Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone) : Implications for protection against UV radiation during thiopurine therapy. / Kalra, Sukirti; Knatko, Elena V.; Zhang, Ying; Honda, Tadashi; Yamamoto, Masayuki; Dinkova-Kostova, Albena T.
In: Cancer Prevention Research, Vol. 5, No. 7, 2012, p. 973-981.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone)
T2 - Implications for protection against UV radiation during thiopurine therapy
A1 - Kalra,Sukirti
A1 - Knatko,Elena V.
A1 - Zhang,Ying
A1 - Honda,Tadashi
A1 - Yamamoto,Masayuki
A1 - Dinkova-Kostova,Albena T.
AU - Kalra,Sukirti
AU - Knatko,Elena V.
AU - Zhang,Ying
AU - Honda,Tadashi
AU - Yamamoto,Masayuki
AU - Dinkova-Kostova,Albena T.
PY - 2012
Y1 - 2012
N2 - 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. ©2012 AACR.
AB - 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. ©2012 AACR.
U2 - 10.1158/1940-6207.CAPR-12-0041
DO - 10.1158/1940-6207.CAPR-12-0041
M1 - Article
JO - Cancer Prevention Research
JF - Cancer Prevention Research
SN - 1940-6207
IS - 7
VL - 5
SP - 973
EP - 981
ER -