Incidence and risk factors associated with development of clinical cardiotoxicity in dogs receiving doxorubicin

Hallman, Briana; Hauck, Marlene; Williams, Laurel E.; Hess, Paul R.; Suter, Steven E.

doi:10.1111/jvim.15414

Cited by 34 publications

(31 citation statements)

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“…Doxorubicin is frequently used in chemotherapy against acute leukaemia, malignant lymphoma, and several solid tumours. Although DOX has been frequently reported to exhibit minimal cardiotoxicity at a single dose, there is still a risk of cardiomyopathy when multiple doses are administered (Hallman et al, 2019). The pathophysiological mechanisms underlying doxorubicin-induced cardiotoxicity include three interrelated respects: accumulation of reactive oxygen species (ROS); dysfunction of topoisomerase IIβ and topoisomerase I; and mitochondrial imbalance of intracellular calcium (Burridge et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Zhang

Liu

et al. 2020

PeerJ

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Background Luteolin (LUT) is a flavonoid found in vegetables and fruits that has diverse functions. Doxorubicin (DOX) is an anthracycline antibiotic that is frequently used for the treatment of various cancers. Unfortunately, the clinical efficacy of DOX is limited by its dose-related cardiotoxicity. In this study, we aimed to investigate the potential mechanism through which LUT attenuates cardiotoxicity in vivo. Methods We evaluated the body weight, heart weight, electrocardiogram, and pathological changes before and after administration of LUT. Moreover, the effects of LUT (50 mg/kg in the low dose group, 100 mg/kg in the high dose group) on biochemical parameters (brain natriuretic peptide, creatine kinase MB, cardiac troponin T, and dehydrogenation of lactate enzyme) and oxidative stress parameters (malondialdehyde and superoxide dismutase) were studied in the sera of cardiotoxicity model rats. We also identified the apoptotic mediators whose expression was induced by LUT by quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR) evaluation. In addition, we used network analysis to predict DOX-induced cardiotoxicity and protection afforded by LUT. Western blotting was used to detect the expression of associated proteins. Results LUT significantly improved DOX-induced cardiotoxicity in a dose-dependent fashion. LUT ameliorated DOX-induced weight loss and heart weight changes, as well as changes in biochemical parameters and oxidative stress parameters in heart injury model rats. LUT’s protective effect was observed via regulation of the apoptotic markers Bcl-2, Bax, and caspase-3 mRNA and protein expression levels. Network analysis showed that the AKT/Bcl-2 signalling pathway was activated; specifically, the PH domain leucine-rich repeats protein phosphatase 1 (phlpp1) was involved in the AKT/Bcl-2 signal pathway. LUT inhibited the activity of phlpp1 leading to positive regulation of the AKT/Bcl-2 pathway, which attenuated doxorubicin-induced cardiotoxicity. Conclusions These results demonstrate that LUT exerted protective effects against DOX-induced cardiotoxicity in vivo by alleviating oxidative stress, suppressing phlpp1 activity, and activating the AKT/Bcl-2 signalling pathway.

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Section: Discussionmentioning

confidence: 99%

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Zhang

Liu

et al. 2020

PeerJ

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“…Changes in LVIDd and FS may indicate development of cardiomyopathy, with systolic dysfunction. Indeed, a recent study in dogs showed that a decrease in FS with DOX treatment was associated with the development of cardiac clinical signs 48 . The relationship between cardiac injury and these echocardiographic parameters is further confirmed by the correlations between LVEF and FS with increasing concentrations of cTnI.…”

