Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs

Moreno‐Sánchez, Rafael; Bravo, Concepciòn; Vásquez, C.; Ayala, Guadalupe; Silveira, Luis H.; Martı́nez-Lavı́n, Manuel

doi:10.1016/s0006-2952(98)00330-x

Cited by 144 publications

(93 citation statements)

References 42 publications

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“…Two different mechanisms could potentially be responsible for the decrease in oxygen consumption: a direct effect on the mitochondrial respiration (well established in the literature; refs. [17][18][19][20] or an effect on the recruitment of macrophages (21). An effect on the recruitment of macrophages is unlikely to be the factor responsible for the decrease in oxygen consumption.…”

Section: Discussionmentioning

confidence: 99%

“…The rationale for this hypothesis is based on a possible dual effect of NSAIDs on the oxygen consumption in tumors. First, NSAIDs are known to uncouple mitochondrial oxidative phosphorylation with important consequences on cell oxygen consumption (17)(18)(19)(20). Second, antiinflammatory drugs could affect the recruitment and migration of macrophages.…”

Section: Introductionmentioning

confidence: 99%

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Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

et al. 2005

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We hypothesized that nonsteroidal antiinflammatory drugs (NSAIDs) might enhance tumor radiosensitivity by increasing tumor oxygenation (pO 2 ), via either a decrease in the recruitment of macrophages or from inhibition of mitochondrial respiration. The effect of four NSAIDs (diclofenac, indomethacin, piroxicam, and NS-398) on pO 2 was studied in murine TLT liver tumors and FSaII fibrosarcomas. At the time of maximum pO 2 (t max , 30 minutes after administration), perfusion, oxygen consumption, and radiation sensitivity were studied. Local pO 2 measurements were done using electron paramagnetic resonance. Tumor perfusion and permeability measurements were assessed by dynamic contrast-enhanced magnetic resonance imaging. The oxygen consumption rate of tumor cells after in vivo NSAID administration was measured using high-frequency electron paramagnetic resonance. Tumor-infiltrating macrophage localization was done with immunohistochemistry using CD11b antibody. All the NSAIDs tested caused a rapid increase in pO 2 . At t max , tumor perfusion decreased, indicating that the increase in pO 2 was not caused by an increase in oxygen supply. Also at t max , global oxygen consumption decreased but the amount of tumor-infiltrating macrophages remained unchanged. Our study strongly indicates that the oxygen effect caused by NSAIDs is primarily mediated by an effect on mitochondrial respiration. When irradiation (18 Gy) was applied at t max , the tumor radiosensitivity was enhanced (regrowth delay increased by a factor of 1.7). These results show the potential utility of an acute administration of NSAIDs for radiosensitizing tumors, and shed new light on the mechanisms of NSAID radiosensitization. These results also provide a new rationale for the treatment schedule when combining NSAIDs and radiotherapy. (Cancer Res 2005; 65(17): 7911-6)

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

et al. 2005

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“…47 Coxibs may also increase reactive oxygen species generation via uncoupling of mitochondrial oxidative phosphorylation. 66 Thus, the net result of coxib action in diseased vessels is an increase in the amount of TxA 2 relative to PGI 2 (see Figure 4). In addition to the considerations at the molecular level discussed above, it should be noted that manipulation of the relative balance of COX-1 and COX-2 activity may alter important cardiorenal responses in patients.…”

