Abstract
Obesity and its related metabolic abnormalities, including enhanced oxidative stress and chronic inflammation, are closely related to colorectal tumorigenesis. Pentoxifylline (PTX), a methylxanthine derivative, has been reported to suppress the production of tumor necrosis factor (TNF)-α and possess anti-inflammatory properties. The present study investigated the effects of PTX on the development of carcinogen-induced colorectal premalignant lesions in obese and diabetic mice. Male C57BL/KsJ-db/db mice, which are severely obese and diabetic, were administered weekly subcutaneous injections of the colonic carcinogen azoxymethane (15 mg/kg body weight) for four weeks and then received drinking water containing 125 or 500 ppm PTX for eight weeks. At the time of sacrifice, PTX administration markedly suppressed the development of premalignant lesions in the colorectum. The levels of oxidative stress markers were significantly decreased in the PTX-treated group compared with those in the untreated control group. In PTX-administered mice, the mRNA expression levels of cyclooxygenase (COX)-2, interleukin (IL)-6, and TNF-α, and the number of proliferating cell nuclear antigen (PCNA)-positive cells in the colonic mucosa, were significantly reduced. These observations suggest that PTX attenuated chronic inflammation and oxidative stress, and prevented the development of colonic tumorigenesis in an obesity-related colon cancer model.
Highlights
The increasing worldwide prevalence of obesity presents a serious health issue owing to the elevated risk of medical problems, including diabetes mellitus, ischemic heart disease, stroke, and various types of cancers [1,2]
Administration of the xanthophyll carotenoid astaxanthin, and an angiotensin-converting enzyme inhibitor, suppressed the early phase of colorectal carcinogenesis in experimental obese rodents by the attenuation of inflammation and oxidative stress [15]. These reports suggested that targeting obesity-related metabolic abnormalities such as chronic inflammation and oxidative stress was a promising strategy for the prevention of colorectal cancer (CRC) in obese individuals [4]
This study demonstrated the preventive effects of PTX on the early phase of obesity-related colorectal carcinogenesis
Summary
The increasing worldwide prevalence of obesity presents a serious health issue owing to the elevated risk of medical problems, including diabetes mellitus, ischemic heart disease, stroke, and various types of cancers [1,2]. Administration of the xanthophyll carotenoid astaxanthin, and an angiotensin-converting enzyme inhibitor, suppressed the early phase of colorectal carcinogenesis in experimental obese rodents by the attenuation of inflammation and oxidative stress [15] These reports suggested that targeting obesity-related metabolic abnormalities such as chronic inflammation and oxidative stress was a promising strategy for the prevention of CRC in obese individuals [4]. A useful preclinical rodent model has been developed in C57BL/KsJ-db/db (db/db) mice, which have a leptin receptor mutation and display hyperphagic obesity and diabetes [22], after the injection of a colonic carcinogen azoxymethane (AOM) This appears to be a feasible model to investigate obesity-related colorectal carcinogenesis [14,23,24,25]. We investigated the effects of PTX on the development of premalignant lesions in the mouse model of obesity-related and AOM-induced colorectal carcinogenesis
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