Abstract 6123: An indole compound MA-35 attenuates tumorigenesis in an inflammation-induced colon cancer model

Abstract

Abstract Backgrounds: In inflammatory bowel disease (IBD), chronic inflammation results in the development of colon cancer known as colitis-associated cancer (CAC), that is associated with tumor necrosis factor-α (TNF-α) signaling. In addition, intestinal fibrosis in IBD patients is a common clinical complication, which is promoted by transforming growth factor β1 (TGF-β1). In our previous study, mitochonic acid (MA-35), derivative of indole-3-acetic acid known as a plant hormone auxin, showed anti-TNF-α effect by inhibiting IκB kinase (IKK) phosphorylation and anti-TGF-β1 effect by inhibiting Smad3 phosphorylation in a renal fibrosis mouse model. Aim: To identify the possible mechanism of anti-tumor effects and anti-fibrotic effects of MA-35 using azoxymethane (AOM)/ dextran sulfate sodium (DSS)-induced CAC mouse model. Methods and Results: MA-35 was orally administered every day for 70 days in an AOM/DSS model with a feeding tube. There was no difference in weight loss between the AOM/DSS group and the AOM/DSS+MA-35 group, however the disease activity index score and the survival rate were improved by MA-35. MA-35 also blocked progression of the anemia and shortening of the colon induced by AOM/DSS. MA-35 surprisingly reduced the formation of tumors in the colon. In the microscopic evaluation, MA-35 reduced inflammation and fibrosis in area with dysplasia. Furthermore, the TNF-α mRNA level in the colon tended to be reduced and the interleukin 6, TGF-β1 and fibronectin 1 mRNA levels in the colon were significant reduced by MA-35. In western blotting, MA-35 inhibited IKK phosphorylation, and both NF-κB p65 phosphorylation and TNF-α as the downstream signals for p-IKK in human colorectal cancer cell line HT-29. Similarly, MA-35 inhibited Smad2/3 phosphorylation, and both fibronectin 1 and TGF-β1 as the downstream signals for p-Smad2/3 in HT-29. Conclusions: MA-35 inhibited the development of CAC by reducing inflammation and fibrosis in an AOM/DSS mouse model by inhibiting both TNF-α signaling and TGF-β1 signaling. MA-35 may be a potent therapeutic agent for inhibiting the development of CAC in IBD patients. Citation Format: Keigo Kanehara, Shinobu Ohnuma, Takeshi Naitoh, Michiaki Uuno, Takaaki Abe. An indole compound MA-35 attenuates tumorigenesis in an inflammation-induced colon cancer model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6123.