Section: Pharmacology and Molecular Biology Of Inhibition Of Prostanomentioning

confidence: 99%

Cyclooxygenase Inhibition and Cardiovascular Risk

2005

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O ver the past several months clinicians have been confronted at an escalating rate with reports describing the risks of COX-2 inhibitors (coxibs). Information on this class of drugs appears not only in traditional medical journals and textbooks, but also on the Web sites of regulatory agencies, professional societies, and pharmaceutical manufacturers. [1][2][3][4][5][6][7][8][9] An unusual, but noteworthy, aspect of the state of affairs is the high rate of reporting new findings and opinions (at times voiced in a strident tone) in the lay press. 10 -13 Understandably, patients are concerned about the potential risks associated with their antiinflammatory medications, and now, either spontaneously or in response to a public health warning, call their healthcare professional with questions or arrive for an office visit armed with publicly accessed information they wish to discuss.Owing to the widespread use of antiinflammatory drugs and the fact that the reported risks are cardiovascular in nature, we offer the readers of Circulation this special article. Our goals are to provide an overview of the relevant biology and pharmacology, to synthesize the data on the cardiovascular risks associated with antiinflammatory medications, to offer suggestions on strategies for prescribing these medications, and to make observations on the regulatory and research implications of the data and their interpretation. Biology of EicosanoidsEicosanoids are oxidized derivatives of the polyunsaturated long-chain fatty acids, arachidonic acid and eicosapentaenoic acid, that serve many roles in cardiovascular biology and disease. Eicosanoid biosynthesis can be initiated by release of arachidonic acid from membrane phospholipids by lipases (predominantly of the phospholipase A 2 type) (Figure 1). Once mobilized, arachidonic acid is oxygenated into eicosanoids along the following 4 pathways: (1) prostaglandin (PG) endoperoxide synthase (cyclooxygenase [COX]), (2) lipoxygenase (LO), (3) P450 epoxygenase, and (4) (nonenzymatic) isoprostane synthesis. Details of the pharmacology of products of the LO, epoxygenase, and isoprostane pathways, as well as the lipoxins, are reviewed elsewhere. 14 -16 Here, we focus on products of the COX pathway. These derivatives of arachidonic acid are collectively referred to as prostanoids and comprise the PGs and thromboxanes. COX, a key enzyme in eicosanoid metabolism, converts arachidonic acid liberated from membrane phospholipids into PGG 2 and PGH 2 .The fate of PGH 2 and the distribution of prostanoids formed from it depend on the cell type in which it is synthesized and the tissue-specific isomerases found within that cell. For example, leukocytes, vascular smooth muscle cells, endothelial cells, and platelets express PGE synthase and, as a result, are all capable of generating the inflammatory prostanoid PGE 2 ; platelets express thromboxane synthase and elaborate the prothrombotic, vasoconstrictor prostanoid thromboxane A 2 ; and endothelial cells express PGI synthase and synthesize the antithromb...

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“…In particular, most acidic NSAIDs can transduce protons across the inner mitochondrial membrane (Moreno-Sanchez et al, 1999). The re-entry of protons into the mitochondrial matrix decreases the mitochondrial membrane potential (⌬ m ) and unleashes the flow of electrons in the respiratory chain, thus stimulating basal respiration (Pessayre et al, 2002).…”

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confidence: 99%

The Anti-Inflammatory Drug, Nimesulide (4-Nitro-2-phenoxymethane-sulfoanilide), Uncouples Mitochondria and Induces Mitochondrial Permeability Transition in Human Hepatoma Cells: Protection by Albumin

Berson

Cazanave²,

Descatoire³

et al. 2006

J Pharmacol Exp Ther

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Like other nonsteroidal anti-inflammatory drugs, nimesulide (4-nitro-2-phenoxymethane-sulfoanilide) triggers hepatitis in a few recipients. Although nimesulide has been shown to uncouple mitochondrial respiration and cause hepatocyte necrosis in the absence of albumin, mechanisms for cell death are incompletely understood, and comparisons with human concentrations are difficult because 99% of nimesulide is albumin-bound. We studied the effects of nimesulide, with or without a physiological concentration of albumin, in isolated rat liver mitochondria or microsomes and in human hepatoma cells. Nimesulide did not undergo monoelectronic nitro reduction in microsomes. In mitochondria incubated without albumin, nimesulide (50 M) decreased the mitochondrial membrane potential (⌬ m ), increased basal respiration, and potentiated the mitochondrial permeability transition (MPT) triggered by calcium preloading. In HUH-7 cells incubated for 24 h without albumin, nimesulide (1 mM) decreased the ⌬ m and cell NAD(P)H and increased the glutathione disulfide/reduced glutathione ratio and cell peroxides; nimesulide triggered MPT, ATP depletion, high cell calcium, and caused mostly necrosis, with rare apoptotic cells. Coincubation with either cyclosporin A (an MPT inhibitor) or the combination of fructose-1,6-diphosphate (a glycolysis substrate) and oligomycin (an ATPase inhibitor) prevented the decrease in ⌬ m , ATP depletion, and cell death. A physiological concentration of albumin abolished the effects of nimesulide on isolated mitochondria or HUH-7 cells. In conclusion, the weak acid, nimesulide, uncouples mitochondria and triggers MPT and ATP depletion in isolated mitochondria or hepatoma cells incubated without albumin. However, in the presence of albumin, only a fraction of the drug enters cells or organelles, and uncoupling and toxicity are not observed.

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Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs

Cited by 144 publications

References 42 publications

Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

Tumor Radiosensitization by Antiinflammatory Drugs: Evidence for a New Mechanism Involving the Oxygen Effect

Cyclooxygenase Inhibition and Cardiovascular Risk

The Anti-Inflammatory Drug, Nimesulide (4-Nitro-2-phenoxymethane-sulfoanilide), Uncouples Mitochondria and Induces Mitochondrial Permeability Transition in Human Hepatoma Cells: Protection by Albumin

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