Sarcoplasmic Reticulum Calcium Release Is Stimulated and Inhibited by Daunorubicin and Daunorubicinol

doi:10.1006/taap.2000.9065

Toxicology and Applied Pharmacology

Volume 169, Issue 2, 1 December 2000, Pages 168-176

https://doi.org/10.1006/taap.2000.9065 Get rights and content

Abstract

Cardiac effects of anthracyclines or their metabolites may include both the stimulation and inhibition of Ca²⁺ release from sarcoplasmic reticulum. In this study, the ability of daunorubicin and its primary metabolite, daunorubicinol, to stimulate and inhibit Ca²⁺ release from canine sarcoplasmic reticulum (SR) vesicles was investigated. It was observed that both daunorubicin and daunorubicinol were several fold more potent at inhibiting than they were at stimulating SR Ca²⁺ release. Respective IC50 inhibition of daunorubicin and daunorubicinol for caffeine-induced calcium release was 1.2 and 0.6 μM, and for spontaneous Ca²⁺ release was 3 and 1 μM. EC50's for daunorubicin- and daunorubicinol-induced calcium release were 30 and 15 μM, respectively. Inhibition of either spontaneous or caffeine-induced SR Ca²⁺ release was inversely related to the amount of Ca²⁺ loaded into the SR before exposure to daunorubicin or daunorubicinol. The free-radical scavenger dithiothreitol did not attenuate the ability of anthracyclines to inhibit SR Ca²⁺ release. A nonquinone daunorubicin derivative, 5-iminodaunorubicin, was less potent than daunorubicin at inhibiting caffeine-induced Ca²⁺ release. These data suggest anthracyclines and their metabolites may produce cardiotoxicity through free-radical independent, concentration-dependent effects on SR Ca²⁺ release. These effects involve either inhibition or stimulation of SR Ca²⁺ release and are partly dependent upon the presence of the quinone moiety.

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Cited by (43)

