Topical application of the synthetic triterpenoid RTA 408 protects mice from radiation-induced dermatitis.
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.
a  Reata Pharmaceuticals, Inc., Irving, Texas 75063; and.
Scott A
SA
Reisman
Chun-Yue I
CY
Lee
Colin J
CJ
Meyer
Joel W
JW
Proksch
Stephen T
ST
Sonis
Keith W
KW
Ward
D000279:Administration, Cutaneous; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000032:analysis; D020405:Dermis / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004817:Epidermis / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D020869:Gene Expression Profiling; D006197:Hair / Q000254:growth & development; D018859:Hair Follicle / Q000187:drug effects / Q000528:radiation effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011855:Radiodermatitis / Q000473:pathology / Q000517:prevention & control*; D012883:Skin Ulcer / Q000209:etiology / Q000517:prevention & control; D014158:Transcription, Genetic / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D011837:Radiation-Protective Agents; D014315:Triterpenes; D003094:Collagen; C000589490:omaveloxolone