Influence of ubiquinone on the inhibitory effect of adriamycin on mitochondrial oxidative phosphorylation

Muhammed, H; Kurup, C. K. Ramakrishna

doi:10.1042/bj2170493

Cited by 14 publications

(12 citation statements)

References 18 publications

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“…It is interesting to note that whereas state 4 respiration is initially stimulated by adriamycin, state 3 respiration is only inhibited. This demonstrates that the drug is more potent under conditions of oxidative phosphorylation, in agreement with recent reports by Muhammed et al [10,43]. Whereas respiratory control is very sensitive to adriamycin, the P/O ratio is hardly affected (not shown), in agreement with data in the literature [8].…”

Section: Effects Of Adriamycin On Respiration and Oxidative Phosphorysupporting

confidence: 83%

“…Adriamycin is known to influence respiration of mitochondria from normal [43] and tumor cells [44]. In an attempt to correlate the binding pattern of adriamycin to its functional effects, a dose-respons e curve for rat liver mitochondrial respiration and oxidative phosphorylation was measured (Fig.…”

Section: Effects Of Adriamycin On Respiration and Oxidative Phosphorymentioning

confidence: 99%

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The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

Nicolay

Timmers

Spoelstra

et al. 1984

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The interaction of adriamycin with cardiolipin in model membranes and in various membrane preparations derived from rat liver mitochondria was studied and the results are analyzed in the light of a possible specific interaction between adriamycin and cardiolipin. It was found that adriamycin binds to cardiolipin-containing model membranes with a fixed stoichiometry of two drug molecules per cardiolipin. Furthermore, the extent of drug complexation by mitochondria and mitoplasts (inner membrane plus matrix) is in reasonable agreement with their cardiolipin content. In contrast, adriamycin-binding curves of inner membrane ghosts and submitochondrial particles reveal considerable association to an additional site, presumably RNA. The evidence for the potential importance of RNA as a target comes from experiments on outer membranes and microsomes which both appear to bind substantial amounts of adriamycin. Removal of the major part of the RNA associated with these fractions by EDTA treatment is accompanied by a dramatic reduction of binding capacity. We propose that endogenous RNA present in mitochondria and mitoplasts is not accessible for adriamycin at low concentrations of the drug due to the presence of an intact lipid barrier. This potential site comes to expression in ghosts and submitochondriai particles, due to the absence of an intact lipid bilayer and due to the inside-out orientation of the limiting membrane, respectively. Electron microscopical studies show that adriamycin induces dramatic changes in mitochondrial morphology, similar to the uncoupler-induced effects described by Knoll and Brdiczka (Biochim. Biophys. Acta 733, 102-110 (1983)). Adriamycin has an uncoupling effect on mitochondrial respiration and oxidative phosphorylation. The concentration dependence of this effect correlates with the adriamycin-binding curve for mitochondria which implies that only bound adriamycin actively inhibits respiration.

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Section: Effects Of Adriamycin On Respiration and Oxidative Phosphorysupporting

confidence: 83%

Section: Effects Of Adriamycin On Respiration and Oxidative Phosphorymentioning

confidence: 99%

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

Nicolay

Timmers

Spoelstra

et al. 1984

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Mitochondrial dysfunction promoted by DOX has been extensively studied in heart tissue [28][29][30][31][32][33] because cardiomyopathy is the most prominent side effect observed in patients that receive DOX therapy. However, much less is known about the effects of DOX treatment in the brain.…”

Section: Discussionmentioning

confidence: 99%

Doxorubicin increases the susceptibility of brain mitochondria to Ca2+-induced permeability transition and oxidative damage

