Shirakami Yohei, Kochi Takahiro, Kubota Masaya, Sakai Hiroyasu, Ibuka Takashi, Yoshimi Kazuto, Kuramoto Takashi, Tanaka Takuji, Shimizu Masahito, Seishima Mitsuru
Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
Oncotarget. 2018 Sep 21;9(74):33972-33981. doi: 10.18632/oncotarget.26119.
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.
结肠慢性炎症会增加患结直肠癌的风险。己酮可可碱是一种用于改善血液循环的药物，据报道它能抑制肿瘤坏死因子-α（TNF-α）的产生，并改善炎症性肠病和非酒精性脂肪性肝炎。在本研究中，我们使用具有APC突变且易患结肠癌的京都APCδ大鼠，在啮齿动物模型中研究了己酮可可碱对炎症相关结肠肿瘤发生的影响。雄性京都APCδ大鼠用氧化偶氮甲烷和葡聚糖硫酸钠处理，随后给予含或不含己酮可可碱的水。实验结束时，己酮可可碱组的结直肠肿瘤发生明显受到抑制。己酮可可碱治疗还降低了结肠黏膜中氧化应激标志物以及促炎细胞因子（包括TNF-α和白细胞介素-6）的mRNA水平。己酮可可碱治疗组大鼠结肠的增殖细胞核抗原（PCNA）标记指数和炎症评分也降低。我们还使用内窥镜观察大鼠结肠中的肿瘤进展和炎症情况，发现在实验过程中的几个时间点，己酮可可碱治疗组的炎症分级明显较低。这些发现表明，己酮可可碱治疗可能有助于化学预防炎症相关的结肠癌。