Doxorubicin causes lesions in the electron transport system of skeletal muscle mitochondria that are associated with a loss of contractile function
2019, Journal of Biological Chemistry
Citation Excerpt :
Doxorubicin is member of the anthracycline drug class commonly used to treat a range of cancers and has attracted considerable attention because of its cardiotoxic side effects. Doxorubicin and its metabolite, doxorubicinol, also accumulate in skeletal muscle (1, 2), resulting in a myotoxicity, which can persist long beyond the cessation of treatment (3). Patients treated with doxorubicin frequently experience muscle atrophy (4, 5), as well as symptoms of muscle weakness and fatigue (6, 7).
Doxorubicin is an anthracycline-based chemotherapeutic that causes myotoxicity with symptoms persisting beyond treatment. Patients experience muscle pain, weakness, fatigue, and atrophy, but the underlying mechanisms are poorly understood. Studies investigating doxorubicin-induced myotoxicity have reported disrupted mitochondrial function. Mitochondria are responsible for regulating both cellular energy status and Ca²⁺ handling, both of which impact contractile function. Moreover, loss of mitochondrial integrity may initiate muscle atrophy. Skeletal muscle mitochondrial dysregulation may therefore contribute to an overall loss of skeletal muscle quality and performance that may be mitigated by appropriately targeted mitochondrial therapies. We therefore assessed the impact of doxorubicin on muscle performance and applied a multiplexed assay platform to diagnose alterations in mitochondrial respiratory control. Mice received a clinically relevant dose of doxorubicin delivered systemically and were euthanized 72 h later. We measured extensor digitorum longus and soleus muscle forces, fatigue, and contractile kinetics in vitro, along with Ca²⁺ uptake in isolated sarcoplasmic reticulum. Isolated skeletal muscle mitochondria were used for real-time respirometry or frozen for protein content and activity assays. Doxorubicin impaired muscle performance, which was indicated by reduced force production, fatigue resistance, and sarcoplasmic reticulum–Ca²⁺ uptake, which were associated with a substrate-independent reduction in respiration and membrane potential but no changes in the NAD(P)H/NAD(P)⁺ redox state. Protein content and dehydrogenase activity results corroborated these findings, indicating that doxorubicin-induced mitochondrial impairments are located upstream of ATP synthase within the electron transport system. Collectively, doxorubicin-induced lesions likely span mitochondrial complexes I–IV, providing potential targets for alleviating doxorubicin myotoxicity.
Anti-oxidant effect of bergamot polyphenolic fraction counteracts doxorubicin-induced cardiomyopathy: Role of autophagy and c-kitposCD45negCD31neg cardiac stem cell activation
2018, Journal of Molecular and Cellular Cardiology
Citation Excerpt :
The increased production of ROS, in turn, induces lipid peroxidation leading to cardiomyocyte membrane damage. In addition, DOXO can enter the mitochondria causing increased Ca2+ current along with inhibition of sarcoplasmic reticulum function; decreased activity of Na+, K+-ATPase [5] release of cytochrome C and, finally, cardiomyocyte death generally by apoptosis [6]. Myofibrillar loss and cytoplasmic vacuolization, caused by dilation of the sarcoplasmic reticulum in myocardial cells, are the most common histological features found in anthracycline-induced cardiomyopathy.
Doxorubicin (DOXO) is one of the most widely used antineoplastic drugs. Despite its highly beneficial effects against several malignancies, the clinical use of DOXO is often associated to cardiomyopathy that leads to congestive heart failure.
Here we investigated the antioxidant and cardioprotective effects of a polyphenol-rich fraction of citrus bergamot (BPF), in DOXO-induced cardiac damage in rats. Moreover, we evaluated the effect of BPF on cardiomyocyte survival and resident endogenous cardiac stem/progenitor cell (eCSC) activation.
Adult male Wistar rats were i.p. injected with saline (serving as controls, CTRL, n = 10), BPF (20 mg/kg daily for 14 consecutive days, n = 10), DOXO (6 doses of 2,5 mg/Kg from day 1 to day 14, n = 10), and DOXO + BPF (n = 10). Animals were then sacrificed 7 days later (i.e., at 21 days).
DOXO administration reduced cardiac function at 21 days, an adverse effect significantly attenuated in animals receiving DOXO + BPF. No changes were detected in rats receiving just saline or BPF alone.
The cardioprotective effect of BPF on DOXO acute toxicity was also associated with a significant antioxidant effect coupled with protective autophagy restoration, and attenuation of cardiomyocyte apoptosis and reactive hypertrophy. Finally, treatment of rats with BPF prevented eCSCs attrition by DOXO which was followed by a limited but significant increase of newly-formed BrdU⁺ cardiomyocytes.
In conclusion, BPF reduces DOXO-induced cardiotoxicity by counteracting reactive oxygen species (ROS) overproduction, thereby restoring protective autophagy and attenuating cardiomyocyte apoptosis and pathologic remodeling. This beneficial effects on the early toxicity of DOXO is associated with enhanced CSCs survival and regenerative potential. Overall these data point to a potential clinical role by diet supplementation with polyphenol-rich fraction of citrus bergamot in counteracting antracycline-induced cardiomyopathy.
Anthracycline, Trastuzumab, and Cardiovascular Toxicity
2018, Comprehensive Toxicology: Third Edition
In cancer treatment, the pervasive late effects of radiation and chemotherapy limit their utility, especially in children, in whom treatment often leads to lifelong morbidity and excess mortality. Advances in understanding the molecular pathways related to tumorigenesis have led to the development of targeted therapies, but recurrent late effects, as in the case of trastuzumab, and unexpectedly high rates of cardiotoxicity highlight gaps in our understanding of drug pathways and the mechanisms of treatment toxicity. Here, we review the mechanisms of anthracycline activity in tumor and cardiac cells, as well as the clinical manifestations and their associated cardiotoxicity, prevention strategies, and monitoring recommendations. We also describe the cardiac effects of trastuzumab with specific attention to its interaction with anthracyclines.
Anthracycline, Herceptin, and CV Toxicity
2010, Comprehensive Toxicology, Second Edition
Pervasive late effects limit the utility of radiation and chemotherapy, particularly in the pediatric setting, where treatment at a young age often leads to lifelong morbidity and excess mortality. While advances in the understanding of molecular pathways related to tumorigenesis have led to the development of targeted therapies, recurrent late effects and, as in the case of trastuzumab, unexpectedly high rates of cardiotoxicity highlight gaps in our current understanding of drug pathways and the mechanisms of treatment toxicity. Here we review the mechanisms of anthracycline activity in tumor and cardiac cells as well as the clinical manifestations with their associated cardiotoxicity. We also describe the cardiac effects of trastuzumab with specific attention to its interaction with anthracyclines.
Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase
2010, Bioorganic and Medicinal Chemistry
A series of indazole-dione derivatives were synthesized by the 1,3-dipolar cycloaddition reaction of appropriate substituted benzoquinones or naphthoquinones and N-carboalkoxyamino diazopropane derivatives. These compounds were evaluated for their effects on human carbonyl reductase. Several of the analogs were found to serve as substrates for carbonyl reductase with a wide range of catalytic efficiencies, while four analogs display inhibitory activities with IC₅₀ values ranging from 3–5 μM. Two of the inhibitors were studied in greater detail and were found to be noncompetitive inhibitors against both NADPH and menadione with K_I values ranging between 2 and 11 μM. Computational studies suggest that conformation of the compounds may determine whether the indazole-diones bind productively to yield product or nonproductively to inhibit the enzyme.
Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats
2006, International Journal of Cardiology
Daunorubicin is an anthracycline anti-tumor agent; anthracycline chemotherapy in cancer can cause severe cardiomyopathy leading to a frequently fatal congestive heart failure; the first-line treatment is diuretics and digoxin. Recently, angiotensin-converting enzyme inhibitors have been shown to be effective in the treatment of such toxicity. The purpose of this study was to investigate the effects of angiotensin II type-1 receptor antagonist (candesartan) in a rat model of daunorubicin-induced cardiomyopathy.
Rats were treated with a cumulative dose of 9 mg/kg body weight daunorubicin (i.v.). 28 days later, after the development of cardiomyopathy, animals were randomly assigned to candesartan-treated (5 mg/kg/day, p.o.) or vehicle-treated groups; age-matched normal rats were used as the control group. Candesartan treatment was continued for 28 days. Hemodynamic and echocardiographic parameters were measured, cardiac protein and mRNA were analyzed, and histopathological analyses of myocardial fibrosis, cell size and apoptosis were conducted.
Following cardiomyopathy, left ventricular end diastolic pressure and left ventricular systolic dimension were significantly elevated; while % fractional shortening and Doppler E/A ratio were significantly reduced. Cardiomyopathic hearts showed significant increases in % fibrosis, % apoptosis, and myocyte diameter/body weight ratio; candesartan treatment reversed these changes. Fas-L protein overexpression in myopathic hearts was significantly suppressed by treatment with candesartan. Moreover, SERCA2 mRNA and protein expression were both down-regulated in myopathic hearts and restored to normal by candesartan treatment, significantly.
Our findings suggest that candesartan treatment significantly improved the left ventricular function and reversed the myocardial pathological changes investigated in this model of daunorubicin-induced cardiomyopathy; suggesting its potentials in limiting daunorubicin cardiotoxicity.

