Colorectal Cancer (CRC) Prevention by Urolithin A in Rodent CRC models

根据美国癌症协会目前的估计，结直肠癌(CRC)是美国第三种最常见的癌症。美国2022年的结直肠癌病例数量为106180例结肠癌新发病例和44850例直肠癌新发病例。男性患结直肠癌的终生风险约为1/23(4.3%)，女性约为1/25(4.0%)。结直肠癌也是导致男性和女性癌症相关死亡的第三大原因，如果将男女人数加在一起，则是第二大最常见的癌症死亡原因。尽管多年来与生活方式相关的危险因素的改变、改进的CRC治疗和早期筛查有助于显著降低诊断率和总体死亡率，但在年轻人(55岁)中，CRC的发病率和死亡率一直在稳步上升。 家族性腺瘤性息肉病(FAP)是一种遗传性结直肠癌综合征，由APC肿瘤抑制基因的种系致病变异引起。FAP影响胃肠道，以数百至数千例癌前病变大肠息肉发展为特征。未经治疗的FAP患者有100%发生结直肠癌的风险。目前对FAP患者的护理标准包括频繁的结肠镜检查和发现晚期病变时预防性结肠切除术。然而，结肠切除术与显著的发病率相关，并且不能预防结肠外疾病的表现，包括胃息肉、十二指肠息肉和癌症，以及甲状腺癌。虽然一些临床研究表明，包括舒林酸、塞来昔布和二十碳五烯酸(EPA)在内的非类固醇抗炎药对FAP具有化学保护作用，但尚未有FDA批准的药物用于这一适应症。 随着人们对植物化学物质用于癌症治疗和预防的兴趣与日俱增，最近的研究表明，鞣花酸(EA)是一种存在于水果和蔬菜中的多酚及其微生物代谢产物，即尿脂素，在各种模型系统中抑制癌症相关途径和炎症。在所有的尿石素中，尿素A(UA)在临床前研究中被证明对癌症信号和相关的炎症性疾病具有很高的生物活性。最近的一份报告表明，口服UA通过诱导CD8+T细胞的有丝分裂和Wnt信号，抑制散发性结直肠癌小鼠模型的肠道肿瘤生长。口服UA也被证明可以通过激活Nrf2途径增强肠道屏障的完整性来预防TNBS和DSS诱导的C57BL/6小鼠结肠炎。在FAP的化学预防中利用mTOR抑制作用的研究越来越受到人们的关注。在FAP小鼠模型的肠息肉中，mTORC1通路被激活，该通路的激活被证明是APC缺陷的肠细胞增殖所必需的。在FAP小鼠模型中，用mTOR抑制剂雷帕霉素和伊波利莫斯阻断mTORC1通路可限制肠道肿瘤的发生、息肉的形成和降低死亡率。在基因工程胰腺癌拦截小鼠模型中，口服UA可减少mTOR信号的激活，抑制肿瘤生长，同时提高存活率。尿酸对多种疾病的影响已经在临床上进行了研究，包括衰老和骨骼肌功能。这些临床研究表明，直接补充尿酸的耐受性很好，在健康的成年人中可以产生较高的全身浓度。

Colorectal cancer (CRC) is the third most common cancer diagnosed in the United States as per the current estimates of The American Cancer Society. The number of CRC cases in the United States for 2022 are 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer. The lifetime risk of developing CRC is about 1 in 23 (4.3%) for men and 1 in 25 (4.0%) for women. CRC is also the third leading cause of cancer-related deaths in men and in women, and the second most common cause of cancer deaths when numbers from both sexes are combined. Although changes in lifestyle-related risk factors, improved CRC treatments, and early screening has helped reduce the diagnosis and overall death rates considerably over the years, there has been a steady increase in CRC incidence and death rate among younger adults (<55 years). Familial adenomatous polyposis (FAP) is a hereditary CRC syndrome caused by germline pathogenic variants of the APC tumor suppressor gene . FAP affects the gastrointestinal tract and is characterized by the development of hundreds to thousands of precancerous colorectal polyps. FAP patients when left untreated carry a 100% risk of developing CRC. The current standard of care for FAP patients includes frequent colonoscopies and prophylactic colectomy upon detection of advanced lesions. However, colectomy is associated with significant morbidity and does not prevent extra- colonic disease manifestations including gastric polyposis, duodenal polyposis and cancer, and thyroid cancer . While some clinical studies have demonstrated chemoprotective benefit of the NSAIDs including sulindac, celecoxib and eicosapentaenoic acid (EPA) for FAP, there are no FDA-approved drugs for this indication. In line with the growing interest in phytochemicals for cancer treatment and prevention , recent studies have demonstrated that Ellagic acid (EA), a polyphenol found in fruits and vegetables and its microbiota metabolites, the urolithins, suppress cancer associated pathways and inflammation in various model systems . Out of all urolithins, Urolithin A (UA) has been shown to display high bioactivity against cancer signaling and related inflammatory diseases in preclinical studies. A recent report demonstrated that oral administration of UA suppresses intestinal tumor growth in a sporadic CRC mouse model through induction of mitophagy and Wnt-signaling in CD8+ T cells. Oral administration of UA has also been shown to prevent TNBS- and DSS- induced colitis in C57BL/6 mice by enhancing the gut barrier integrity through activation of Nrf2 pathway. There has been a growing interest in the field on exploiting mTOR inhibition in chemoprevention of FAP. The mTORC1 pathway is activated in intestinal polyps of FAP mouse models, activation of which has been shown to be required for the proliferation of APC-deficient enterocytes . Blocking mTORC1 pathway with mTOR inhibitors rapamycin and everolimus limited intestinal tumor initiation, polyp formation, and reduced mortality in FAP mouse models. Oral administration of UA decreased activation of mTOR signaling and inhibited tumor growth while improving survival in a genetically engineered pancreatic cancer interception mouse model. UA has been studied clinically for effects on various diseases, including aging and skeletal muscle function . These clinical studies have shown that direct supplementation with UA is well tolerated and can yield high systemic concentrations in healthy adults.