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Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone)

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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 journalArticle

Harvard

Kalra, S, Knatko, EV, Zhang, Y, Honda, T, Yamamoto, M & Dinkova-Kostova, AT 2012, 'Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy' Cancer Prevention Research, vol 5, no. 7, pp. 973-981.

APA

Kalra, S., Knatko, E. V., Zhang, Y., Honda, T., Yamamoto, M., & Dinkova-Kostova, A. T. (2012). Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy. Cancer Prevention Research, 5(7), 973-981doi: 10.1158/1940-6207.CAPR-12-0041

Vancouver

Kalra S, Knatko EV, Zhang Y, Honda T, Yamamoto M, Dinkova-Kostova AT. Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone): Implications for protection against UV radiation during thiopurine therapy. Cancer Prevention Research. 2012;5(7):973-981.

Author

Kalra, Sukirti; Knatko, Elena V.; Zhang, Ying; Honda, Tadashi; Yamamoto, Masayuki; Dinkova-Kostova, Albena T. / Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone) : Implications for protection against UV radiation during thiopurine therapy.

In: Cancer Prevention Research, Vol. 5, No. 7, 2012, p. 973-981.

Research output: Contribution to journalArticle

Bibtex - Download

@article{77c4c4062c044597b23bcd47a690dc66,
title = "Highly potent activation of Nrf2 by topical tricyclic bis(cyano enone)",
author = "Sukirti Kalra and Knatko, {Elena V.} and Ying Zhang and Tadashi Honda and Masayuki Yamamoto and Dinkova-Kostova, {Albena T.}",
year = "2012",
volume = "5",
number = "7",
pages = "973--981",
journal = "Cancer Prevention Research",
issn = "1940-6207",

}

RIS (suitable for import to EndNote) - Download

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 -

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