Abstract
Chronic inflammation in the colorectum increases the risk of colorectal cancer development. Pentoxifylline, a medicine used for improving the circulation, has been reported to inhibit TNF-α production and to ameliorate inflammatory bowel disease and non-alcoholic steatohepatitis. In this study, we investigated the effects of pentoxifylline on inflammation-related colon tumorigenesis in a rodent model using Kyoto APC delta rats, which have APC mutation and are susceptible to colon carcinogenesis. Male Kyoto APC delta rats were treated with azoxymethane and dextran sodium sulfate, and were subsequently administered water, with or without pentoxifylline. At the end of the experiment, the development of colorectal tumor was significantly inhibited in the pentoxifylline group. The pentoxifylline treatment also lowered the levels of oxidative stress markers and mRNAs of pro-inflammatory cytokines, including TNF-α and IL-6, in the colon mucosa. The PCNA labeling index and the inflammation score were also decreased in the colon of rats in the pentoxifylline -treated group. We also used an endoscopy to observe the tumor progression and inflammation in the colon of rats, revealing that inflammation grade was significantly lower in pentoxifylline-treated group at several points during the experiment. These findings suggest that pentoxifylline treatment might be useful for chemoprevention of inflammation-related colon cancer.
Highlights
Colorectal cancer (CRC) is a common malignant disease with high mortality
The colorectal carcinogenesis model employed in this study, in which KAD rats were treated with AOM/dextran sodium sulfate (DSS), appears to be highly useful in mimicking human colorectal carcinogenesis in inflamed colorectum, because this animal model involves Apc mutation, carcinogen exposure, and tissue inflammation [16, 22, 23]
We focused on evaluating the effectiveness of PTX against CRC development, because it is reported to www.oncotarget.com have anti-cancer activities besides being anti-inflammatory [10, 13, 29]
Summary
Colorectal cancer (CRC) is a common malignant disease with high mortality. The clinical incidence of CRC has increased gradually over the past decade, and it is considered as one of the most important health issues worldwide [1]. 5-aminosalicylic acid (ASA), an anti-inflammatory drug, has been shown to protect against CRC development in patients with IBD [6, 7] This indicates that the agents targeting inflammation-associated molecules can suppress the development of IBD-related CRC. Based on the studies mentioned above, we expected that PTX might have anti-inflammatory properties, which can contribute in attenuating chronic inflammation in the bowel and suppress CRC development in inflamed colon. To confirm this hypothesis, the potential chemopreventive ability of PTX was examined in a colitis-related mouse CRC model induced by AOM and dextran sodium sulfate (DSS) [14, 15]. Endoscopic examination of rat colon was performed to investigate its usability in observing and evaluating tumor progression and inflammation in the colorectum
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