La doxorubicine induit un stress oxydant, des dommages à l’ADN conduisant aussi bien à la mort des cellules cancéreuses que des cardiomyocytes. De nos jours, plusieurs hypothèses non reliées à la mort cellulaire et impliquant d’autres mécanismes ou l’altération des signalisations cardiaques telles que la signalisation β-adrénergique ont émergé. Cette thèse a donc pour objectif l’étude du rôle d’Epac, facteur d’échange directement activé par l’AMP cyclique, lui-même produit après stimulation β-adrénergique, dans la cardiotoxicité induite par la doxorubicine. En effet, la doxorubicine induit une cardiomyopathie dilatée 15 semaines après traitement associée à une altération de l’homéostasie calcique. Ces altérations sont corrélées à la modulation temps et dose-dépendantes de la signalisation d’Epac. Cette même altération globale de la signalisation d’Epac a également été observée in vitro après 24h de traitement à la dox. De plus, l’inhibition spécifique d’Epac 1 a permis la prévention des dommages à l’ADN et de façon subséquente de la mort des cardiomyocytes. L’invalidation du gène d’Epac1 chez la souris a également permis la prévention in vivo des altérations de l’homéostasie calcique ainsi que de la fonction cardiaque induite par la dox. Enfin, l’inhibition d’Epac n’interfère pas avec l’efficacité antitumorale de la doxorubicine sur différentes lignées cancéreuses. En conclusion, nous avons identifié Epac comme nouvelle cible thérapeutique de la cardiotoxicité induite par la dox permettant sa prévention sans réduire l’efficacité du traitement anticancéreux. / The mechanisms underlying doxorubicin (Dox)-induced cardiotoxicity involve reactive oxygen species generation, DNA intercalation and topoisomerase II (TopII) inhibition which trigger DNA damage, oxidative stress, alteration of calcium homeostasis and lead to cardiomyocyte death. Now, evidences have emerged that Dox may promote cardiotoxicity by alternative mechanisms or by signaling pathways modulation including β-adrenergic signaling unrelated directly to cell death. This study provides in vitro and in vivo evidence of the guanine exchange factor directly activated by Epac role, a guanine exchange factor directly activated by cyclic AMP produced after β-AR stimulation, in cardiotoxicity induced by doxorubicin. Indeed, Dox leads to the development of a dilated cardiomyopathy (DCM) 15 weeks post treatment in mice associated with calcium homeostasis abnormalities. These alterations were associated with time- and dose-dependent alterations of Epac signaling. The same alterations of Epac signaling were observed in vitro after 24h of dox treatment. Furthermore, we first showed that the specific pharmacologic or genetic inhibition of Epac1 but not Epac2 prevents the deleterious effects of Dox in vitro. These cardioprotection were confirmed in vivo in transgenic Knock-out Epac1 mice. Epac 1 inhibition did not interfere with the attempted Dox antitumor efficiency on tumor cell lines. Altogether, these findings identify the cAMP-binding protein, Epac, as a potential therapeutic target of dox-induced cardiotoxicity.

Objective: To evaluate whether abnormal concentrations in cardiac and inflammatory biomarkers could predict reductions in left ventricular ejection fraction (LVEF) for cancer patients undergoing curative treatment. Materials and Methods: Longitudinal testing was performed for high-sensitivity cardiac troponin I (hs-cTnI), N-terminal pro-B-type natriuretic peptide (NT-proBNP), heart-type fatty acid binding protein (H-FABP) and C-reactive protein (CRP) in HER2+ breast cancer (BC) patients receiving adjuvant trastuzumab treatment (n=22) and in lymphoma patients treated with radiotherapy (n=4). Sex-specific and overall upper limit of normal (ULN) cutoffs were used to identify abnormal results with a reduction in LVEF (<50% and decrease of ≥10% from baseline) indicative of cardiotoxicity. A secondary analysis was performed on the BC patients with normal LVEFs (n=12 with baseline prior to chemotherapy through to 6-months on trastuzumab) with 15 blood collections spaced between 6- and 254-days post-baseline LVEF measurement. Results: A majority of the BC patients had evidence of myocardial injury (hs-cTnI >female ULN=90%) or myocardial dysfunction (NT-proBNP >overall ULN=91%) at any timepoint with fewer patients having abnormal CRP or H-FABP concentrations (H-FABP >ULN=14%; CRP >ULN=45%). Myocardial injury and dysfunction were most evident during the first two cycles of trastuzumab treatment, with myocardial injury also evident during this early timeframe in the female lymphoma patients (3 with hs-cTnI >ULN). In the 12 patients who completed trastuzumab with normal LVEFs (median=60% at 6-months), myocardial injury (hs-cTnI >ULN) and dysfunction (NT-proBNP >ULN) was evident in >50% of patients. Four of the 22 patients did develop cardiotoxicity, but there was no difference in biomarker concentrations between patients with or without cardiotoxicity. Conclusion: The use of the recommended ULN cutoffs identified myocardial injury and dysfunction in a majority of cancer patients in this setting. Biomarker assessments did not relate to cardiac functional imaging studies. Future studies are warranted to assess different cutoffs or biomarker combinations for predicting cardiotoxicity. / Thesis / Master of Science (MSc)

