Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes

O’Connell, João Lucas; Romano, Minna Moreira Dias; Pulici, Érica Carolina Campos; Carvalho, Eduardo Elias Vieira de; Souza, Fernanda Rodrigues de; Tanaka, Denise Mayumi; Maciel, Benedito Carlos; Salgado, Hélio César; Fazan-Junior, Rubens; Rossi, Marcos A.; Simões, Marcus Vinı́cius

doi:10.1016/j.etp.2017.01.004

Cited by 31 publications

(22 citation statements)

References 25 publications

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“…Furthermore, the interstitial fibrosis observed in the myocardial tissue of the dogs given free DOX and higher dose of CS-CaCO 3 NP-DOX (at cumulative dose of 250 mg/m 2 ) was in agreement with chronic model showing cardiomyocyte damage and fibrosis [ 79 , 80 ], which could be as a result of cardiomyocyte compensatory action toward regeneration of myofiber undergoing degeneration or necrosis.…”

Section: Discussionsupporting

confidence: 82%

Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs

Danmaigoro

Selvarajah

Noor

et al. 2018

Advances in Pharmacological Sciences

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Doxorubicin (DOX) is a potent anticancer agent with cytotoxic effects which limit its clinical usage. This effect is due to its nonselective nature causing injury to the cells as a result of reactive free oxygen radical's release. Cockleshell-derived calcium carbonate nanoparticle (CS-CaCO3NP) is a pH-responsive carrier with targeted delivery potentials. This study aimed at evaluating the toxicity effects of repeated dose administration of DOX-loaded CS-CaCO3NP in healthy dogs. Fifteen dogs with an average body weight of 15 kg were randomized equally into 5 groups. Dogs were subjected to 5 doses at every 3-week interval with (i) normal saline, (ii) DOX, 30 mg/m2, and the experimental groups: CS-CaCO3NP-DOX at (iii) high dose, 50 mg/m2, (iv) clinical dose, 30 mg/m2, and (v) low dose, 20 mg/m2. Radiographs, electrocardiography, and blood samples were collected before every treatment for haematology, serum biochemistry, and cardiac injury assessment. Heart and kidney tissues were harvested after euthanasia for histological and ultrastructural evaluation. The cumulative dose of DOX 150 mg/m2 over 15 weeks revealed significant effects on body weight, blood cells, functional enzymes, and cardiac injury biomarkers with alterations in electrocardiogram, myocardium, and renal tissue morphology. However, the dogs given CS-CaCO3NP-DOX 150 mg/m2 and below did not show any significant change in toxicity biomarker as compared to those given normal saline. The study confirmed the safety of repeated dose administration of CS-CaCO3NP-DOX (30 mg/m2) for 5 cycles in dogs. This finding offers opportunity to dogs with cancer that might require long-term administration of DOX without adverse effects.

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Section: Discussionsupporting

confidence: 82%

Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs

Danmaigoro

Selvarajah

Noor

et al. 2018

Advances in Pharmacological Sciences

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“…Other pharmacological inductions of heart damage used doxorubicin to induce cardiomyopathy [64] and cyclophosphamide to induce cardiotoxicity [63]. Both doxorubicin and cyclophosphamide are anticancer drugs with cardiotoxicity as their major adverse effect [72,73] and are commonly used to induce cardiotoxicity and heart failure (HF) in animal models [74][75][76][77]. Hypercholesterolemia is commonly induced by high fat or cholesterol diet.…”

Section: Animal Studiesmentioning

confidence: 99%

The Efficacy of Squalene in Cardiovascular Disease Risk-A Systematic Review

et al. 2020

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Introduction: Cardiovascular disease (CVD) is the leading cause of death worldwide. Squalene (SQ), an intermediate for the cholesterol biosynthesis, has been proposed to act similarly to statins via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in the liver. Purpose: This paper explores the effects of SQ in CVD. Methods: A systematic review of the literature was performed to identify relevant studies about SQ and CVD. A comprehensive search in Medline and Scopus for relevant studies published between the years 1946 and 2019 was performed. The main inclusion criteria were that the study was published in English; that the study reported association or effect of SQ and CVD; and that CVD should be related to lifestyle variables, aging, or experimentally induced conditions. Results: The literature searches identified 5562 potentially relevant articles, whereby 21 studies met the inclusion criteria. There were three human studies and 18 animal experimental studies included in this paper. Only one human study reported positive outcome of SQ in CVD. The remaining two studies reported inconsistent and/or no effect. For animal studies, 15 studies reported positive effect while the remaining reported negative and/or no effect of SQ on various related parameters. Conclusions: This evidence-based review emphasizes the potential of SQ being used for cardiovascular-related diseases. The effect of SQ, especially of plant-based warrants further exploration. Controlled human observational studies should be performed to provide comprehensive evidence.

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“…The exact pathogenesis of DOXO-induced cardiotoxicity is not fully understood even if it is assumed that it is multifactorial [ 9 , 10 , 11 , 12 ]. Several lines of evidence indicate that DOXO-induced cardiomyopathy is characterized by abnormal calcium homeostasis, but most of the studies published report only the effects of long-term DOXO-administration [ 13 , 14 , 15 , 16 ]. Recently, we have demonstrated that DOXO administration is able to induce calcium dysregulation and Connexin43 (Cx43) re-arrangement in a rat cardiomyoblast cell line already evident after a short-term administration [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment

Pecoraro

Rodríguez‐Sinovas

Marzocco

et al. 2017

IJMS

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The use of Doxorubicin (DOXO), a potent antineoplastic agent, is limited by the development of cardiotoxicity. DOXO-induced cardiotoxicity is multifactorial, although alterations in calcium homeostasis, seem to be involved. Since even the Connexin43 (Cx43) plays a pivotal role in these two phenomena, in this study we have analyzed the effects of DOXO on Cx43 expression and localization. Damage caused by anthracyclines on cardiomyocytes is immediate after each injection, in the present study we used a short-term model of DOXO-induced cardiomyopathy. C57BL/6j female mice were randomly divided in groups and injected with DOXO (2 or 10 mg/kg i.p.) for 1–3 or 7 days once every other day. Cardiac function was assessed by Echocardiography. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII) and phospholamban (PLB) expression were assessed by Western blot analysis, intracellular [Ca2+] were detected spectrofluorometrically by means of Fura-2 pentakis (acetoxymethyl) ester (FURA-2AM), and Cx43 and pCx43 expression and localization was analyzed by Western blot and confirmed by immunofluorescence analysis. DOXO induces impairment in Ca2+ homeostasis, already evident after a single administration, and affects Cx43 expression and localization. Our data suggest that DOXO-induced alterations in Ca2+ homeostasis causes in the cells the induction of compensatory mechanisms until a certain threshold, above which cardiac injury is triggered.

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Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes

Cited by 31 publications

References 25 publications

Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs

Toxicity and Safety Evaluation of Doxorubicin-Loaded Cockleshell-Derived Calcium Carbonate Nanoparticle in Dogs

The Efficacy of Squalene in Cardiovascular Disease Risk-A Systematic Review

Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment

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