Heart Lung Circ. 2019 Oct;28(10):1454-1456

Authors: Croft AJ, Ngo DTM, Sverdlov AL

PMID: 31495502 [PubMed - indexed for MEDLINE]

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Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations.

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Intercalating TOP2 Poisons Attenuate Topoisomerase Action at Higher Concentrations.

Mol Pharmacol. 2019 10;96(4):475-484

Authors: Atwal M, Swan RL, Rowe C, Lee KC, Lee DC, Armstrong L, Cowell IG, Austin CA

Abstract

Topoisomerase II (TOP2) poisons are effective cytotoxic anticancer agents that stabilize the normally transient TOP2-DNA covalent complexes formed during the enzyme reaction cycle. These drugs include etoposide, mitoxantrone, and the anthracyclines doxorubicin and epirubicin. Anthracyclines also exert cell-killing activity via TOP2-independent mechanisms, including DNA adduct formation, redox activity, and lipid peroxidation. Here, we show that anthracyclines and another intercalating TOP2 poison, mitoxantrone, stabilize TOP2-DNA covalent complexes less efficiently than etoposide, and at higher concentrations they suppress the formation of TOP2-DNA covalent complexes, thus behaving as TOP2 poisons at low concentration and inhibitors at high concentration. We used induced pluripotent stem cell (iPSC)-derived human cardiomyocytes as a model to study anthracycline-induced damage in cardiac cells. Using immunofluorescence, our study is the first to demonstrate the presence of topoisomerase IIβ (TOP2B) as the only TOP2 isoform in iPSC-derived cardiomyocytes. In these cells, etoposide robustly induced TOP2B covalent complexes, but we could not detect doxorubicin-induced TOP2-DNA complexes, and doxorubicin suppressed etoposide-induced TOP2-DNA complexes. In vitro, etoposide-stabilized DNA cleavage was attenuated by doxorubicin, epirubicin, or mitoxantrone. Clinical use of anthracyclines is associated with cardiotoxicity. The observations in this study have potentially important clinical consequences regarding the effectiveness of anticancer treatment regimens when TOP2-targeting drugs are used in combination. These observations suggest that inhibition of TOP2B activity, rather than DNA damage resulting from TOP2 poisoning, may play a role in doxorubicin cardiotoxicity. SIGNIFICANCE STATEMENT: We show that anthracyclines and mitoxantrone act as topoisomerase II (TOP2) poisons at low concentration but attenuate TOP2 activity at higher concentration, both in cells and in in vitro cleavage experiments. Inhibition of type II topoisomerases suppresses the action of other drugs that poison TOP2. Thus, combinations containing anthracyclines or mitoxantrone and etoposide may reduce the activity of etoposide as a TOP2 poison and thus reduce the efficacy of drug combinations.

PMID: 31399497 [PubMed - indexed for MEDLINE]

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Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiotoxicity.

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Effects of Calorie Restriction and Voluntary Exercise on Doxorubicin-Induced Cardiotoxicity.

Integr Cancer Ther. 2019 Jan-Dec;18:1534735419843999

Authors: Hall SE, Smuder AJ, Hayward R

Abstract

INTRODUCTION: Doxorubicin (DOX) is a widely used chemotherapeutic agent with known cardiotoxic properties, while calorie restriction (CR) and exercise have well-documented cardioprotective effects. No studies have investigated the effects of CR alone or the combined effects of CR and exercise on DOX cardiotoxicity.

METHODS: Rats were divided into 4 groups based on their food intake (ad libitum or CR) and activity (sedentary or voluntary wheel running [WR]). After completing a 16-week treatment, animals received either DOX (15 mg/kg) or saline (SAL) and cardiac function was measured 5 days after treatment. Chromatography was used to quantify left ventricular DOX accumulation.

RESULTS: Left ventricular developed pressure (LVDP), end systolic pressure (ESP), and left ventricular maximal rate of pressure development (dP/dtmax) were significantly higher in the CR + DOX group when compared with DOX. Fractional shortening, LVDP, ESP, dP/dtmax, and dP/dtmin were significantly higher in the CR + WR + DOX group compared with the DOX group. In addition, the CR + WR + DOX group showed significantly higher LVDP and ESP compared with the WR + DOX group. DOX accumulation in the heart was 5-fold lower ( P < .05) in the CR + WR + DOX group compared with the DOX group.

CONCLUSION: This is the first study to demonstrate that CR can reduce cardiac DOX accumulation, and confirms the protective role of CR against DOX-induced cardiac dysfunction. Our data also show that combining a known cardioprotective intervention, exercise training, with CR results in additive benefits in the protection against DOX cardiotoxicity.

PMID: 30999765 [PubMed - indexed for MEDLINE]

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Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

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Systemic Blockade of ACVR2B Ligands Protects Myocardium from Acute Ischemia-Reperfusion Injury.

Mol Ther. 2019 03 06;27(3):600-610

Authors: Magga J, Vainio L, Kilpiö T, Hulmi JJ, Taponen S, Lin R, Räsänen M, Szabó Z, Gao E, Rahtu-Korpela L, Alakoski T, Ulvila J, Laitinen M, Pasternack A, Koch WJ, Alitalo K, Kivelä R, Ritvos O, Kerkelä R

Abstract

Activin A and myostatin, members of the transforming growth factor (TGF)-β superfamily of secreted factors, are potent negative regulators of muscle growth, but their contribution to myocardial ischemia-reperfusion (IR) injury is not known. The aim of this study was to investigate if activin 2B (ACVR2B) receptor ligands contribute to myocardial IR injury. Mice were treated with soluble ACVR2B decoy receptor (ACVR2B-Fc) and subjected to myocardial ischemia followed by reperfusion for 6 or 24 h. Systemic blockade of ACVR2B ligands by ACVR2B-Fc was protective against cardiac IR injury, as evidenced by reduced infarcted area, apoptosis, and autophagy and better preserved LV systolic function following IR. ACVR2B-Fc modified cardiac metabolism, LV mitochondrial respiration, as well as cardiac phenotype toward physiological hypertrophy. Similar to its protective role in IR injury in vivo, ACVR2B-Fc antagonized SMAD2 signaling and cell death in cardiomyocytes that were subjected to hypoxic stress. ACVR2B ligand myostatin was found to exacerbate hypoxic stress. In addition to acute cardioprotection in ischemia, ACVR2B-Fc provided beneficial effects on cardiac function in prolonged cardiac stress in cardiotoxicity model. By blocking myostatin, ACVR2B-Fc potentially reduces cardiomyocyte death and modifies cardiomyocyte metabolism for hypoxic conditions to protect the heart from IR injury.

PMID: 30765322 [PubMed - indexed for MEDLINE]

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New prospects for the management of cardiovascular effects of tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

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New prospects for the management of cardiovascular effects of tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

Rev Port Cardiol. 2019 01;38(1):1-9