Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): implications for protection against UV radiation during thiopurine therapy.
Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation-induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility.
Division of Cancer Research, Medical Research Institute, University of Dundee, Dundee, Scotland, UK.
Sukirti
S
Kalra
Elena V
EV
Knatko
Ying
Y
Zhang
Tadashi
T
Honda
Masayuki
M
Yamamoto
Albena T
AT
Dinkova-Kostova
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000287:Administration, Topical; D000818:Animals; D002478:Cells, Cultured; D019610:Cytoprotection; D003598:Cytoskeletal Proteins / Q000502:physiology; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D051379:Mice; D008812:Mice, Hairless; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000528:radiation effects; D010616:Phenanthrenes / Q000008:administration & dosage* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D013866:Thioguanine / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C531972:TBE 31; D013866:Thioguanine