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.

It has been known that anthracycline-based chemotherapy has the potential to cause cardiac dysfunction in breast cancer patients; however, recently evidence has shown that the addition of trastuzumab increases this risk. The study objective was to compare the cost-effectiveness of monitoring for cardiotoxicity with B-type natriuretic peptide (BNP), multi-gated acquisition scanning (MUGA), echocardiography (ECHO) or no monitoring from a payer’s prospective. Cost-effectiveness was compared between alternatives using an incremental cost-effectiveness ratio with outcomes of 1) quality-adjusted life-years and 2) percentage of patients diagnosed with each monitoring strategy. Costs estimates (in 2010 U.S. Dollars) of each strategy (obtained from the Center for Medicare and Medicaid Services website [www.cms.gov]) included the cost of the test, cost of treating heart failure once discovered (which includes medications, routine office visits, medication management) and the cost of potential acute care (which includes emergency department visits and hospitalizations). Estimates for the probabilities of heart failure development, disease progression, need for acute care, and mortality, as well as utility estimates for all disease stages were obtained from published literature. A 15-year time-frame was used with a 3% discount rate for both costs and QALYs. In the base-case analysis, the average costs and QALYs for monitoring patients were $10,062/ 6.92 QALY, $13,627/4.22 QALY, $14,739/ 6.61 QALY and $15,656/ 6.49 QALY for BNP, No Monitoring, ECHO and MUGA respectively. When comparing all alternatives to BNP, the ICER values were negative, indicating that BNP was the dominant monitoring strategy. Percent detection was similar between the three monitoring methods [21-22 % for HER-2(-) and 30-31% for HER-2(+) patients]. Again BNP was dominant over the other monitoring strategies. Sensitivity analyses were robust to changes in discount rate, probability of patients testing HER-2 (+), probability of patients being diagnosed in an asymptomatic stage, incidence of cardiac dysfunction in patients receiving anthracycline therapy ± trastuzumab and estimate of disutility associated with additional testing. A probabilistic sensitivity analysis conducted via Monte Carlo simulation led to the same conclusion as the base-case analysis; BNP was the dominant strategy over all monitoring alternatives. / text

