Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition

Tomilov, Alexey; Allen, Sonia; Hui, Chun Kiu; Bettaieb, Ahmed; Cortopassi, Gino A

doi:10.1016/j.phrs.2018.09.024

Cited by 23 publications

(30 citation statements)

References 85 publications

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“…Our findings strengthen the evidence for a tight control of glucose transport in glioblastoma and suggest that combinations of drugs acting on GLUT/SLC2A [83] or interfering with their trafficking may be effective for glioblastoma treatment.…”

Section: Discussionsupporting

confidence: 84%

“…Many of the proteins involved in this pathway represent druggable targets. No small molecule inhibitor of SHC3 is known, but, recently, an inhibitor of the closely related protein SHC1 has been described [83]. Moreover, other proteins in the pathway, for instance PARP1, have highly specific inhibitors that are currently tested alone or in combination with temozolamide against glioblastoma, both in experimental models and human subjects [84][85][86].…”

Section: Discussionmentioning

confidence: 99%

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A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation

Azzalin

Brambilla

Arbustini

et al. 2020

Cells

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Adaptation of glioblastoma to caloric restriction induces compensatory changes in tumor metabolism that are incompletely known. Here we show that in human glioblastoma cells maintained in exhausted medium, SHC adaptor protein 3 (SHC3) increases due to down-regulation of SHC3 protein degradation. This effect is reversed by glucose addition and is not present in normal astrocytes. Increased SHC3 levels are associated to increased glucose uptake mediated by changes in membrane trafficking of glucose transporters of the solute carrier 2A superfamily (GLUT/SLC2A). We found that the effects on vesicle trafficking are mediated by SHC3 interactions with adaptor protein complex 1 and 2 (AP), BMP-2-inducible protein kinase and a fraction of poly ADP-ribose polymerase 1 (PARP1) associated to vesicles containing GLUT/SLC2As. In glioblastoma cells, PARP1 inhibitor veliparib mimics glucose starvation in enhancing glucose uptake. Furthermore, cytosol extracted from glioblastoma cells inhibits PARP1 enzymatic activity in vitro while immunodepletion of SHC3 from the cytosol significantly relieves this inhibition. The identification of a new pathway controlling glucose uptake in high grade gliomas represents an opportunity for repositioning existing drugs and designing new ones.

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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation

Azzalin

Brambilla

Arbustini

et al. 2020

Cells

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“…The pharmacological co-inducer of Hsp72, BGP-15, showed promising results in mdx mice by increasing muscle strength, architecture, and contractile function in the diaphragm when given at an early age [ 109 , 127 ]. Idebenone was created for the treatment of Alzheimer’s disease and could be considered an insulin sensitizer [ 128 ]. In mdx mice, idebenone improved running performance [ 129 ].…”

Section: Activation Of the Cellular Pathways In Skeletal Muscle Cementioning

confidence: 99%

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

Herbelet

Rodenbach

Paepe

et al. 2020

IJMS

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In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.

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“…In line with a protective activity against mitochondrial dysfunction, it was recently suggested that idebenone could also have anti-diabetic activity based on an insulin-sensitizing effect. This activity was suggested to be based on its ability to inhibit the interaction of p52Shc with the insulin receptor [10].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

et al. 2020

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Short-chain quinones (SCQs) have been identified as potential drug candidates against mitochondrial dysfunction, which is largely dependent on their reversible redox characteristics of the active quinone core. We recently synthesized a SCQ library of > 148 naphthoquinone derivatives and identified 16 compounds with enhanced cytoprotection compared to the clinically used benzoquinone idebenone. One of the major drawbacks of idebenone is its high metabolic conversion in the liver, which significantly restricts its therapeutic activity. Therefore, this study assessed the metabolic stability of the 16 identified naphthoquinone derivatives 1–16 using hepatocarcinoma cells in combination with an optimized reverse-phase liquid chromatography (RP-LC) method. Most of the derivatives showed significantly better stability than idebenone over 6 hours (p < 0.001). By extending the side-chain of SCQs, increased stability for some compounds was observed. Metabolic conversion from the derivative 3 to 5 and reduced idebenone metabolism in the presence of 5 were also observed. These results highlight the therapeutic potential of naphthoquinone-based SCQs and provide essential insights for future drug design, prodrug therapy and polytherapy, respectively.

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Idebenone is a cytoprotective insulin sensitizer whose mechanism is Shc inhibition

Cited by 23 publications

References 85 publications

A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation

A New Pathway Promotes Adaptation of Human Glioblastoma Cells to Glucose Starvation

Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents

Metabolic Stability of New Mito-Protective Short-Chain Naphthoquinones

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