Twisting and Ironing: Doxorubicin Cardiotoxicity by Mitochondrial DNA Damage

Nitiss, Karin C.; Nitiss, John L.

doi:10.1158/1078-0432.ccr-14-0821

Cited by 53 publications

(42 citation statements)

References 12 publications

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“…Several mechanisms have been suggested to mediate DOXinduced toxicity to cardiomyocytes (4,25), whereas endothelial injury has received little attention (26,27). In our experiments, the apoptosis-associated DNA fragmentation was observed approximately to the same extent in cardiomyocytes and ECs.…”

Section: Discussionsupporting

confidence: 54%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

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Section: Discussionsupporting

confidence: 54%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

106

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“…In vitro and in vivo experiments have determined that doxorubicin could induce cardiomyocyte loss and heart dysfunction in a dose-dependent manner [24], which was confirmed by our study. However, the underlying mechanisms of doxorubicin cardiotoxicity are still unclear.…”

Section: Discussionsupporting

confidence: 86%

Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity

et al. 2016

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Doxorubicin (adriamycin), an anthracycline antibiotic, is commonly used to treat many types of solid and hematological malignancies. Unfortunately, clinical usage of doxorubicin is limited due to the associated acute and chronic cardiotoxicity. Previous studies demonstrated that Astragalus polysaccharide (APS), the extracts of Astragalus membranaceus, had strong anti-tumor activities and anti-inflammatory effects. However, whether APS could mitigate chemotherapy-induced cardiotoxicity is unclear thus far. We used a doxorubicin-induced neonatal rat cardiomyocyte injury model and a mouse heart failure model to explore the function of APS. GFP-LC3 adenovirus-mediated autophagic vesicle assays, GFP and RFP tandemly tagged LC3 (tfLC3) assays and Western blot analyses were performed to analyze the cell function and cell signaling changes following APS treatment in cardiomyocytes. First, doxorubicin treatment led to C57BL/6J mouse heart failure and increased cardiomyocyte apoptosis, with a disturbed cell autophagic flux. Second, APS restored autophagy in doxorubicin-treated primary neonatal rat ventricular myocytes and in the doxorubicin-induced heart failure mouse model. Third, APS attenuated doxorubicin-induced heart injury by regulating the AMPK/mTOR pathway. The mTOR inhibitor rapamycin significantly abrogated the protective effect of APS. These results suggest that doxorubicin could induce heart failure by disturbing cardiomyocyte autophagic flux, which may cause excessive cell apoptosis. APS could restore normal autophagic flux, ameliorating doxorubicin-induced cardiotoxicity by regulating the AMPK/mTOR pathway.

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“…The hypothesis that iron chelators may reduce the cardiotoxicity induced by anthracyclines suggests that dexrazoxane may be a clinically useful cardioprotective agent (9,79). Doxorubicin is a potent Top2 inhibitor.…”

Section: The Use Of Cardioprotectionmentioning

confidence: 99%

Cardiotoxicity of Anthracyclines

Cardinale

Fabiani

Cipolla

2020

Front. Cardiovasc. Med.

275

214

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Cardiotoxicity is a feared side effect that may limit the clinical use of anthracyclines. It may indeed affect the quality of life and survival of patients with cancer, regardless of oncological prognosis. This paper provides an overview of anthracycline-induced cardiotoxicity in terms of definition, classification, incidence, risk factors, possible mechanisms, diagnosis, and treatment. We also report effective strategies for preventing cardiotoxicity. In addition, we discuss limiting current approaches, the need for a new classification, and early cardiotoxicity detection and treatment. Probably, anthracycline-induced cardiotoxicity is a continuous phenomenon that starts from myocardial cell injury; it is followed by left ventricular ejection fraction (LVEF) and, if not diagnosed and cured early, progressively leads to symptomatic heart failure. Anthracycline-induced cardiotoxicity can be detected at a preclinical phase. The role of biomarkers, in particular troponins, in identifying subclinical cardiotoxicity and its therapy with angiotensin-converting enzyme inhibitors (mainly enalapril) to prevent LVEF reduction is a recognized and effective strategy. If cardiac dysfunction has already occurred, partial or complete LVEF recovery may still be obtained in case of early detection of cardiotoxicity and prompt heart failure treatment.

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Twisting and Ironing: Doxorubicin Cardiotoxicity by Mitochondrial DNA Damage

Cited by 53 publications

References 12 publications

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Astragalus polysaccharide restores autophagic flux and improves cardiomyocyte function in doxorubicin-induced cardiotoxicity

Cardiotoxicity of Anthracyclines

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