醛糖还原酶抑制剂非达司他阻止 Apc 小鼠高脂肪饮食诱导的肠道息肉。
Aldose Reductase Inhibitor, Fidarestat Prevents High-fat Diet-induced Intestinal Polyps in Apc Mice.
机构信息
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, Texas 77555, United States.
出版信息
Curr Cancer Drug Targets. 2018;18(9):905-911. doi: 10.2174/1568009617666170808105633.
BACKGROUND
Recent epidemiological and experimental studies have shown that obesity is a major risk factor for Colorectal Cancer (CRC). Regular intake of high fat-containing diet can promote obesity and metabolic syndrome by increasing the insulin resistance and inflammatory response which contribute to carcinogenesis. Previously, we have shown that inhibition of polyol pathway enzyme aldose reductase (AR) prevents carcinogens- and inflammatory growth factorsinduced CRC. However, the effect of AR inhibition on a high-fat diet (HFD)-induced formation of intestinal polyps in Apc-deficient Min (multiple intestinal neoplasia; ApcMin/+) mice is not known.
METHODS
We examined the effect of AR inhibitor, fidarestat on the HFD-induced formation of preneoplastic intestinal polyps in ApcMin/+ mice which is an excellent model of colon cancer.
RESULTS
APC mice fed for 12 weeks of HFD caused a significant increase in the formation of polyps in the small and large intestines and fidarestat given along with the HFD prevented the number of intestinal polyps. Fidarestat also decreased the size of the polyps in the intestines of HFDtreated APC Min mice. Further, the expression levels of beta-catenin, PCNA, PKC-β2, P-AKT, Pp65, COX-2, and iNOS in the small and large intestines of HFD-treated mice significantly increased, and AR inhibitor prevented it.
CONCLUSION
Our results thus suggest that fidarestat could be used as a potential chemopreventive drug for intestinal cancers due to APC gene mutations.
背景
最近的流行病学和实验研究表明，肥胖是结直肠癌（CRC）的一个主要危险因素。经常摄入高脂肪含量的饮食会通过增加胰岛素抵抗和炎症反应来促进肥胖和代谢综合征，从而促进癌变。此前，我们已经表明，抑制多元醇途径酶醛糖还原酶（AR）可预防致癌物和炎症生长因子诱导的 CRC。然而，AR 抑制剂对 Apc 缺陷 Min（多发性肠肿瘤；ApcMin/+）小鼠高脂肪饮食（HFD）诱导的肠息肉形成的影响尚不清楚。
方法
我们研究了 AR 抑制剂 fidarestat 对 ApcMin/+小鼠 HFD 诱导的前肿瘤性肠息肉形成的影响，ApcMin/+小鼠是结肠癌的优秀模型。
结果
HFD 喂养 12 周的 APC 小鼠会导致小肠和大肠中息肉的形成显著增加，而与 HFD 一起给予的 fidarestat 可防止肠息肉的形成数量。Fidarestat 还可减小 HFD 处理的 APC Min 小鼠肠道中息肉的大小。此外，HFD 处理的小鼠小肠和大肠中β-catenin、PCNA、PKC-β2、P-AKT、Pp65、COX-2 和 iNOS 的表达水平显著增加，而 AR 抑制剂可防止这种情况发生。
结论
因此，我们的研究结果表明，fidarestat 可能因其 APC 基因突变而成为一种用于预防肠道癌症的潜在化学预防药物。
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