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.