Doxorubicin (DOX) is a broad-spectrum and effective chemotherapeutic agent, but its use in oncologic practice is limited by dose-dependent cumulative cardiotoxicity. DOX-induced cardiotoxicity is in large part due to its ability to cause oxidative stress. Multidrug resistance associated protein 1 (MRP1/ABCC1) is a member of the ATP-binding cassette (ABC) transporter superfamily. By effluxing a wide variety of endogenous and exogenous substrates, Mrp1 plays important physiological roles in multiple tissues and also protects normal tissues against toxicants. However, the role of MRP1 in heart is largely unknown. The role of Mrp1 in DOX-induced cardiotoxicity was investigated in Mrp1 null (Mrp1-/-) and their C57BL (WT) littermates. Chronic DOX caused body weight loss and hemotoxicity, and these adverse effects were significantly exacerbated in Mrp1-/- vs WT mice. Importantly, loss of Mrp1 potentiated DOX-induced cardiotoxicity, presenting as worsened cardiac function and more cellular apoptosis in DOX treated Mrp1-/- mice. Mrp1 also protected neonatal mouse cardiomyocytes (CM) and cardiac fibroblasts (CF) culture against DOX cytotoxicity in vitro. This was demonstrated by the decreased cell survival, more apoptosis and more DNA damage in DOX treated Mrp1-/- vs WT cells. In addition, the effects of deletion of Mrp1 was studied on glutathione (GSH)/glutathione disulfide (GSSG) homeostasis, glutathione conjugate of 4-hydroxy-2-nonenal (GS-HNE) accumulation, protein oxidative damage and expression of antioxidant enzymes. Loss of Mrp1 led to significantly higher GSH and GSSG basal levels in heart. Following DOX treatment, Mrp1-/- CM and CF showed increased GSH and GSSG levels vs WT cells. Meanwhile, DOX increased expression of the GSH synthesis enzymes in Mrp1-/- but not WT cells. Thus, increased GSH synthesis may contribute to the further increase in the GSH pool in DOX-treated Mrp1-/- cells. DOX induced comparable increases of GS-HNE concentration in WT and Mrp1-/- mice hearts. Finally, expression of extracellular superoxide dismutase (ECSOD/SOD3) was significantly lower in Mrp1-/- vs. WT CM treated with either saline or DOX. In summary, this study is the first to document a protective role of Mrp1 in DOX-induced cardiotoxicity. It gives critical information regarding the potential adverse sequelae of introduction of MRP1 inhibitors as adjuncts to clinical chemotherapy of multidrug resistant tumors.

Orientador: Ana Cláudia de Melo Stevanato Nakamune / Banca: Camila Renata Corrêa Camacho / Banca: Paulo Cesar Ciarlini / Resumo: A doxorrubicina (DXO) é eficaz contra diferentes formas de câncer, em adultos e crianças, porém seu uso pode causar cardiotoxicidade aguda e crônica, associada ao aumento do estresse oxidativo. Alguns antioxidantes naturais demonstraram ser eficazes em minimizar esses efeitos da DXO, no entanto, o chá mate (CM), não foi avaliado neste contexto. Nossa hipótese é que o pré-tratamento com CM por 30 dias, reduz o dano oxidativo agudo no coração e assim preserva a função cardíaca. Para testar essa hipótese, foram investigados os efeitos do pré-tratamento diário de ratos Wistar machos com 40 mg/kg m.c. de CM, contra a cardiotoxicidade aguda induzida por DXO. Para a escolha da dose de CM ratos Wistar foram divididos em grupo tratados com doses diferentes de chá (10, 20 e 40 mg/m.c., gavagem) e DXO (grupos CM + DXO). Os grupos controle (C), tratados com DXO (DXO) receberam água (1,0 mL, gavagem). Os grupos receberam CM solúvel diluído em água (8 mg/mL). No 29° do tratamento com CM, administrou-se uma dose de DXO (15 mg/kg m.c. - IP) aos grupos DXO e CM + DXO. No 31° dia, após administração de tiopental (50 mg/kg m.c.) associado à lidocaína (4,0 mg/kg m.c.), foram submetidos ao eletrocardiograma (ECG) antes da punção cardíaca (Autorização CEUA FOA: 416/2015). Creatina quinase total (CK) e a fração MB (CK-MB), foram estimadas no plasma. No homogenato de coração (KCl 1,15% m/v) foram quantificadas as substâncias reativas ao ácido tiobarbitúrico (TBARS), glutationa (GSH), atividade de su... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Doxorubicin (DXO) is effective against different forms of cancer in adults and children, but its use may cause acute and chronic cardiotoxicity associated with increased oxidative stress. Some natural antioxidants have been shown to be effective in minimizing the effects of DXO; however, mate tea (CM), has not been evaluated in this context. Our hypothesis is that CM pretreatment for 30 days, reduces acute oxidative damage in the heart. To test this hypothesis, the effects of daily pretreatment of male Wistar rats at 40 mg / kg m.c. of CM, against acute cardiotoxicity induced by DXO were investigated. For the choice of CM dose, Wistar rats were divided into groups treated with different doses of tea (10, 20 and 40 mg / mc, gavage) (CM + DXO groups). Groups control (C), treated with DXO (DXO) received water (1.0 mL, gavage). The CM + DXO groups received soluble CM diluted in water (8 mg / mL) during the same period. At 29 ° of CM treatment, DXO and CM + DXO groups were given a dose of DXO (15 mg / m.c.-IP). On the 31st day, after administration of lidocaine (4.0 mg / kg mc) thiopental (50 mg / kg mc), all rats were submitted to electrocardiogram (ECG) prior to cardiac puncture (CEUA FOA Authorization: 416 / 2015). Total creatine kinase (CK) and MB fraction (CK-MB) were estimated in plasma. The thiobarbituric acid reactive substances (TBARS), glutathione (GSH), total superoxide dismutase (SOD) activity and the cytoplasmic isoform SOD1, in addition to SOD1 expression, were quantified in the heart homogenate (KCl 1.15% m / v), Total Akt and p-Akt, by western blotting. Pretreatment with 40 mg / kg m.c. of CM prevented a increased heart rate, prolongation of the QTc and PR interval, increase in plasma CK and CK-MB, and TBARS in the tissue. It also prevented the reduction of GSH, SOD and SOD1. In addition, the increase... / Mestre