Section: Discussionmentioning

confidence: 78%

Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin‐induced cardiotoxicity

Beaumier

Robinson

et al. 2020

Veterinary Internal Medicne

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Background: Long-term use of doxorubicin (DOX) is limited by cumulative dosedependent cardiotoxicity.Objectives: Identify plasma extracellular vesicle (EV)-associated microRNAs (miRNAs) as a biomarker for cardiotoxicity in dogs by correlating changes with cardiac troponin I (cTnI) concentrations and, echocardiographic and histologic findings.Animals: Prospective study of 9 client-owned dogs diagnosed with sarcoma and receiving DOX single-agent chemotherapy (total of 5 DOX treatments). Dogs with clinically relevant metastatic disease, preexisting heart disease, or breeds predisposed to cardiomyopathy were excluded.Methods: Serum concentration of cTnI was monitored before each treatment and 1 month after the treatment completion. Echocardiography was performed before treatments 1, 3, 5, and 1 month after completion. The EV-miRNA was isolated and sequenced before treatments 1 and 3, and 1 month after completion.Results: Linear mixed model analysis for repeated measurements was used to evaluate the effect of DOX. The miR-107 (P = .03) and miR-146a (P = .02) were significantly downregulated whereas miR-502 (P = .02) was upregulated. Changes in miR-502 were significant before administration of the third chemotherapeutic dose.When stratifying miRNA expression for change in left ventricular ejection fraction, upregulation of miR-181d was noted (P = .01). Serum concentration of cTnI changed significantly but only 1 month after treatment completion, and concentrations correlated with left ventricular ejection fraction and left ventricular internal dimension in diastole.Abbreviations: cTnI, cardiac troponin I; DOX, doxorubicin; E 0 , peak myocardial velocity in early diastole; ECG, electrocardiography; EV, extracellular vesicle; EV-miRNA, extracellular vesicle-associated miRNA; FAC, fractional area change; FS, fractional shortening; IVCT, isovolumic contraction time; IVRT, isovolumic relaxation time; LA:Ao, left atrium to aorta ratio; LVEF, left ventricular ejection fraction; LVIDdN, left ventricular end-diastolic internal diameter normalized to body weight; LVIDsN, left ventricular end-systolic internal diameter normalized to body weight; miRNAs, microRNAs; S 0 , peak myocardial velocity in systole.

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“…This may explain why some dogs with B-cell lymphoma do not respond or partially respond to TOPIIa inhibitors. It is worth mentioning that cy-totoxic drugs can cause numerous side effects and in extreme cases can lead to the patient's death [16,40,44,51]. Unfortunately, despite the use of numerous lymphoma classifications, it is currently not possible, based solely on histopathological examination and the lymphoma immunophenotype, to determine the most effective therapy for individual patient.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, the adverse reactions associated with the use of doxorubicin are observed. The most common is the cardiotoxicity that develops with long-term use and chemotherapy-induced myelotoxicity [14,40,51,53]. The possibility of determining in which patients the use of doxorubicin would be beneficial and in which its use would not bring satisfactory results ©Polish Society for Histochemistry and Cytochemistry Folia Histochem Cytobiol.…”

Section: Discussionmentioning

confidence: 99%

Study of DNA topoisomerase IIa expression in canine lymphomas and its potential role as a marker of sensitivity to anthracycline-based chemotherapy in dogs

Klimiuk¹,

Łopuszyński

Bulak

et al. 2020

Folia Histochem Cytobiol.

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Introduction. Canine lymphoma remains one of the most chemotherapy-responsive neoplasia in dogs. Many factors affect the prognosis in dogs treated for lymphoma, but indications for a specific treatment regimen in individual animals with lymphoma are poorly defined. Topoisomerase IIa (TOPIIa) is a key enzyme in DNA replication and a molecular target for TOPIIa inhibitors, including anthracyclines. The aim of this study was to determine the expression of TOPIIa in canine malignant lymphomas. The relationship between TOPIIa expression in canine lymphomas and potential sensitivity of neoplastic cells to anthracycline-based chemotherapy is discussed. Materials and method. Samples of formalin-fixed paraffin-embedded lymph nodes from 47 dogs with different subtypes of non-Hodgkin's (34 B-cell and 13 T-cell) lymphoma were immunohistochemically labeled with anti-TOPIIa. The number of positive cells and the intensity of the reaction were taken into account in order to assess TOPIIa expression. Results. TOPIIa expression was evident in all cases, although differences in the number of positive cells and intensity of the reaction were demonstrated between B-cell and T-cell lymphoma groups as well as within individual groups. Based on the established scoring system, in the B-cell lymphoma group statistically higher expression of TOPIIa was found compared to the T-cell lymphoma group (P = 0.006). In B-cell lymphoma group moderate (41.18%) and strong (32.35%) TOPIIa expression predominated, whereas among T-cell lymphoma group the majority were cases with a weak (46.15%) TOPIIa expression. Conclusion. These preliminary results indicate that further studies are needed to determine the prognostic value of TOPIIa expression with regard to the sensitivity of canine B-cell lymphomas to anthracycline-based chemotherapy regimen. Nevertheless, this study indicates the possibility of choosing the appropriate treatment of canine lymphoma based on

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Incidence and risk factors associated with development of clinical cardiotoxicity in dogs receiving doxorubicin

Cited by 34 publications

References 31 publications

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Luteolin attenuates doxorubicin-induced cardiotoxicity by modulating the PHLPP1/AKT/Bcl-2 signalling pathway

Extracellular vesicular microRNAs as potential biomarker for early detection of doxorubicin‐induced cardiotoxicity

Study of DNA topoisomerase IIa expression in canine lymphomas and its potential role as a marker of sensitivity to anthracycline-based chemotherapy in dogs

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