The Triterpenoid RTA 408 is a Robust Mitigator of Hematopoietic Acute Radiation Syndrome in Mice

Goldman, Devorah C.; Alexeev, Vitali; Lash, Elizabeth; Guha, Chandan; Rodeck, Ulrich; Fleming, William H.

doi:10.1667/rr13900.1

Cited by 14 publications

(12 citation statements)

References 25 publications

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“…Purified SFN has been safely used in many clinical trials for various human diseases, including autism and recurrence of prostate cancer [ 22 , 41 ]. A Bardoxolone Methyl derivative, RTA 408, has shown promise as an anti-inflammatory agent, as well as a mitigator of radiation-induced impaired hematopoietic cell proliferation [ 42 , 43 ]. Additionally, a combination of NRF2 inducers and statins has been proposed to additively increase fetal hemoglobin in erythroid cells, with encouraging preclinical results [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

et al. 2016

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Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide. Our previous results indicate that the reduced oxidative stress capacity of sickle erythrocytes may be caused by decreased expression of NRF2 (Nuclear factor (erythroid-derived 2)-like 2), an oxidative stress regulator. We found that activation of NRF2 with sulforaphane (SFN) in erythroid progenitors significantly increased the expression of NRF2 targets HMOX1, NQO1, and HBG1 (subunit of fetal hemoglobin) in a dose-dependent manner. Therefore, we hypothesized that NRF2 activation with SFN may offer therapeutic benefits for SCD patients by restoring oxidative capacity and increasing fetal hemoglobin concentration. To test this hypothesis, we performed a Phase 1, open-label, dose-escalation study of SFN, contained in a broccoli sprout homogenate (BSH) that naturally contains SFN, in adults with SCD. The primary and secondary study endpoints were safety and physiological response to NRF2 activation, respectively. We found that BSH was well tolerated, and the few adverse events that occurred during the trial were not likely related to BSH consumption. We observed an increase in the mean relative whole blood mRNA levels for the NRF2 target HMOX1 (p = 0.02) on the last day of BSH treatment, compared to pre-treatment. We also observed a trend toward increased mean relative mRNA levels of the NRF2 target HBG1 (p = 0.10) from baseline to end of treatment, but without significant changes in HbF protein. We conclude that BSH, in the provided doses, is safe in stable SCD patients and may induce changes in gene expression levels. We therefore propose investigation of more potent NRF2 inducers, which may elicit more robust physiological changes and offer clinical benefits to SCD patients.Trial Registration: ClinicalTrials.gov NCT01715480

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Section: Discussionmentioning

confidence: 99%

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

et al. 2016

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“…It is currently under clinical investigation for the prevention of cataract surgery-induced loss of corneal endothelial cells, prevention of radiation-induced dermatitis in breast cancer patients undergoing radiotherapy, treatment of solid tumors including melanoma and lung cancer, and treatment of Friedreich’s Ataxia and mitochondrial myopathies. Previous studies have demonstrated that RTA 408 has significant cytoprotective effects attributed to the activation of the Nrf2 pathway [16] , [17] , [18] , [19] . The present study investigates the connection between RTA 408 and the Nrf2 pathway as well as multiple antioxidant enzymes in RPE cells.…”

Section: Introductionmentioning

confidence: 98%

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

et al. 2016

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“…It is currently under clinical investigation for the prevention of radiation-induced dermatitis in breast cancer patients undergoing radiotherapy (ClinicalTrials.gov Identifier: NCT02142959) [28], the treatment of solid tumors including melanoma and lung cancer (ClinicalTrials.gov Identifier:NCT02029729) [29],intervention of Friedreich's Ataxia (ClinicalTrials.gov Identifier:NCT02255435) and mitochondrial myopathies (ClinicalTrials.gov Identifier: NCT02255422) [30,31]. Previous studies have demonstrated that RTA-408 has significant cytoprotective effects based on its ability to activate the Nrf2 pathway [32]. A recent study also demonstrated that the neuroprotective and disease-modifying effects of RTA-408 could be attributed to Keap1 inhibition [33].…”

Section: Introductionmentioning

confidence: 99%

The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling

Sun¹,

Xie²,

Hu³

et al. 2020

Redox Biology

117

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The dysregulation of ROS production and osteoclastogenesis is involved in the progress of osteoporosis. To identify novel and effective targets to treat this disease, it is important to explore the underlying mechanisms. In our study, we firstly tested the effect of the Nrf2 activator RTA-408, a novel synthetic triterpenoid under clinical investigation for many diseases, on osteoclastogenesis. We found that it could inhibit osteoclast differentiation and bone resorption in a time- and dose-dependent manner. Further, RTA-408 enhanced the expression and activity of Nrf2 and significantly suppressed RANKL-induced reactive oxygen species (ROS) production. Nrf2 regulates the STING expression and STING induces the production of IFN-β. Here, we found that RTA-408 could suppress STING expression, but that it does not affect Ifnb1 expression. RANKL-induced degradation of IκBα and the nuclear translocation of P65 was suppressed by RTA-408. Although this compound was not found to influence STING–IFN-β signaling, it suppressed the RANKL-induced K63-ubiquitination of STING via inhibiting the interaction between STING and the E3 ubiquitin ligase TRAF6. Further, adenovirus-mediated STING overexpression rescued the suppressive effect of RTA-408 on NF-κB signaling and osteoclastogenesis. In vivo experiments showed that this compound could effectively attenuate ovariectomy (OVX)-induced bone loss in C57BL/6 mice by inhibiting osteoclastogenesis. Collectively, we show that RTA-408 inhibits NF-κB signaling by suppressing the recruitment of TRAF6 to STING, in addition to attenuating osteoclastogenesis and OVX-induced bone loss in vivo, suggesting that it could be a promising candidate for treating osteoporosis in the future.

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The Triterpenoid RTA 408 is a Robust Mitigator of Hematopoietic Acute Radiation Syndrome in Mice

Cited by 14 publications

References 25 publications

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

Phase 1 Study of a Sulforaphane-Containing Broccoli Sprout Homogenate for Sickle Cell Disease

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

The Nrf2 activator RTA-408 attenuates osteoclastogenesis by inhibiting STING dependent NF-κb signaling

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