Cardiotoxicity associated with many cancer drugs is a critical issue facing physicians these days and a huge hurdle that must be overcome for a side effects-free cancer therapy. Survival of cardiac myocytes is compromised upon the exposure to certain chemotherapeutic drugs. Unfortunately, the mechanisms implicated in cardiac toxicity and the pathways governing myocyte survival are poorly understood. The following thesis addresses the mechanisms underlying the cardiotoxicity of two anticancer drugs, doxorubicin (DOX) and Imatinib mesylate (Gleevec). Transcription factor GATA-4, has recently emerged as an indispensable factor in the adult heart adaptive response and cardiomyocyte survival. Therefore, the specific aim of this project was to determine the role of GATA-4, its upstream regulators, as well as partners in survival. A combination of cell and molecular techniques done on in vivo, and ex vivo models were utilized to tackle these issues. In this study, we confirmed the cardiotoxicity of the anticancer drug, Imatinib mesylate and found to be age dependent. GATA-4, already known to be implicated in DOX-induced toxicity, was confirmed as an Imatinib target. At the molecular level, we identified IGF-1 and AKT as upstream regulators of GATA-4. Moreover, we confirmed ZFP260 (PEX-1), a key regulator of the cardiac hypertrophic response, as a GATA-4 collaborator in common prosurvival pathways. Collectively, these results provide new insights on the mechanisms underlying drug-induced cardiotoxicity and raise the exciting possibility that cancer drugs are negatively affecting the same prosurvival pathway(s), in which GATA-4 is a critical component. Therapeutic interventions aimed at enhancing GATA-4 activity may be interesting to consider in the context of treatments with anticancer drugs.

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Hydroxychloroquine, initially used as an antimalarial, is used as an immunomodulatory and anti-inflammatory agent for the management of autoimmune and rheumatic diseases such as systemic lupus erythematosus. Lately, there has been interest in its potential efficacy against severe acute respiratory syndrome coronavirus 2, with several speculated mechanisms. The purpose of this review is to elaborate on the mechanisms surrounding hydroxychloroquine. The review is an in-depth analysis of the antimalarial, immunomodulatory, and antiviral mechanisms of hydroxychloroquine, with detailed and novel pictorial explanations. The mechanisms of hydroxychloroquine are related to potential cardiotoxic manifestations and demonstrate potential adverse effects when used for coronavirus disease 2019 (COVID-19). Finally, current literature associated with hydroxychloroquine and COVID-19 has been analyzed to interrelate the mechanisms, adverse effects, and use of hydroxychloroquine in the current pandemic. Currently, there is insufficient evidence about the efficacy and safety of hydroxychloroquine in COVID-19.KEY MESSAGES HCQ, initially an antimalarial agent, is used as an immunomodulatory agent for managing several autoimmune diseases, for which its efficacy is linked to inhibiting lysosomal antigen processing, MHC-II antigen presentation, and TLR functions. HCQ is generally well-tolerated although severe life-threatening adverse effects including cardiomyopathy and conduction defects have been reported. HCQ use in COVID-19 should be discouraged outside clinical trials under strict medical supervision.