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¹: To whom correspondence should be addressed at VA Medical Center (151), 500 W. Fort St., Boise ID 83702. Telephone: (208) 422-1000 (ext. 7683). Fax: (208) 422-1155. E-mail: [email protected].

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Toxicology and Applied Pharmacology

Abstract

References (25)

Sarcoplasmic reticulum genes are selectively down-regulated in cardiomyopathy produced by doxorubicin in rabbits

J. Mol. Cell. Cardiol.

The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps: A correlative study of cardiac muscle with isolated membrane fractions

J. Biol. Chem.

Anthracycline-induced tension in permeabilized cardiac fibers: Evidence for the activation of the calcium release channel of sarcoplasmic reticulum

J. Mol. Cell. Cardiol.

Daunorubicin-induced cardiac injury in the rabbit: A role for daunorubicinol?

Toxicol. Appl. Pharmacol.

Doxorubicin-induced calcium release from cardiac sarcoplasmic reticulum vesicles

J. Mol. Cell. Cardiol.

Protein measurement with the folin phenol reagent

J. Biol. Chem.

Spontaneous calcium release from sarcoplasmic reticulum: General description and effects of calcium

J. Biol. Chem.

Daunorubicin Cardiotoxicity: Evidence for the importance of the quinone moiety in a free-radical independent mechanism

Biochem. Pharm.

Sulfhydryl oxidation induces rapid calcium release from sarcoplasmic reticulum vesicles

J. Biol. Chem.

Reactive disulfides trigger calcium release from sarcoplasmic reticulum via an oxidation reaction

J. Biol. Chem.

Contractile failure in chronic doxorubicin-induced cardiomyopathy

J. Mol. Cell. Cardiol.

The role of biotransformation in anthracycline-induced cardiotoxicity in mice

J. Pharmacol. Exp. Ther.

Cited by (43)

Doxorubicin causes lesions in the electron transport system of skeletal muscle mitochondria that are associated with a loss of contractile function

Anti-oxidant effect of bergamot polyphenolic fraction counteracts doxorubicin-induced cardiomyopathy: Role of autophagy and c-kit<sup>pos</sup>CD45<sup>neg</sup>CD31<sup>neg</sup> cardiac stem cell activation

Anthracycline, Trastuzumab, and Cardiovascular Toxicity

Anthracycline, Herceptin, and CV Toxicity

Synthesis of 3-[(N-carboalkoxy)ethylamino]-indazole-dione derivatives and their biological activities on human liver carbonyl reductase

Effects of angiotensin II receptor blocker (candesartan) in daunorubicin-induced cardiomyopathic rats

Regular ArticleSarcoplasmic Reticulum Calcium Release Is Stimulated and Inhibited by Daunorubicin and Daunorubicinol

Abstract

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Mol. Cell. Cardiol.

Toxicol. Appl. Pharmacol.

J. Mol. Cell. Cardiol.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Pharm.

J. Biol. Chem.

J. Biol. Chem.

Contractile failure in chronic doxorubicin-induced cardiomyopathy

J. Mol. Cell. Cardiol.

The role of biotransformation in anthracycline-induced cardiotoxicity in mice

J. Pharmacol. Exp. Ther.

Regular Article
Sarcoplasmic Reticulum Calcium Release Is Stimulated and Inhibited by Daunorubicin and Daunorubicinol