Cardoso

Santos

Carvalho

et al. 2008

Free Radical Biology and Medicine

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This study was aimed at investigating the effects of subchronic administration of doxorubicin (DOX) on brain mitochondrial bioenergetics and oxidative status. Rats were treated with seven weekly injections of vehicle (sc, saline solution) or DOX (sc, 2 mg kg −1 ), and 1 week after the last administration of the drug the animals were sacrificed and brain mitochondrial fractions were obtained. Several parameters were analyzed: respiratory chain, phosphorylation system, induction of the permeability transition pore (PTP), mitochondrial aconitase activity, lipid peroxidation markers, and nonenzymatic antioxidant defenses. DOX treatment induced an increase in thiobarbituric acid-reactive substances and vitamin E levels and a decrease in reduced glutathione content and aconitase activity. Furthermore, DOX potentiated PTP induced by Ca 2+ . No statistical differences were observed in the other parameters analyzed. Altogether our results show that DOX treatment increases the susceptibility of brain mitochondria to Ca 2+ -induced PTP opening and oxidative stress, predisposing brain cells to degeneration and death.© 2008 Elsevier Inc. All rights reserved. IntroductionDoxorubicin (DOX) is a potent broad-spectrum antineoplastic agent effective in the treatment of a wide variety of cancers, including both solid tumors and leukemias [1]. However, the chronic administration of this drug can induce toxicity to nontarget tissues, cardiotoxicity being the best known side effect [2]. DOX-induced cardiotoxicity has been attributed to a number of effects, including the direct inhibition of key transporters involved in ion homeostasis, alterations in cellular iron and calcium metabolism, disruption of sarcoplasmic reticulum function, mitochondrial dysfunction, and apoptotic cell loss [3]. The mechanisms underlying these events seem to be linked to an increased production of reactive oxygen species (ROS) and oxidative damage [3]. Oxidative stress results from an imbalance between the generation of ROS and reactive nitrogen species and their removal by the cellular antioxidant system [4] and has been implicated in many neurodegenerative disorders [5,6].Several studies in breast cancer survivors and other patients undergoing DOX-based chemotherapy have reported persistent changes in cognitive functions, including memory loss and difficulty in the performance of daily life tasks [4]. Despite the well-known side effects of DOX treatment in the heart, little is known about its effects in the brain. Park et al. [7] showed that DOX generates free radicals in cultured astrocytes and decreases cell viability in a concentration-dependent manner. Similarly, in a study made in primary neuronal cultures, Lopes et al. [2] observed that DOX can induce neuronal cell death by necrosis and apoptosis in a concentration-dependent manner.Mitochondria play a central role in both cell life and cell death [8]. These organelles are essential for the production of ATP through oxidative phosphorylation and regulation of intracellular Ca 2+ homeostasis and are t...

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“…A number of studies on doxorubicin have suggest ed that damage to mitochondrial structures [15], lysis of cristac [19], or changes in the respiratory chain [20] can induce in the cardiac cell a serious imbalance of cellular respiratory control with significant reduction of intracellular ATP concentration [21].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Endogenous Respiration in Rat Heart Slices as a Measure of Mitoxantrone Cardiac Toxicity

Neri

Cini-Neri

1986

Oncology

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Anthracycline antibiotics are among the more active agents currently available for the treatment of solid tumors. Their use is limited by the development of severe cardiomyopathy. This makes it necessary to subject new anticancer agents to laboratory and clinical tests in order to determine their capacity to damage cardiac cells. Mitoxantrone is an anthracenedione derivative with structural and functional similarities to doxorubicin. Comparative trials on rat suggest that mitoxantrone induced cardiac toxicity might be less marked than that caused by doxorubicin, while some clinical studies report a significant incidence of cardiac failure following mitoxantrone administration. The present study was undertaken to evaluate (in vitro) the effect of increasing concentrations of mitoxantrone on respiratory control, measuring oxygen uptake of rat heart slices in a Warburg manometric apparatus. Over a period of 60 min, cellular endogenous respiration was progressively inhibited by increasing mitoxantrone concentration (from 5 to 20 μM). The date show that the rate of oxygen uptake levels off with time at all concentrations except the lowest (5 μM) and with the control. Oxygen uptake values range from 2.87 to 1.41 μl/mg dry weight and differ significantly as compared to controls (p <0.01). The values of oxygen uptake between 0 and 20 min show that a linear correlation is approached by all the date group and if we consider an exponential relation (i.e., log slope versus dose), the linear correlation coefficient is somewhat improved (r = –0.939). These results indicate that mitoxantrone, in a manner analogous to doxorubicin, inhibits cellular respiration and impairs the cardiac respiratory control. This impairment is probably one of the aspects of cellular damage leading to cardiac failure. Moreover, in a recent study we observed the same pathological lesions induced by doxorubicin in the heart of rats treated with mitoxantrone.

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Influence of ubiquinone on the inhibitory effect of adriamycin on mitochondrial oxidative phosphorylation

Cited by 14 publications

References 18 publications

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

The interaction of adriamycin with cardiolipin in model and rat liver mitochondrial membranes

Doxorubicin increases the susceptibility of brain mitochondria to Ca2+-induced permeability transition and oxidative damage

Inhibition of Endogenous Respiration in Rat Heart Slices as a Measure of Mitoxantrone Cardiac Toxicity

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