomyocyte has been considered a classical cellular target, other cells including various types of undifferentiated cells are involved in myocardial homeostasis. Such perspective may shed light on previously unrecognized aspects of cardiotoxicity and promote new experimental and clinical cardioprotective strategies. In this review, different cellular targets of doxorubicin are discussed with the focus on cardiac progenitor cells, oxidative stress, DNA damage, senescence and apoptosis all of which contribute to their compromised functional properties.

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“…It is generally believed that the formation of the 7-deoxyaglycone metabolite inactivates the parent molecule. However, the 7-deoxyaglycone metabolite has been implicated in the production of ROS by intercalating with the inner mitochondrial membrane due to the increase in lipid solubility that accompanies the loss of the sugar moiety [14,112]. This intercalation into membranes has also been thought to cause a form of benign acute toxicity in the human myocardium via ROS production [32], although the cardiotoxicity is not to the extent of that observed for the parent molecule.…”

Section: D) Reductive Deglycosidation Of Anthracy-clines (Deoxyaglycomentioning

confidence: 99%

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines –

Edwardson¹,

Narendrula²,

Chewchuk³

et al. 2015

CDM

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Abstract:Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxocity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.

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Ranolazine in the prevention of anthracycline cardiotoxicity

Cited by 27 publications

References 140 publications

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Effects of ranolazine in a model of doxorubicin‐induced left ventricle diastolic dysfunction

Doxorubicin cardiotoxicity and target cells: a broader perspective

Role of Drug Metabolism in the Cytotoxicity and Clinical Efficacy of Anthracyclines –

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