The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation

Liu, Xiaobin; Ward, Keith W.; Xavier, Christy; Jann, Jamieson; Clark, Abbot F.; Pang, Iok‐Hou; Wu, Hongli

doi:10.1016/j.redox.2015.12.005

Cited by 64 publications

(38 citation statements)

References 43 publications

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“…We hypothesized that upregulation of NRF2 and NRF2 driven antioxidant enzymes might be part of the protective mechanism induced by AβPP overexpression in MC. Consistent with our work and this hypothesis, recent studies have reported that: 1) NRF2-deficient mice develop AMD-like retinal pathology with photoreceptor loss [52]; 2) upregulation and activation of NRF2 protect RPE cells [53] and photoreceptors [54,55] against oxidative stress in in vitro and in vivo models of retinal degeneration; 3) pharmacological activation of NRF2 inhibited gliosis of MC in an in vivo model of retinal degeneration and increased NRF2 responsive antioxidants in cultured MC [56]. Interestingly, several studies also showed pivotal role for NRF2 in the brain astrocytes.…”

Section: Aβpp Induced the Er-associated Degradation Of Misfolded Protsupporting

confidence: 92%

AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

Chalour

Maoui

Rat

et al. 2018

CAR

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Section: Aβpp Induced the Er-associated Degradation Of Misfolded Protsupporting

confidence: 92%

AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

Chalour

Maoui

Rat

et al. 2018

CAR

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“…Nrf2 is activated when cells are exposed to oxidative stress. To date, a wide variety of Nrf2 activators have been reported [10] , [11] , [12] , [13] . Among them, a highly effective novel triterpenoid, RS9, was recently isolated as an Nrf2-specific activator [12] , [14] .…”

Section: Introductionmentioning

confidence: 99%

Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival

et al. 2018

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Non-exudative age-related macular degeneration (AMD) is mainly caused by the accumulation of lipofuscin and drusen on the retinal pigment epithelium (RPE). Both oxidative stress and autophagic dysfunction accelerate the deposition of lipofuscin at the RPE. One of the key regulators in the response against oxidative stress is the NF-E2-Related Factor 2 (Nrf2)-kelch like ECH associated protein 1 (Keap1) axis, which is also closely associated with the autophagy pathway. Nrf2 activation upregulates the expression levels of certain anti-oxidative enzymes [e.g. Heme oxygenase-1 (HO-1)], which attenuates oxidative damage. However, until now, the relationship between cytoprotective effects of Nrf2 activation and autophagic degradation remain unclear. To address these questions, we investigated the effects of a novel Nrf2 activator, RS9, on RPE damage. We found that RS9 protected ARPE-19 cells against NaIO3-induced oxidative damage, and that the protective effects of RS9 were inhibited by co-treatment with zinc protoporphyrin, an HO-1 inhibitor. Next, we examined the involvement of autophagic degradation in the protective effects of RS9. Co-treatment with RS9 and chloroquine, a lysosomal acidification inhibitor, inhibited the protective effect. Furthermore, western blotting and immunostaining showed that RS9 accelerated autophagy flux and induced transient upregulation of p62 [also known as sequestosome 1 (SQSTM1)]. Co-treatment with chloroquine and RS9 also inhibited the degradation of autophagosomes. Transient upregulation of SQSTM1 by RS9 was unaltered by HO-1 knockdown using siRNA. RS9 and chloroquine had the same actions in light damaged adult zebrafish retina as those in vitro. In conclusion, we clarified the relationship between acceleration of the autophagy pathway and the cytoprotective effects of Nrf2 activation in RPE cells and zebrafish retina. These findings indicated that Nrf2 activation could be a promising therapeutic approach for non-exudative AMD by supporting RPE maintenance.

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“… 11 – 13 Along these lines, pretreatment with omaveloxolone also protects retinal pigment epithelial cells from oxidative destruction via activation of Nrf2. 14 Based on in vitro and animal studies, omaveloxolone exhibited high protein binding with extensive tissue distribution, making it a suitable potential oncologic agent.…”

Section: Introductionmentioning

confidence: 99%

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

Creelan¹,

Gabrilovich²,

Gray³

et al. 2017

OTT

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BackgroundOmaveloxolone is a semisynthetic oleanane triterpenoid that potently activates Nrf2 with subsequent antioxidant function. We conducted a first-in-human Phase I clinical trial (NCT02029729) with the primary objectives to determine the appropriate dose for Phase II studies, characterize pharmacokinetic and pharmacodynamic parameters, and assess antitumor activity.MethodsOmaveloxolone was administered orally once daily continuously in a 28-day cycle for patients with stage 4 relapsed/refractory melanoma or non-small cell lung cancer. An accelerated titration design was employed until a grade 2-related adverse event (AE) occurred. A standard 3+3 dose escalation was employed. Single-dose and steady-state plasma pharmacokinetics of the drug were characterized. Downstream Nrf2 activation was assessed in peripheral blood mononuclear cells by quantification of target gene mRNA expression.ResultsOmaveloxolone was tested at four dose levels up to 15 mg given orally once daily. No dose-limiting toxicities were detected, and the maximum tolerated dose was not determined. All drug-related AEs were either grade 1 or 2 in severity, and none required clinical action. The most common drug-related AEs were elevated alkaline phosphatase (18%) and anemia (18%). No drug interruptions or reductions were required. Omaveloxolone was rapidly absorbed and exhibited proportional increases in exposure across dose levels. With some exceptions, an overall trend toward time-dependent and dose-dependent activation of Nrf2 antioxidant genes was observed. No confirmed radiologic responses were seen, although one lung cancer subject did have stable disease exceeding 1 year.ConclusionsOmaveloxolone has favorable tolerability at biologically active doses, although this trial had a small sample size which limits definitive conclusions. These findings support further investigation of omaveloxolone in cancer.

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The novel triterpenoid RTA 408 protects human retinal pigment epithelial cells against H2O2-induced cell injury via NF-E2-related factor 2 (Nrf2) activation

Abstract: Graphical abstract

Cited by 64 publications

References 43 publications

AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

AβPP-induced UPR Transcriptomic Signature of Glial Cells to Oxidative Stress as an Adaptive Mechanism to Preserve Cell Function and Survival

Transient acceleration of autophagic degradation by pharmacological Nrf2 activation is important for retinal pigment epithelium cell survival

Safety, pharmacokinetics, and pharmacodynamics of oral omaveloxolone (RTA 408), a synthetic triterpenoid, in a first-in-human trial of patients with advanced solid tumors

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