title: Aldose reductase inhibition suppresses azoxymethane-induced colonic premalignant lesions in C57BL/KsJ-db/db mice.
abstract: Type-2 diabetes and obesity-related metabolic abnormalities are major risk factors for the development of colon cancer. In the present study, we examined the effects of polyol pathway enzyme aldose reductase (AR) inhibitor, fidarestat, on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db obese mice. Our results indicate that fidarestat given in the drinking water caused a significant reduction in the total number of colonic premalignant lesions in the AOM treated obese mice. Further, the expression levels of PKC-β2, AKT, COX-2 and iNOS in the colonic mucosa of AOM-treated mice were significantly decreased by fidarestat. The serum levels of IL-1α, IP-10, MIG, TNF-α and VEGF are significantly suppressed in AOM + fidarestat treated obese mice. Fidarestat also decreased the expression of COX-2, iNOS, XIAP, survivin, β-catenin and NF-κB in high glucose-treated HT29 colon cancer cells. In conclusion, our results indicate that fidarestat inhibits the development of colonic premalignant lesions in an obesity-related colon cancer and is chemopreventive to colorectal carcinogenesis in obese individuals.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Ashish
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shoeb
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Tammali
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: Kota V
authors.initials: KV
authors.lastname: Ramana
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, USA. Electronic address: ssrivast@utmb.edu.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001397:Azoxymethane; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000201:enzymology / Q000235:genetics; D018384:Oxidative Stress / Q000187:drug effects; D011230:Precancerous Conditions / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D004791:Enzyme Inhibitors; D048289:Imidazolidines; D018836:Inflammation Mediators; C077139:fidarestat; D000449:Aldehyde Reductase; D001397:Azoxymethane
keywords: Aldose reductase; Colon cancer; Obesity; Oxidative stress and inflammation