The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab–Mediated Cardiac Dysfunction

Goyal, Vineet; Bews, Hilary; Cheung, David; Premecz, Sheena; Mandal, Soma; Shaikh, Bilal; Best, Ryan; Bhindi, R.; Chaudhary, Rakesh; Ravandi, Amir; Thliveris, James A.; Singal, Pawan K.; Niraula, Saroj; Jassal, Davinder S.

doi:10.1016/j.cjca.2016.06.002

Cited by 37 publications

(28 citation statements)

References 32 publications

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“…However, the ability of MET to protect the myocardium may be reduced over time, emphasising the need to incorporate alternative therapies as an adjunct to improve the endogenous antioxidant status of the diabetic heart. As such, studies have presented data reporting on the preventive properties of NAC in hyperglycaemia-induced oxidative stress [11,[32][33][34][35]. Dludla (2018) performed a systematic review confirming the ameliorative properties of NAC and highlighted that there is a scarcity of data reporting on the comparative effect of NAC with common glucose-lowering therapies on the diabetic myocardium [11].…”

Section: Discussionmentioning

confidence: 99%

An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage

et al. 2019

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Chronic hyperglycaemia is a major risk factor for diabetes-induced cardiovascular dysfunction. In a hyperglycaemic state, excess production of reactive oxygen species (ROS), coupled with decreased levels of glutathione, contribute to increased lipid peroxidation and subsequent myocardial apoptosis. N-acetylcysteine (NAC) is a thiol-containing antioxidant known to protect against hyperglycaemic-induced oxidative stress by promoting the production of glutathione. While the role of NAC against oxidative stress-related cardiac dysfunction has been documented, to date data is lacking on its beneficial effect when used with glucose lowering therapies, such as metformin (MET). Thus, the aim of the study was to better understand the cardioprotective effect of NAC plus MET against hyperglycaemia-induced cardiac damage in an H9c2 cardiomyoblast model. H9c2 cardiomyoblasts were exposed to chronic high glucose concentrations for 24 h. Thereafter, cells were treated with MET, NAC or a combination of MET and NAC for an additional 24 h. The combination treatment mitigated high glucose-induced oxidative stress by improving metabolic activity i.e. ATP activity, glucose uptake (GU) and reducing lipid accumulation. The combination treatment was as effective as MET in diminishing oxidative stress, lipid peroxidation and apoptosis. We observed that the combination treatment prevented hyperglycaemic-induced cardiac damage by increasing GLUT4 expression and mitigating lipid accumulation via phosphorylation of both AMPK and AKT, while decreasing nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), as well as protein kinase C (PKC), a known activator of insulin receptor substrate-1 (IRS-1), via phosphorylation at Ser307. On this basis, the current results support the notion that the combination of NAC and MET can shield the diabetic heart against impaired glucose utilization and therefore its long-term protective effect warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage

et al. 2019

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“…Despite the previous studies, we found out that N-acetylcysteine can reduce the troponin I level. In this regard, Goyal et al, have shown the cardioprotective effect of N-acetylcysteine amide on murine models receiving chemotherapy; while N-acetylcysteine was not evaluated in their study [16]. Our results show that since troponin I level may be lowered by the administration of N-acetylcysteine in breast cancer patients, it can reduce the risk of anthracycline-induced cardiomyopathy.…”

Section: Discussionmentioning

confidence: 51%

The Effect of N-Acetylcysteine Administration to Prevent Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients

Khazdooz

Nourian

Jalaeikhoo

et al. 2019

Multidiscip Cancer Investig

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Introduction: Anthracyclines are one of the classes of chemotherapy drugs that are widely used to treat many types of cancers including breast cancer. Taking this class of medications has a significant relationship with cardiac dysfunction. N-acetylcysteine has antioxidant properties and may be effective in preventing cardiac dysfunctions. In this study, we investigated the effect of N-acetylcysteine in preventing cardiotoxicity in breast cancer patients receiving anthracycline. Methods: A total of 60 breast cancer patients who underwent chemotherapy with anthracyclines were enrolled in the present case-control study and divided into two groups. The case group received 600 mg of N-acetylcysteine per day adjacent to chemotherapy; while the control group did not receive this medication. One month after the last chemotherapy session, troponin I was measured as a predictor of cardiotoxicity. Results: Troponin I was positive in one patient in the case group compared with 3 patients in the control group without any significant difference among groups (P> 0.05) However, the respective mean±SD level of troponin I was 0.120±0.039 and 0.192±0.063 in the case and control groups with a statistically significant difference among groups (P <0.001). Conclusions: Administration of 600 mg N-acetylcysteine per day during the anthracyclinebased chemotherapy protocol in breast cancer patients may reduce the mean troponin I levels which can be a prediction of reduced anthracyclines cardiotoxicity.

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“…Oxidation can cause a vast number of changes in the structure of fatty acids forming various types of structurally and functionally different biomolecules. In chemotherapy-induced cardiomyopathy OxPC have been shown to correlate with myocardial toxicity, left ventricular dysfunction and cell death (Bordun et al 2015; Goyal et al 2016; Koleini et al 2014). Given the biological activity of OxPC, they are not only bystanders of cellular ROS production but also have toxic effects towards cardiomyocytes in a different scenario, reperfusion injury (Ganguly et al 2018; White et al 2013; White et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

et al. 2018

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Doxorubicin (Dox)-induced cardiotoxicity, a limiting factor in the use of Dox to treat cancer, can be mitigated by the mitogenic factor FGF2 in vitro, via a heme oxygenase 1 (HO-1)-dependent pathway. HO-1 upregulation was reported to require protein kinase CK2 activity. We show that a mutant non-mitogenic FGF2 (S117A-FGF2), which does not activate CK2, is cardioprotective against acute cardiac ischemic injury. We now investigate the potential of S117A-FGF2 to protect cardiomyocytes against acute Dox injury and decrease Dox-induced upregulation of oxidized phospholipids. The roles of CK2 and HO-1 in cardiomyocyte protection are also addressed.Rat neonatal cardiomyocyte cultures were used as an established in vitro model of acute Dox toxicity. Pretreatment with S117A-FGF2 protected against Dox-induced: oxidative stress; upregulation of fragmented and non-fragmented oxidized phosphatidylcholine species, measured by LC/MS/MS; and cardiomyocyte injury and cell death measured by LDH release and a live-dead assay. CK2 inhibitors (TBB and Ellagic acid), did not affect protection by S117A-FGF2 but prevented protection by mitogenic FGF2. Furthermore, protection by S117A-FGF2, unlike that of FGF2, was not prevented by HO-1 inhibitors and S117A-FGF2 did not upregulate HO-1. Protection by S117A-FGF2 required the activity of FGF receptor 1 and ERK.We conclude that mitogenic and non-mitogenic FGF2 protect from acute Dox toxicity by common (FGFR1) and distinct, CK2/HO-1- dependent or CK2/HO-1-independent (respectively), pathways. Non-mitogenic FGF2 merits further consideration as a preventative treatment against Dox cardiotoxicity.

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The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab–Mediated Cardiac Dysfunction

Cited by 37 publications

References 32 publications

An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage

An In Vitro Study on the Combination Effect of Metformin and N-Acetyl Cysteine against Hyperglycaemia-Induced Cardiac Damage

The Effect of N-Acetylcysteine Administration to Prevent Anthracycline-Induced Cardiotoxicity in Breast Cancer Patients

Non-mitogenic FGF2 protects cardiomyocytes from acute doxorubicin-induced toxicity independently of the protein kinase CK2/heme oxygenase-1 pathway

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