Wy-14,643 and fenofibrate inhibit mitochondrial respiration in isolated rat cardiac mitochondria

Zungu, Makhosazane; Felix, Rebecca; Essop, M. Faadiel

doi:10.1016/j.mito.2006.09.001

Cited by 21 publications

(14 citation statements)

References 33 publications

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“…Here, we found that fenofibrate treatment enhances the activities of citrate synthase and NADH oxidase in most organs like the liver, kidney, lung and heart; especially in liver, there was a significant increase in enzyme activity, suggesting that fenofibrate improves mitochondrial respiratory function. However, previous studies showed that fenofibrate impairs mitochondrial respiratory function [25,26], while other studies showed that cardiac citrate synthase activity is unaffected by fenofibrate treatment [27]. The discrepancy between our study and others may be due to the different fenofibrate dosage and experimental model.…”

contrasting

confidence: 99%

Effects of Doxorubicin and Fenofibrate on the Activities of NADH Oxidase and Citrate Synthase in Mice

Yao

Zhang

et al. 2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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Doxorubicin (Dox) has widely been used as an anticancer drug, but its use is limited by serious toxicity to the heart, kidney and liver. Mitochondrial dysfunction is one of the potential mechanisms of toxicity but not fully understood. Fenofibrate, one of the peroxisome proliferator-activated receptor-alpha (PPARa) ligands, is involved in lipid metabolism which takes place primarily in the mitochondria, so mitochondrial function may be affected by fenofibrate. Therefore, we investigated the effects of DOX and fenofibrate on activities of both mitochondrial citrate synthase and NADH oxidase, which are marker enzymes in the tricarboxylic acid (TCA) cycle and a measure of the complex I-III-IV activity in electron transport chain, respectively. Dox (15 mg ⁄ kg) and ⁄ or fenofibrate (100 mg ⁄ kg ⁄ day) were administered to mice for 3 or 14 days, and the activities of citrate synthase and NADH oxidase were measured. Our study showed that Dox significantly inhibits the activity of citrate synthase while fenofibrate induces the activity. Similar to citrate synthase, NADH oxidase activity was also induced by fenofibrate except in spleen but inhibited by Dox except in the heart and liver. Furthermore, fenofibrate not only protects citrate synthase activity from Dox-induced toxicity in the ventricle but also significantly rescues NADH oxidase activity in the kidney. These results reveal the actions of fenofibrate and Dox on the mitochondria, and the underlying mechanism may be related to the toxicity of Dox, which has clinical implications in the side effects of Dox treatment by modulation of mitochondrial function. Doxorubicin (Dox), an anthracycline anticancer drug, is effectively and frequently used to treat a variety of tumour malignancies [1,2]. Unfortunately, its clinical use is limited by its serious toxicity to the heart, brain, kidney and liver. Over the past years, a great deal has been learnt about the mechanisms of its toxicity; for example, previous studies showed that Dox not only inhibits both DNA and RNA synthesis but also targets key cellular enzymes such as topoisomerases I and II [3], which results in DNA damage, G1 and G2 growth arrest, and induction of apoptosis. Accumulating evidence shows that Dox can cause mitochondrial dysfunction [4-6] but its precise mechanisms remain unknown.Mitochondria functions as primary energy providers to relentlessly produce enough ATP to sustain life processes through oxidative phosphorylation, which is tightly coupled to the tricarboxylic acid (TCA) cycle [7,8]. Citrate synthase and NADH oxidase, which are mitochondrial marker enzyme in the TCA cycle and a measure of the complex I-III-IV activity in electron transport chain, respectively [9], are key markers of mitochondrial function [10,11]. Most notably, complexes I (NADH: ubiquinone oxidoreductase), the first electron transport complexes, was shown to be inactivated by Dox through a superoxide-dependent mechanism [12]. These studies by Kotamraju et al. have provided compelling suggestions for establishing D...

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confidence: 99%

Effects of Doxorubicin and Fenofibrate on the Activities of NADH Oxidase and Citrate Synthase in Mice

Yao

Zhang

et al. 2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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“…Parallel to the long-term metabolic effects, we have observed several anticancer responses to FF that are difficult to explain by using a PPAR␣-dependent mechanism of action (12)(13)(14)(15). Other examples of a possible off-target action of FF include the effects of cell membrane fluidity in endothelial cells (5,20) and the inhibition of oxygen consumption by isolated cardiac and liver mitochondria (31,32).…”

Section: Discussionmentioning

confidence: 98%

“…However, in comparison with the anticancer effects of other potent agonists of PPAR␣, those of FF are much more pronounced, implying that FF may also act in a PPAR␣-independent manner. In this regard, FF was shown to alter the expression of growth differentiation factor 15 (20); affect cell membrane fluidity in a manner similar to that of cholesterol (30); and interfere with the respiratory function of isolated liver and heart mitochondria (31,32). Here we report the novel observation that FF, but not its PPAR␣-active metabolite FA, accumulates in the mitochondrial fraction of human glioblastoma cells.…”

