The indole compound MA-35 attenuates tumorigenesis in an inflammation-induced colon cancer model

Keigo Kanehara,Michiaki Unno,Takeshi Naitoh,Hideyuki Suzuki,Chitose Suzuki,Shinobu Ohnuma,Keisuke Sato,Hideaki Karasawa,Yoshitake Kanazawa,Shoji Kokubo,Takehiro Suzuki,Takaaki Abe

doi:10.1038/s41598-019-48974-9

Keigo Kanehara, Michiaki Unno + Show 10 more

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https://doi.org/10.1038/s41598-019-48974-9

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Journal: Scientific Reports	Publication Date: Sep 4, 2019
Citations: 17	License type: open-access

Affiliation: Tohoku University

Abstract

In inflammatory bowel disease, chronic inflammation results in the development of colon cancer known as colitis-associated cancer. This disease is associated with tumor necrosis factor-α (TNF-α) signaling. In addition, intestinal fibrosis is a common clinical complication that is promoted by transforming growth factor β1 (TGF-β1). In our previous study, MA-35 attenuated renal fibrosis by inhibiting both TNF-α and TGF-β1 signaling. This study aimed to identify the possible antitumor effects and antifibrotic effects of MA-35 using an AOM/DSS mouse model. MA-35 was orally administered every day for 70 days in the AOM/DSS mouse model. There was no difference in weight loss between the AOM/DSS group and the AOMDSS + MA-35 group, but the disease activity index score and the survival rate were improved by MA-35. MA-35 blocked the anemia and shortening of the colon induced by AOM/DSS. MA-35 reduced the macroscopic formation of tumors in the colon. In the microscopic evaluation, MA-35 reduced inflammation and fibrosis in areas 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 significantly reduced by MA-35. These results suggested that MA-35 inhibited AOM/DSS-induced carcinogenesis by reducing inflammation and fibrosis.

Highlights

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), is clinically characterized by dysregulated intestinal inflammation
Because Mitochonic acid 35 (MA-35) had no influence on body weight, liver weight, liver histology, serum ALT, and serum tumor necrosis factor-α (TNF-α) in our previous study[25], we hypothesized that the influence of MA-35 treatment alone may be negligible in mice
We reported that MA-35 inhibited TNF-α/IKK signaling and transforming growth factor β1 (TGF-β1)/Smad[3] signaling in the human hepatic stellate cell line LX-2 cells and rat kidney NRF-49F fibroblasts[25]

Summary

Introduction

Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn’s disease (CD), is clinically characterized by dysregulated intestinal inflammation. Several investigators demonstrated TNF-α inhibition in the same animal model prevents the www.nature.com/scientificreports/. We recently found that MA-35 showed anti-TNF-α activity mediated by inhibiting IκB kinase (IKK) phosphorylation, which attenuated the hepatic and renal inflammation in the mice[25]. MA-35 concurrently showed an anti-TGF-β1 effect by inhibiting Smad[3] phosphorylation and reducing the Smad3-driven expression of fibrotic genes. These dual blockades of TNF-α and TGF-β1 attenuated inflammation and renal fibrosis[25]. Because TNF-α plays a key role in the development of CAC, we examined the anti-tumor effect of MA-35 by inhibiting TNF-α signaling in AOM/DSS mouse model. The anti-fibrotic effect of MA-35 by inhibiting TGF-β1 signaling was examined

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