CU06-1004 inhibits the progression of chronic colitis and colitis-associated colorectal cancer by suppressing inflammation

Dongyeop Kim¹Yeomyeong Kim²Haiying Zhang²Ye-Seul Kim¹Minyoung Noh²Cho-Rong Bae²Young-guen Kwon^1,2Sang-Jun Ha^1,3*

• ¹Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea
• ²Department of Bio Research, Curacle Co. Ltd, Seoul, Republic of Korea
• ³Brain Korea 21 (BK21) FOUR Program, Yonsei Education & Research Center for Biosystems, Yonsei University, Seoul, Republic of Korea

Background: Ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), is a chronic inflammatory disorder of the colon. Chronic intestinal inflammation plays a critical role in the increased risk of developing colitis-associated cancer (CAC). CU06-1004, an endothelial dysfunction blocker, can alleviate acute colitis by suppressing inflammation and regulating colonic vascular dysfunction. However, whether CU06-1004 suppresses chronic intestinal inflammation and prevents the development of CAC remains unclear. Methods: In this study, we investigated the protective effects of CU06-1004 by suppressing inflammation in both the dextran sulfate sodium (DSS)-induced chronic colitis model and the azoxymethane (AOM)/DSS-induced colorectal cancer mouse models. We evaluated the expression of key pro-inflammatory cytokines, assessed histological characteristics in the animals, and examined the expression of key genes associated with inflammation. Results: In the DSS-induced chronic colitis model, our results showed that CU06-1004 treatment suppressed inflammation, as evidenced by disease activity index scores, colon length, colon damage, and histological analysis. Furthermore, CU06-1004 administration reduced the levels of various inflammatory cytokines and factors (tumor necrosis factor-α, interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase), decreased immune cell infiltration (F4/80+ macrophages and CD177+ neutrophils), and alleviated inflammation by inhibiting vascular adhesion molecules. Moreover, in the AOM/DSS-induced colorectal cancer model as well, CU06-1004 significantly reduced the severity of colitis. CU06-1004 treatment also significantly reduced both the number and size of AOM/DSS-induced colorectal tumors, suppressed inflammation, and inhibited the malignant proliferation of epithelial cells. Additionally, CU06-1004 treatment downregulated the expression of the key colorectal cancer marker β-catenin and its target gene c-Myc in AOM/DSS-induced mice, thereby inhibiting tumor growth. Conclusion: Our findings suggest that CU06-1004 inhibits inflammation-induced tumorigenesis by modulating the inflammatory response in the colon. Consequently, CU06-1004 could represent a promising therapeutic candidate for the prevention of colorectal cancer through modulation of inflammation.