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confidence: 83%

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Wilk

Wyczechowska

Zapata

et al. 2015

Molecular and Cellular Biology

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e Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPAR␣). FF and several other agonists of PPAR␣ have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPAR␣-independent mechanism explaining FF's cytotoxicity in vitro and in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPAR␣-dependent metabolic switch from glycolysis to fatty acid ␤-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase-mammalian target of rapamycin-autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells. F enofibrate (FF) is a common lipid-lowering drug and a potent agonist of peroxisome proliferator-activated receptor alpha (PPAR␣). Multiple reports indicate a beneficial role for lipid-lowering drugs, including fibrates and statins, as anticancer agents (1-7). For example, a 10-year, all-cause mortality study involving 7,722 patients treated with different fibrates revealed that the use of these drugs is associated with a significantly lower total mortality rate and a reduced probability of death from cancer (8). In cell culture and animal studies, various members of the fibrate family, which are all agonists of PPAR␣, demonstrate interesting anticancer effects, which are not fully understood. FF inhibited tumor growth by reducing both inflammation and angiogenesis in host tissue (5). Clofibrate attenuated ovarian cancer cell proliferation (9, 10), and gemfibrozil (GEM) inhibited the invasiveness of glioblastoma cells (11). In our previous work, FF synergized with staurosporine to reduce melanoma lung metastases (3, 12), significantly reduced glioblastoma invasiveness (13), and triggered apoptotic death in medulloblastoma (14) and human glioblastoma cell lines by inducing the FOXO3A-Bim apoptotic pathway (15). All of these studies encouraged the use of FF as a supplemental anticancer drug, a concept supported by recent clinical trials in which chronic administration of FF along with chemotherapeutic agents used at relatively low doses minimizes the toxicity and acute side effects of chemotherapy while maintaining efficacy for patients wit...

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“…13,14) However, the development of PPARα/γ dual agonists including muraglitazar, were suspended due to the risk of cardiovascular events, carcinogenicity and the potential risks of liver injury and/or renal dysfunction [15][16][17] : Overactivation of PPAR with both PPARα and PPARγ agonist activity may lead to carcinogenesis and to adverse effects in the liver, heart and kidney. 14,[18][19][20][21] Thus, PPARγ partial agonists, such as INT-131, have been researched and studied clinically. 22) They showed higher efficacy with lower toxicity in experimental diabetic animals; however, none of them has been successfully developed.…”

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confidence: 99%

Novel 2,7-Substituted (<i>S</i>)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists with Protein–Tyrosine Phosphatase 1B Inhibition

Otake

Azukizawa

Takeda

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of 2,7-substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were synthesized and biologically evaluated. (S)-2-(2-Furylacryloyl)-7-[2-(2-methylindane-2-yl)-5-methyloxazol-4-yl] methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid tert-butylamine salt (13jE) was identified as a potent human peroxisome proliferator-activated receptor γ (PPARγ)-selective agonist (EC 50 85 nM) and human protein-tyrosine phosphatase 1B (PTP-1B) inhibitor (IC 50 1.0 µM). Compound 13jE partially activated PPARγ, but not PPARα or PPARδ, and antagonized farglitazar, a full PPARγ agonist. C max after the oral administration of 13jE at 10 mg/kg was 28.6 µg/mL (53 µM) in male Sprague-Dawley (SD) rats. Repeated administration of 13jE and rosiglitazone for 14 d at 10 mg/kg/d decreased plasma glucose and triglyceride levels significantly in male KK-A y mice. Rosiglitazone, but not 13jE, significantly increased the plasma volume and liver weight. In conclusion, 13jE showed stronger hypoglycemic and hypolipidemic effects and weaker hemodilution and hepatotoxic effects than rosiglitazone, suggesting that its safer efficacy may be due to its partial PPARγ agonism and PTP-1B inhibition.

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Wy-14,643 and fenofibrate inhibit mitochondrial respiration in isolated rat cardiac mitochondria

Cited by 21 publications

References 33 publications

Effects of Doxorubicin and Fenofibrate on the Activities of NADH Oxidase and Citrate Synthase in Mice

Effects of Doxorubicin and Fenofibrate on the Activities of NADH Oxidase and Citrate Synthase in Mice

Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

Novel 2,7-Substituted (<i>S</i>)-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acids: Peroxisome Proliferator-Activated Receptor γ Partial Agonists with Protein–Tyrosine Phosphatase 1B Inhibition

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