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

Research Inst Of Fox Chase Can Ctr, Philadelphia PA

Investigators

Abstract

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.