RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity

Probst, Brandon L.; Isaac, Treviño; Lyndsey, McCauley; Bumeister, Ron; Dulubova, Irina; Wigley, W. Christian; Ferguson, Deborah

doi:10.1371/journal.pone.0122942

Cited by 79 publications

(74 citation statements)

References 52 publications

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“…Unfortunately, the trial was stopped in 2012 due to a higher rate of cardiovascular events observed in the bardoxolone methyl group compared to placebo [208]. A new CDDO derivative (RTA 408) is already developed and being tested in clinical trials for a variety of non-neurodegenerative diseases, [209–212]. More recently, a clinical trial using RTA 408 was initiated for Friedreich's ataxia, a neurodegenerative condition responsible for cerebellar ataxia due to impaired production of the protein frataxin leading to profound deficiencies in mitochondrial respiration (ClinicalTrials.gov Identifier NCT02255435).…”

Section: Discussionmentioning

confidence: 99%

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

Johnson

2015

Free Radical Biology and Medicine

288

228

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The brain is very sensitive to changes in redox status; thus maintaining redox homeostasis in the brain is critical for the prevention of accumulating oxidative damage. Aging is the primary risk factor for developing neurodegenerative diseases. In addition to age, genetic and environmental risk factors have also been associated with disease development. The primary reactive insults associated with the aging process are a result of oxidative stress (OS) and nitrosative stress (NS). Markers of increased oxidative stress, protein and DNA modification, inflammation, and dysfunctional proteostasis have all been implicated in contributing to the progression of neurodegeneration. The ability of the cell to combat OS/NS and maintain a clearance mechanism for misfolded aggregating proteins determines whether or not it will survive. A critical pathway in this regard is the Nrf2 (nuclear factor erythroid 2-related factor 2)- antioxidant response element (ARE) pathway. Nrf2 activation has been shown to mitigate a number of pathologic mechanisms associated with Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This review will focus on the role of Nrf2 in these diseases and the potential for Nrf2 activation to mitigate disease progression.

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Section: Discussionmentioning

confidence: 99%

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

Johnson

2015

Free Radical Biology and Medicine

288

228

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“…Its oral formulation BG-12 has been recently approved for the treatment of multiple sclerosis (Linker et al, 2011). Other molecules able to stabilize Nrf2 are the quinone compound tert-butylhydroquinone (tBHQ) (Li et al, 2005) and the triterpenoids bardoxolone methyl (Dinkova-Kostova et al, 2005) and RTA 408 (Probst et al, 2015), both of which are currently in clinical trials.…”

Section: Nrf2 Activatorsmentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

143

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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“…The mechanism of action of bardoxolone consists of causing a reversible Michael addition of SH groups in Keap‐1 to attenuate Nrf2 degradation; as mentioned earlier, this is one of the main defence systems against redox stress. Some compounds, such as RTA 408, a novel synthetic triterpenoid related to bardoxolone, are cytotoxic in cancer cells by this mechanism (Probst et al ., ). It is therefore postulated that some of these compounds could act as ‘chemical irritants’ to activate body defences.…”

Section: Nrf2‐mediated Antioxidant Action As a Therapeutic Target In mentioning

confidence: 99%

Redox‐based therapeutics in neurodegenerative disease

McBean

López

Wallner

2016

British J Pharmacology

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This review describes recent developments in the search for effective therapeutic agents that target redox homeostasis in neurodegenerative disease. The disruption to thiol redox homeostasis in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis is discussed, together with the experimental strategies that are aimed at preventing, or at least minimizing, oxidative damage in these diseases. Particular attention is given to the potential of increasing antioxidant capacity by targeting the Nrf2 pathway, the development of inhibitors of NADPH oxidases that are likely candidates for clinical use, together with strategies to reduce nitrosative stress and mitochondrial dysfunction. We describe the shortcomings of compounds that hinder their progression to the clinic and evaluate likely avenues for future research. LINKED ARTICLESThis article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc Abbreviations 6(OH)DA, 6-hydroxydopamine; AD, Alzheimer's disease; ADME(T), absorption, distribution, metabolism and excretion/toxicity; ALS, amyotrophic lateral sclerosis; APP, amyloid precursor protein; ARE, antioxidant response element; ASSNAC, S-allylmercapto-N-acetyl cysteine; Aβ, amyloid-β; CA, carnosic acid; DMF, dimethylfumarate; EAE, experimental autoimmune encephalomyelitis; EpRE, electrophile response element; GCL, glutamate cysteine ligase; GR, glutathione reductase; Grx, glutaredoxin; GSK-3β, glycogen synthase kinase-3β; Keap1, Kelch-like ECH-associated protein-1; MMF, monomethylfumarate; MPTP, 1-methyl, 4-phenyl-1,2,3,6-tetrahydropyridine; MS, multiple sclerosis; MPO, myeloperoxidase; NAC, N-acetylcysteine; NACA, N-acetylcysteine amide; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase-1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; PD, Parkinson's disease; PS1, pre-senelin-1; RNS, reactive nitrogen species; SN, substantia nigra; Trx, thioredoxin; TrxR, thioredoxin reductase; xCT, functional subunit of the x c À exchanger Disruption of cerebral redox homeostasis is a common occurrence in a range of human neurodegenerative disorders, and although much is understood of mechanistic dysfunction, the gap between knowledge and the availability of effective therapies remains wide. In this review, we focus on the potential for developing therapeutic agents that promote the availability of thiol redox antioxidants or boost the antioxidant capacity of cells via stimulation of the transcription factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2). In addition, we discuss options for reducing ROS production by inhibition of NADPH oxidases (NOXs), limiting nitrative stress or targeting mitochondrial dysfunction. Other potential strategies for limiting oxidative stress in neurodegenerative disease include nutrient and vitamin supplementation and metal chelators, which are excluded from the discussion. These approaches are t...

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RTA 408, A Novel Synthetic Triterpenoid with Broad Anticancer and Anti-Inflammatory Activity

Cited by 79 publications

References 52 publications

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

Nrf2—a therapeutic target for the treatment of neurodegenerative diseases

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Redox‐based therapeutics in neurodegenerative disease

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