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Carcinogenesis Advance Access published online on November 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn246
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Aldose Reductase Deficiency in Mice Prevents Azoxymethane –Induced Colonic Preneoplastic Aberrant Crypt Foci Formation

Ravinder Tammali1, Aramati BM Reddy1, Kota V Ramana1, J Mark Petrash2 and Satish K Srivastava1,*

1 From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-0647
2 Departments of Ophthalmology and Visual Science, and Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA

* To whom correspondence should be addressed: Tel: (409) 772-3926; Fax: (409) 772-9679; Email: ssrivast{at}utmb.edu

Aldose reductase (AR; EC 1.1.1.21 [EC] ), a NADPH dependent aldo-keto reductase, has been shown to be involved in oxidative stress signaling initiated by inflammatory cytokines, chemokines and growth factors. Recently, we have shown that inhibition of this enzyme prevents the growth of colon cancer cells in vitro as well as in nude mice xenografts. Here in, we investigated the mediation of AR in the formation of colonic preneoplastic aberrant crypt foci (ACF) using azoxymethane (AOM) –induced colon cancer mice model. Male BALB/c mice were administrated with AOM without or with AR inhibitor, sorbinil and at the end of the protocol, all the mice were euthanized and colons were evaluated for ACF formation. Administration of sorbinil significantly lowered the number of AOM-induced ACF. Similarly, AR null mice administered with AOM demonstrated significant resistance to ACF formation. Furthermore, inhibition of AR or knockout of AR gene in the mice significantly prevented AOM-induced expression of iNOS and Cox-2 proteins as well as their mRNA. AR inhibition or knockdown also significantly decreased the phosphorylation of PKCβ2 and NF-{kappa}B as well as expression of preneoplastic marker proteins such as cyclin D1 and β-catenin in mice colons. Our results suggest that AR mediates the formation of ACF in AOM-treated mice and thereby inhibition of AR could provide an effective chemopreventive approach for the treatment of colon cancer.

Key Words: Aldose reductase • knockout mice • colon cancer • ACF • AOM

Received June 23, 2008; revised September 26, 2008; accepted October 21, 2008.


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