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Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway

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Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway. / Kalra, Sukirti; Zhang, Ying; Knatko, Elena V.; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T.

In: Cancer Prevention Research, Vol. 4, No. 10, 10.2011, p. 1665-1674.

Research output: Contribution to journalArticle

Harvard

Kalra, S, Zhang, Y, Knatko, EV, Finlayson, S, Yamamoto, M & Dinkova-Kostova, AT 2011, 'Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway' Cancer Prevention Research, vol 4, no. 10, pp. 1665-1674., 10.1158/1940-6207.CAPR-11-0137

APA

Kalra, S., Zhang, Y., Knatko, E. V., Finlayson, S., Yamamoto, M., & Dinkova-Kostova, A. T. (2011). Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway. Cancer Prevention Research, 4(10), 1665-1674. 10.1158/1940-6207.CAPR-11-0137

Vancouver

Kalra S, Zhang Y, Knatko EV, Finlayson S, Yamamoto M, Dinkova-Kostova AT. Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway. Cancer Prevention Research. 2011 Oct;4(10):1665-1674. Available from: 10.1158/1940-6207.CAPR-11-0137

Author

Kalra, Sukirti; Zhang, Ying; Knatko, Elena V.; Finlayson, Stewart; Yamamoto, Masayuki; Dinkova-Kostova, Albena T. / Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway.

In: Cancer Prevention Research, Vol. 4, No. 10, 10.2011, p. 1665-1674.

Research output: Contribution to journalArticle

Bibtex - Download

@article{c990431bc823414ea4efbd284922debe,
title = "Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway",
keywords = "TOPICAL PHOTODYNAMIC THERAPY, TRANSCRIPTION FACTOR NRF2, BLOOD LEUKOCYTE DNA, GLUTATHIONE TRANSFERASES, TRANSPLANT RECIPIENTS, GENE-EXPRESSION, MOUSE-LIVER, UVA LIGHT, CANCER, ENZYMES",
author = "Sukirti Kalra and Ying Zhang and Knatko, {Elena V.} and Stewart Finlayson and Masayuki Yamamoto and Dinkova-Kostova, {Albena T.}",
year = "2011",
doi = "10.1158/1940-6207.CAPR-11-0137",
volume = "4",
number = "10",
pages = "1665--1674",
journal = "Cancer Prevention Research",
issn = "1940-6207",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Oral Azathioprine Leads to Higher Incorporation of 6-Thioguanine in DNA of Skin than Liver: The Protective Role of the Keap1/Nrf2/ARE Pathway

A1 - Kalra,Sukirti

A1 - Zhang,Ying

A1 - Knatko,Elena V.

A1 - Finlayson,Stewart

A1 - Yamamoto,Masayuki

A1 - Dinkova-Kostova,Albena T.

AU - Kalra,Sukirti

AU - Zhang,Ying

AU - Knatko,Elena V.

AU - Finlayson,Stewart

AU - Yamamoto,Masayuki

AU - Dinkova-Kostova,Albena T.

PY - 2011/10

Y1 - 2011/10

N2 - <p>Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to UVA radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacologic activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4, an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy. Cancer Prev Res; 4(10); 1665-74. (C)2011 AACR.</p>

AB - <p>Azathioprine is a widely used anti-inflammatory, immunosuppressive, and anticancer agent. However, chronic treatment with this drug is associated with a profoundly increased risk (in certain cases by more than 100-fold) of developing squamous cell carcinoma of the skin. Incorporation of its ultimate metabolite, thio-dGTP, in DNA results in partial substitution of guanine with 6-thioguanine which, combined with exposure to UVA radiation, creates a source of synergistic mutagenic damage to DNA. We now report that oral treatment with azathioprine leads to a much greater incorporation of 6-thioguanine in DNA of mouse skin than liver. These higher levels of 6-thioguanine, together with the fact that the skin is constantly exposed to UV radiation from the sun, may be responsible, at least in part, for the increased susceptibility of this organ to tumor development. Genetic upregulation of the Keap1/Nrf2/ARE pathway, a major cellular regulator of the expression of a network of cytoprotective genes, reduces the incorporation of 6-thioguanine in DNA of both skin and liver following treatment with azathioprine. Similarly, pharmacologic activation of the pathway by the potent inducer sulforaphane results in lower 6-thioguanine incorporation in DNA and protects 6-thioguanine-treated cells against oxidative stress following exposure to UVA radiation. Protection is accompanied by increased levels of glutathione and induction of multidrug resistance-associated protein 4, an organic anion efflux pump that also exports nucleoside monophosphate analogues. Our findings suggest that activation of the Keap1/Nrf2/ARE pathway could reduce the risk for skin cancer in patients receiving long-term azathioprine therapy. Cancer Prev Res; 4(10); 1665-74. (C)2011 AACR.</p>

KW - TOPICAL PHOTODYNAMIC THERAPY

KW - TRANSCRIPTION FACTOR NRF2

KW - BLOOD LEUKOCYTE DNA

KW - GLUTATHIONE TRANSFERASES

KW - TRANSPLANT RECIPIENTS

KW - GENE-EXPRESSION

KW - MOUSE-LIVER

KW - UVA LIGHT

KW - CANCER

KW - ENZYMES

U2 - 10.1158/1940-6207.CAPR-11-0137

DO - 10.1158/1940-6207.CAPR-11-0137

M1 - Article

JO - Cancer Prevention Research

JF - Cancer Prevention Research

SN - 1940-6207

IS - 10

VL - 4

SP - 1665

EP - 1674

ER -

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