Mechanism of the Physiological Action of Rotenone

Lindahl, Per Eric; Öberg, K.E.

doi:10.1038/187784a0

Cited by 20 publications

(8 citation statements)

References 2 publications

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“…The inhibition of mitochondrial complex I (NADH:ubiquinone oxidoreductase) was established as essential to their mechanism of action and selective toxicity . This finding further highlights the therapeutic potential of 1 and 2 − and is consistent with their being canonical ubiquinone-binding site inhibitors of complex I. − Complex I is a major entry point for electrons into the mitochondrial respiratory chain and an integral contributor to oxidative phosphorylation (OxPhos), which is a target for other potential anticancer compounds, such as metformin , and IACS-010759 from the MD Anderson Cancer Center. It oxidizes the NADH produced by the citric acid cycle and other metabolic pathways, transfers the electrons to ubiquinone to sustain the reduction of molecular oxygen through complexes III and IV, and transports protons across the mitochondrial inner membrane to maintain the proton motive force that drives ATP synthesis and metabolite transport .…”

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confidence: 69%

Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

et al. 2020

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Prostate cancer is one of the leading causes of cancer-related death in men. The identification of new therapeutics to selectively target prostate cancer cells is therefore vital. Recently, the rotenoids rotenone (1) and deguelin (2) were reported to selectively kill prostate cancer cells, and the inhibition of mitochondrial complex I was established as essential to their mechanism of action. However, these hydrophobic rotenoids readily cross the blood–brain barrier and induce symptoms characteristic of Parkinson’s disease in animals. Since hydroxylated derivatives of 1 and 2 are more hydrophilic and less likely to readily cross the blood–brain barrier, 29 natural and unnatural hydroxylated derivatives of 1 and 2 were synthesized for evaluation. The inhibitory potency (IC50) of each derivative against complex I was measured, and its hydrophobicity (Slog10P) predicted. Amorphigenin (3), dalpanol (4), dihydroamorphigenin (5), and amorphigenol (6) were selected and evaluated in cell-based assays using C4-2 and C4-2B prostate cancer cells alongside control PNT2 prostate cells. These rotenoids inhibit complex I in cells, decrease oxygen consumption, and selectively inhibit the proliferation of prostate cancer cells, leaving control cells unaffected. The greatest selectivity and antiproliferative effects were observed with 3 and 5. The data highlight these molecules as promising therapeutic candidates for further evaluation in prostate cancer models.

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confidence: 69%

Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

et al. 2020

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“…Along with the substitution of atmospheric conditions, U2OS cells were placed in drug-free culture medium or in medium supplemented with STS (a broad-spectrum kinase inhibitor that interrupts most—if not all—trophic signaling cascades), 30 mitoxantrone (a DNA-damaging anthracycline), 31 rotenone (an inhibitor of the complex I of the mitochondrial respiratory chain), 32 antimycin A (an inhibitor of the complex III of the mitochondrial respiratory chain), 33 or menadione (a redox-cycling agent that stimulates the overproduction of reactive oxygen species), 34 for 6 or 16 h. At the end of the experiment, culture plates were fixed and processed by a robotized fluorescence microscopy-based imaging platform for the automated quantification of residual cell number.…”

Section: Resultsmentioning

confidence: 99%

Antiapoptotic activity of argon and xenon

et al. 2013

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Although chemically non-reactive, inert noble gases may influence multiple physiological and pathological processes via hitherto uncharacterized physical effects. Here we report a cell-based detection system for assessing the effects of pre-defined gas mixtures on the induction of apoptotic cell death. In this setting, the conventional atmosphere for cell culture was substituted with gas combinations, including the same amount of oxygen (20%) and carbon dioxide (5%) but 75% helium, neon, argon, krypton, or xenon instead of nitrogen. The replacement of nitrogen with noble gases per se had no effects on the viability of cultured human osteosarcoma cells in vitro. Conversely, argon and xenon (but not helium, neon, and krypton) significantly limited cell loss induced by the broad-spectrum tyrosine kinase inhibitor staurosporine, the DNA-damaging agent mitoxantrone and several mitochondrial toxins. Such cytoprotective effects were coupled to the maintenance of mitochondrial integrity, as demonstrated by means of a mitochondrial transmembrane potential-sensitive dye and by assessing the release of cytochrome c into the cytosol. In line with this notion, argon and xenon inhibited the apoptotic activation of caspase-3, as determined by immunofluorescence microscopy coupled to automated image analysis. The antiapoptotic activity of argon and xenon may explain their clinically relevant cytoprotective effects.

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“…To test whether the accumulation of FlAsH/Lumio Green in mitochondria is activity-dependent, we inhibited mitochondrial respiration by a short incubation with 5 lM Rotenone (Lindahl and Oberg 1960). This treatment abolished labeling of the mitochondria by FlAsH/Lumio Green (Fig.…”

Section: Flash/lumio Green Accumulates In Active Mitochondriamentioning

confidence: 99%

Accumulation of FlAsH/Lumio Green in active mitochondria can be reversed by β-mercaptoethanol for specific staining of tetracysteine-tagged proteins

Langhorst

Genisyuerek

Stuermer

2006

Histochem Cell Biol

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Recent advances in the field of small molecule labels for live cell imaging promise to overcome some of the limitations set by the size of fluorescent proteins. We tested the tetracysteine-biarsenical labeling system in live cell fluorescence microscopy of reggie-1/flotillin-2 in HeLa and N2a cells. In both cell types, the biarsenical staining reagent FlAsH/Lumio Green accumulated in active mitochondria and led to mitochondrial swelling. This is indicative of toxic side effects caused by arsenic, which should be considered when this labeling system is to be used in live cell imaging. Mitochondrial accumulation of FlAsH/Lumio Green was reversed by addition of low concentrations of thiol-containing reagents during labeling and a subsequent high stringency thiol wash. Both ethanedithiol and beta-mercaptoethanol proved to be effective. We therefore established a staining protocol using beta-mercaptoethanol as thiol binding site competitor resulting in a specific staining of tetracysteine-tagged reggie-1/flotillin-2 of adequate signal to noise ratio, so that the more toxic and inconvenient ethanedithiol could be avoided. Furthermore, we show that staining efficiency was greatly enhanced by introducing a second tetracysteine sequence in tandem.

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Mechanism of the Physiological Action of Rotenone

Cited by 20 publications

References 2 publications

Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

Hydroxylated Rotenoids Selectively Inhibit the Proliferation of Prostate Cancer Cells

Antiapoptotic activity of argon and xenon

Accumulation of FlAsH/Lumio Green in active mitochondria can be reversed by β-mercaptoethanol for specific staining of tetracysteine-tagged proteins

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