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

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

doi:10.3389/fphar.2020.00339

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

Front Pharmacol. 2020 Mar 24:11:339. doi: 10.3389/fphar.2020.00339. eCollection 2020.

Authors

Zhengshan Tang¹, Dehui Xiong², Jianhui Song², Mao Ye³, Jing Liu², Zi Wang¹, Lei Zhang⁴, Xiaojuan Xiao²

Affiliations

¹ Hepatobiliary and Enteric Surgery Research Center, Xiangya Hospital, Central South University, Changsha, China.
² School of Life Sciences & Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, China.
³ Molecular Science and Biomedicine Laboratory, State Key Laboratory for Chemo/Biosensing and Chemometrics, College of Biology, College of Chemistry and Chemical Engineering, Collaborative Innovation Center for Molecular Engineering for Theranostics, Hunan University, Changsha, China.
⁴ Department of Nephrology, The Second Xiangya Hospital of Central South University, Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, China.

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.

Keywords: combretastatin-A4 phosphate; dextran sodium sulfate; inflammatory cells; proinflammatory cytokines; ulcerative colitis.