Inhibition of mitochondrial oxidative phosphorylation by adriamycin

Muhammed, H; Ramasarma, T.; Kurup, C. K. Ramakrishna

doi:10.1016/0005-2728(83)90155-x

Cited by 75 publications

(25 citation statements)

References 22 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: 92%

“…Moreover, the development of ECG changes shows a good correlation with the impairment of mitochondrial function [8]. Several mechanisms of action have been proposed to explain the adriamycin-induced inhibition of mitochondrial operation, including inhibition of electron transfer and oxidative phosphorylation [10] and initiation of lipid peroxidation [11,12]. The common denominator in these mechanisms is that it involves the action of adriamycin at the mitochondrial membrane level.…”

Section: Introductionmentioning

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: 92%

Section: Introductionmentioning

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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“…At the mitochondrial level, MGBG exhibits inhibition of protein phosphorylation (Gosalvez et al 1974;Mailer and Petering 1976;Muhammed et al 1983;Warrell and Burchenal 1983), impairment of carnitine palmitoyl tranferase and carnitine acetyl transferase (Nikula et al 1985;Brady et al 1987), and an overall damaging effect due to selective inhibition of mitochondrial DNA synthesis (Feuerstein et al 1979). Reported studies on Ehrlich ascites carcinoma cells suggest that the precursor of MGBG, methylglyoxal, induces cytotoxicity by inhibiting the electron flux along Complex I of the mitochondrial respiratory chain (Ray et al 1994).…”

Section: Introductionmentioning

confidence: 99%

Biological activity of antitumoural MGBG: the structural variable

et al. 2007

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The present study aims at determining the structure-activity relationships (SAR's) ruling the biological function of MGBG (methylglyoxal bis(guanylhydrazone)), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase displaying anticancer activity, involved in the biosynthesis of the naturally occurring polyamines spermidine and spermine. In order to properly understand its biochemical activity, MGBG's structural preferences at physiological conditions were ascertained, by quantum mechanical (DFT) calculations.

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“…These include: (i) inhibition of respiration [8][9][10]; (ii) inhibition of enzymes involved in oxidative phosphorylation [11], e.g., the inorganic phosphate carrier [12,13]; (iii) lipid peroxidation [14,15]; (iv) dissociation of the mitochondrial isozyme of creatine kinase from the inner membrane leading to impaired energy metabolism [16,17]. It is important to note that all four mechanisms involve the action of adriamycin at the level of the mitochondrial inner membrane.…”

Section: Introductionmentioning

confidence: 99%

Effects of adriamycin on respiratory chain activities in mitochondria from rat liver, rat heart and bovine heart. Evidence for a preferential inhibition of complex III and IV

Nicolay

Kruijff

1987

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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The inhibition of respiratory chain activities in rat liver, rat heart and bovine heart mitochondria by the anthracycline antibiotic adriamycin was measured in order to determine the adriamyein-sensitive sites. It appeared that complex HI and IV are efficiently affected such that their activities were reduced to 50% of control values at 175 + 25 pM adriamycin. Complex I displayed a minor sensitivity to the drug. Of the complex-l-related activities tested, only duroquinone oxidation appeared sensitive (50% inhibition at approx. 450 I~M adriamycin). Electron-transfer activities catalyzed by complex II remained essentially unaltered up to high drug concentrations. Of the activities measured for this complex, only duroquinone oxidation was significantly affected. However, the adriamycin concentration required to reduce this activity to 50% exceeded I mM. Mitochondria isolated from rat liver, rat heart and bovine heart behaved essentially identical in their response to adriamycin. These data support the conclusion that, in these three mitochondrial systems, the major drug-sensitive sites lie in complex III and IV. Cytochrome c oxidase and succinate oxidase activity in whole mitochondria exhibited a similar sensitivity towards adriamycin, as inner membrane ghosts, suggesting that the drug has direct access to its inner membrane target sites irrespective of the presence of the outer membrane. By measuring NADH and succinate oxidase activities in the presence of exogenously added cytochrome c, it appeared that adriamycin was less inhibitory under these conditions. This suggests that adriamycin competes with cytochrome c for binding to the same site on the inner membrane, presumably cardiolipin.

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Inhibition of mitochondrial oxidative phosphorylation by adriamycin

Cited by 75 publications

References 22 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

Biological activity of antitumoural MGBG: the structural variable

Effects of adriamycin on respiratory chain activities in mitochondria from rat liver, rat heart and bovine heart. Evidence for a preferential inhibition of complex III and IV

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