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

ABSTRACT: Semi-synthetic triterpenoids are antioxidant inflammation modulator (AIM) compounds that inhibit tumor cell growth and metastasis. Compounds in the AIM class bind to Keap1 and attenuate Nrf2 degradation. In the nucleus, Nrf2 increases antioxidant gene expression and reduces pro-inflammatory gene expression. By increasing Nrf2 activity, AIMs reduce reactive oxygen species and inflammation in the tumor microenvironment, which reverses tumor-mediated immune evasion and inhibits tumor growth and metastasis. AIMs also directly inhibit tumor cell growth by modulating oncogenic signaling pathways, such as IKK?/NF-?B. Here, we characterized the in vitro antioxidant, anti-inflammatory, and anticancer activities of RTA 408, a novel AIM that is currently being evaluated in patients with advanced malignancies. At low concentrations (? 25 nM), RTA 408 activated Nrf2 and suppressed nitric oxide and pro-inflammatory cytokine levels in interferon-?-stimulated RAW 264.7 macrophage cells. At higher concentrations, RTA 408 inhibited tumor cell growth (GI50 = 260 ± 74 nM) and increased caspase activity in tumor cell lines, but not in normal primary human cells. Consistent with the direct effect of AIMs on IKK?, RTA 408 inhibited NF-?B signaling and decreased cyclin D1 levels at the same concentrations that inhibited cell growth and induced apoptosis. RTA 408 also increased CDKN1A (p21) levels and JNK phosphorylation. The in vitro activity profile of RTA 408 is similar to that of bardoxolone methyl, which was well-tolerated by patients at doses that demonstrated target engagement. Taken together, these data support clinical evaluation of RTA 408 for cancer treatment.

SUBMITTER: Probst BL

PROVIDER: S-EPMC4405374 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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

Probst Brandon L BL Trevino Isaac I McCauley Lyndsey L Bumeister Ron R Dulubova Irina I Wigley W Christian WC Ferguson Deborah A DA

PloS one 20150421 4

Semi-synthetic triterpenoids are antioxidant inflammation modulator (AIM) compounds that inhibit tumor cell growth and metastasis. Compounds in the AIM class bind to Keap1 and attenuate Nrf2 degradation. In the nucleus, Nrf2 increases antioxidant gene expression and reduces pro-inflammatory gene expression. By increasing Nrf2 activity, AIMs reduce reactive oxygen species and inflammation in the tumor microenvironment, which reverses tumor-mediated immune evasion and inhibits tumor growth and met ...[more]

PMID: 25897966

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Project description:Objective/Hypothesis: To assess the efficacy and mechanism of action of a novel approach to mitigate acute and chronic radiation toxicity in a validated animal model. We propose that synthetic triterpenoid RTA-408, an Nrf2 activator, activates additional protective pathways which stabilize soft tissue during radiation, thereby reducing necrosis and improves surgical outcomes in a subsequently created axial rotational flap. Methods: Experimental animal study utilizing Sprague-Dawley rats were divided into 3 cohorts: (i) radiation + DMSO (inert vehicle), (ii) radiation + RTA-408 (therapeutic drug), and (iii) no radiation + DMSO. Two main groups of rats were utilized in these experiments: (i) rotational flap experiment (n=40) and (ii) transcriptome analysis (n=9). In the first experiment all animals in the radiation cohorts underwent 40 Gy of radiation to the soft tissue of the abdomen. Then all three cohorts underwent surgery with construction of an inferior epigastric axial rotational flap, which was performed 30 days after resolution of acute injury from radiation in the radiation groups. Percentage of flap necrosis, the primary endpoint, was calculated by standardized measurement of tissue necrosis by blinded observers and vascular density measured by CD31 staining. In a second experiment, an additional three cohorts, with identical treatment as described above underwent serial punch biopsies of the abdominal skin before, during, and after radiation and drug/vehicle control treatment. Transcriptome analysis utilizing gene set enrichment analysis and digital PCR were performed at the various timepoints. Results: In the first experiment, 40 rats were divided into the three groups and underwent treatment accordingly. The average flap necrosis was 20% (95% CI, 16-45%) in the radiation control group, 3% (95% CI, 0-11%) in the non-irradiated control, and 3% (95% CI, 0.2-10%) in the radiation group treated with RTA-408. Vascular density was preserved in the treatment group as compared to the radiated control. Nine rats were included in the second experiment, and transcriptome analyses in the treatment group revealed robust activation of antioxidant pathways with induced expression of genes associated with hypoxia and adipogenesis/angiogenesis. Conclusions: Administration of RTA-408 during radiation treatment in a rat model resulted in transcriptome changes which appear to mitigate the toxic effects of radiation, preserving capillary networks and improving flap survival and tissue healing after subsequent surgery. Such reductions in toxicity may have broad implications for functional outcomes and salvage surgery following therapeutic irradiation.

Dataset Information

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

Publications

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

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