Allopurinol Suppresses Azoxymethane-Induced Colorectal Tumorigenesis in C57BL/KsJ-db/db Mice

Junichi Kato,Hiroyasu Sakai,Taku Mizutani,Takashi Ibuka,Kimihiro Yamaguchi,Masahito Shimizu,Hiroshi Nakamura,Soranobu Ninomiya,Yohei Shirakami,Takuji Tanaka,Takayasu Ideta,Masaya Kubota

doi:10.3390/gidisord2040035

Abstract

Obesity and related metabolic disorders, including chronic inflammation and enhanced oxidative stress, are closely associated with the development and progression of colorectal cancer. Previous epidemiological studies have demonstrated that increased serum uric acid is associated with the risk for various types of cancer, including colon cancer. This study examined the effects of a xanthine oxidase inhibitor allopurinol, widely used as a uric acid lowering medicine, on colorectal tumorigenesis in obese mice. Male C57BL/KsJ-db/db mice were injected with azoxymethane (15 mg/kg body weight) and then received drinking water containing allopurinol (30 mg/kg body weight) for fourteen weeks. At the time of sacrifice, allopurinol treatment significantly inhibited the development of colonic premalignant lesions. In the allopurinol-treated group, cellular proliferation in colonic mucosa was significantly suppressed, which was evaluated by the expression of proliferating cell nuclear antigen. Allopurinol also inhibited macrophage infiltration in the adipose tissue and decreased the serum level of TNF-α. The values of oxidative stress markers were markedly decreased in the allopurinol-treated group compared to those in the control group. These findings suggest that allopurinol attenuated chronic inflammation and decreased oxidative stress, preventing the development of colonic pre-neoplastic lesions in obesity-associated colon tumorigenesis model.

Highlights

Colorectal cancer (CRC) is a serious health concern, with high mortality and an increasing incidence worldwide [1]
The relative kidney weight of the mice treated with AOM/allopurinol was significantly higher than that of the mice treated with AOM alone at the end of the experiment
We demonstrated that the xanthine oxidase inhibitor, allopurinol, which is widely used for lowering serum Uric acid (UA) levels, markedly suppressed the development of colorectal pre-neoplastic lesions induced by AOM in obese db/db mice

Summary

Introduction

Colorectal cancer (CRC) is a serious health concern, with high mortality and an increasing incidence worldwide [1]. Obesity and the related metabolic syndrome are known to be major risk factors for the development and progression of various malignancies, including CRC [2,3,4]. Metabolic syndrome comprises pathological conditions, such as high blood pressure, hyperglycemia, elevated serum triglyceride levels, and dyslipidemia [5]. While UA has potent antioxidant ability [6,7], elevated UA levels cause hyperuricemia, leading to gout. As serum UA levels increase with alcohol consumption and other dietary factors, hyperuricemia is considered to Gastrointest. As increased serum UA was reported to be associated with the exacerbation of steatohepatitis [22], decreased levels of ALT were thought to be related with reduced

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Discussion

Conclusion