Inhibition of oxidative phosphorylation in tumor cells and mitochondria by daunomycin and adriamycin

Mailer, Kathleen; Petering, David H.

doi:10.1016/0006-2952(76)90434-2

Cited by 69 publications

(15 citation statements)

References 5 publications

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“…It appears therefore that ADR, DNR and AD-32, irrespective of their ability to bind to DNA, affected membrane permeability functions dependent on the metabolic energy supply, by impairing mitochondrial activity. Interactions at the mitochondrial level, resulting in impaired metabolic reactions have been already observed by several authors (Gosalvez et al, 1974;Iwamoto et al, 1974;Ferrero et al, 1976;Mailer & Petering, 1976;Folkers et al, 1977;Goormaghtigh et al, 1982;Solaini et al, 1985) and our findings are consistent with these reports.…”

Section: Discussionsupporting

confidence: 94%

“…Many studies have provided evidence that anthracyclines interact with the cells at different sites, such as DNA (Di Marco et al, 1974), membranes (Goldman et al, 1978, Goormaghtigh andRuysschaert, 1984) and mitochondria (Gosalvez et al, 1974;Ferrero et al, 1976;Mailer & Petering, 1976), however, it is not yet well understood to what extent these interactions are involved in the mechanisms that induce cytotoxicity.…”

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confidence: 99%

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Anthracycline-induced inhibition of membrane permeability functions dependent on metabolic energy

Croce¹,

Prosperi²,

Supino³

et al. 1986

Br J Cancer

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Summary The influence of anthracyclines on membrane permeability functions has been investigated in HeLa cells by monitoring the efflux of fluorescein. Release of the fluorescent dye, dependent on the metabolic energy supply, occurs after the intracellular accumulation and enzymatic hydrolysis of the non-fluorescent substrate fluorescein diacetate (FDA). Flow cytometric evaluation of the efflux kinetics showed that adriamycin (ADR), N-trifluoroacetyladriamycin-14-valerate (AD-32) and daunorubicin (DNR) inhibited the permeability process. The degree of inhibition was dependent, though to different extent, on the intracellular concentration of each drug. An increase in the efflux rate was always observed when the cells were treated with the drugs in the presence of 20 mM glucose. Relationship of these effects with energetic metabolism was supported by the finding that ATP levels were lowered by the drugs and increased by glucose. Evaluation of the cytotoxicity induced by each drug showed that the intracellular amount necessary to inhibit cell survival by 50% was of the same order of magnitude as that which decreases to 50% membrane permeability to fluorescein. These results indicate a correspondence in the concentrations of anthracyclines required for inducing cytotoxicity and for inhibiting membrane permeability functions dependent on the metabolic energy supply.

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Section: Discussionsupporting

confidence: 94%

mentioning

confidence: 99%

Anthracycline-induced inhibition of membrane permeability functions dependent on metabolic energy

Croce¹,

Prosperi²,

Supino³

et al. 1986

Br J Cancer

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“…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%

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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“…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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Inhibition of oxidative phosphorylation in tumor cells and mitochondria by daunomycin and adriamycin

Cited by 69 publications

References 5 publications

Anthracycline-induced inhibition of membrane permeability functions dependent on metabolic energy

Anthracycline-induced inhibition of membrane permeability functions dependent on metabolic energy

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

Biological activity of antitumoural MGBG: the structural variable

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