Aldose reductase deficiency in mice prevents azoxymethane-induced colonic preneoplastic aberrant crypt foci formation

Abstract

Aldose reductase (AR; EC 1.1.1.21), an nicotinamide adenine dinucleotide phosphate-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. Herein, 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 inducible nitric oxide synthase and cyclooxygenase-2 proteins as well as their messenger RNA. AR inhibition or knockdown also significantly decreased the phosphorylation of protein kinase C (PKC) beta2 and nuclear factor kappa binding protein as well as expression of preneoplastic marker proteins such as cyclin D1 and beta-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.

Identification and expression analysis of the aldo–ketoreductase1-B10 gene in primary malignant liver tumours

“…Small interfering RNA-mediated knock down of AKR1B10 in cancer cells resulted in 50% decrease of cell growth rate and in decreased expression of preneoplastic marker proteins such as cyclin D1 and beta-catenin in mice colons [40,41].…”

Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice

“…Our recent studies in human colon cancer cells, human lens epithelial cells, vascular endothelial cells and vascular smooth muscle cells suggest that the polyol pathway enzyme, aldose reductase (AR), a member of aldo–keto reductase super family, is a regulator of ROS signals induced by growth factors, cytokines, chemokines, lipo-polysaccharide and high glucose (HG) [12–19]. Overexpression of AR has been shown in the tissues of diabetic and obese subjects [20,21].…”

Aldose Reductase Inhibition Prevents Hypoxia-induced Increase in Hypoxia-inducible Factor-1α (HIF-1α) and Vascular Endothelial Growth Factor (VEGF) by Regulating 26 S Proteasome-mediated Protein Degradation in Human Colon Cancer Cells

“…Most remarkably, in the nude mouse xenograft model, we have shown that inhibition of AR by AR siRNA as well as by the AR inhibitor fidarestat completely prevented progression of tumor growth of human colon cancer cells (SW480 and HT29) implanted in nude mice subcutaneously (21). Furthermore, recent results with azoxymethane model in male BALB/c mice showed that inhibition of AR by pharmacological inhibitor of AR as well as AR gene knockout in mice significantly prevented aberrant crypt foci formation and azoxymethane-induced expression of inflammatory markers, inducible nitric oxide synthase and cyclooxygenase-2 (Cox-2) and preneoplastic marker proteins, cyclin D1 and ␤-catenin and activation of NF-B in mouse colons (25). However, the involvement of AR in the hypoxia-mediated carcinogenesis is unknown.…”