Topical Application of the Synthetic Triterpenoid RTA 408 Protects Mice from Radiation-Induced Dermatitis

Abstract

Free radicals produced during cancer radiotherapy often leads to dermatitis, with the insult ranging from mild erythema to moist desquamation and ulceration. This toxicity can be dose limiting and promote chronic complications, such as fibrosis and wound recurrence. The purpose of this study was to evaluate if RTA 408, a synthetic triterpenoid that potently activates the antioxidative transcription factor Nrf2 and inhibits the proinflammatory transcription factor nuclear factor-kappa b (NF-κB), could protect skin from radiation-induced dermatitis. Mice were irradiated (10 Gy/day) on days 0-2 and 5-7, and RTA 408 (0.01%, 0.1% and 1.0%) was topically applied once daily starting on day 5 or up to day 40. Dermatitis severity was evaluated using a scale ranging from 0 (normal) to 5 (frank ulceration), as well as histologically. The mRNA expression of Nrf2 and NF-κB target genes in skin was also evaluated. RTA 408 (0.01%, 0.1% and 1.0%) reduced the percentage of animal-days with scores ≥2 by 11%, 31% and 55% and scores ≥3 by 16%, 60% and 80%, respectively. Dose-dependent improvements in the appearance of skin were also manifestly visible, with RTA 408 at 1.0% eliciting a normal macroscopic appearance by the end of the treatment period on day 40, including substantial hair regrowth. Moreover, 1.0% RTA 408 markedly reduced epidermal and collagen thickening, prevented dermal necrosis and completely alleviated skin ulcers. These improvements were associated with significant increases in Nrf2 target genes and significant decreases in NF-κB target genes. Together, these data indicate that RTA 408 represents a potentially promising new therapy for the treatment of radiation-induced dermatitis.

Radiation Protection of the Gastrointestinal Tract and Growth Inhibition of Prostate Cancer Xenografts by a Single Compound

“…Nrf-2 activation by the CDDO derivatives CDDO-ethylamide (EA) and CDDO-ME has been proposed to improve survival of irradiated mice (44). We observed that topical application of RTA 408 markedly reduced radiation dermatitis in mice associated with significant increases in Nrf2 target genes and significant decreases in NF-kB target genes (45). Interestingly, radiation protection of normal prostate epithelial cells contrasted by growth inhibition of prostate cancer cells in vivo has been very recently described for dimethylamineparthenolide (DMAPT) (46).…”

Novel Nrf2 activators from microbial transformation products inhibit blood–retinal barrier permeability in rabbits

“…These compounds have been reported to inhibit inflammatory mediators, induce cell differentiation and induce apoptosis of cancer cells in vitro and also to be effective in many pathological models (Liby and Sporn, ). In addition, one of the CDDO scaffolds, RTA 408, is currently being tested in clinical trials for the treatment of, for example, radiation‐induced dermatitis (http://ClinicalTrials.gov identifier: NCT02142959) (Reisman et al ., ).…”

Full Length Interleukin 33 Aggravates Radiation-Induced Skin Reaction

“…Starting on day 2 and every second day thereafter, animals were scored in a blinded manner for ear thickness and dermatitis. Dermatitis scoring of all animals was performed analog to the Cancer Therapy Evaluation Program scale (31, 32). Briefly, dermatitis scoring ranged from: 0 = normal, no changes; 1 = mild erythema; 2 = moderate to severe erythema, slight desquamation; 3 = desquamation of 25–50% of irradiated area; 4 = desquamation of >50% of irradiated area; to 5 = frank ulcer.…”