Antitumor Drug Combretastatin-A4 Phosphate Aggravates the Symptoms of Dextran Sulfate Sodium-Induced Ulcerative Colitis in Mice.

Zhengshan Tang,Mao Ye,Dehui Xiong,Zi Wang,Xiaojuan Xiao,Lei Zhang,Jing Liu,Jianhui Song

doi:10.3389/fphar.2020.00339

Abstract

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) that causes long-lasting inflammation and ulcers in the innermost lining of the colon and rectum. Previous studies demonstrated that resveratrol suppresses colitis and colon cancer associated with colitis by improving glucose metabolism, but resveratrol use is limited by its low oral bioavailability. Combretastatin-A4 phosphate (CA4P) is a vascular-disrupting agent with antitumor activity. CA4P is structurally similar to resveratrol, but whether CA4P has the same effect as resveratrol on UC is not clear. In this study, we examined the pharmacological effects of CA4P administration on dextran sulfate sodium (DSS)-induced inflammation in a mouse model of UC. C57BL/6 mice were administered 2.5% DSS in the drinking water to induce acute UC. CA4P (11 mg/kg/d) was injected intraperitoneally daily. The Disease Activity Index (DAI) score and histological score were evaluated to determine the severity of UC. Colon tissues and blood samples were collected for histological analyses. The results show that CA4P plus DSS significantly decreased colon length (P < 0.05 versus DSS+PBS group) and body weight (P < 0.001 versus PBS group), while increased spleen weight (P < 0.01 versus DSS+PBS group), DAI score (P < 0.01 versus DSS+PBS group), and histological score (P < 0.01 versus DSS+PBS group). Moreover, CA4P exacerbated the pathological features of colitis and significantly increased proinflammatory cytokines (IL-1β, IL-6, TNF-α) and inflammatory cells (neutrophil, lymphocyte, monocyte). These findings reveal that CA4P aggravates the symptoms of DSS-induced UC and provide a key reference for the potential of CA4P as an anticancer drug.

Highlights

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) that causes long-lasting inflammation and sores in the innermost lining of large intestine and rectum (Deuring et al, 2013)
Mice with dextran sulfate sodium (DSS)-induced UC exhibited 13% body weight loss compared to mice in the Combretastatin-A4 phosphate (CA4P) and Phosphate-buffered saline (PBS) groups, whereas DSSinduced UC mice treated with 11 mg/kg/d CA4P exhibited 9%
We found that spleen weight increased in DSStreated mice, and this increase was more significant in the DSS +CA4P group than in the DSS+PBS group (Figure 3A)

Summary

Introduction

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) that causes long-lasting inflammation and sores (ulcers) in the innermost lining of large intestine (colon) and rectum (Deuring et al, 2013). The colonic mucosa of UC patients have increased levels of inflammatory cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, and IL-6 (Bouguen et al, 2011). The transcription factor nuclear factorkappa B (NF-kB) is responsible for the transactivation of these inflammatory cytokines, which results in the perpetuation of mucosal inflammation and promotes the inflammatory process in UC patients (Bonizzi and Karin, 2004; Atreya et al, 2008; Chen et al, 2018)

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