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

Abstract

Ulcerative colitis (UC) is an idiopathic inflammatory bowel disease (IBD) that causes longlasting 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-1b, IL-6, TNF-a) 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.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…significantly reduced body weight, colorectal length and increased disease activity index in DSS-induced mice. mRNA expression of TNF-α, IL-6 and IL-1β in colon tissue was found higher in DSS + CA-4P group than DSS-stimulated ulcerative colitis model group [34]. angiogenesis, cell migration and metastasis [30].…”

“…significantly reduced body weight, colorectal length and increased disease activity index in DSS-induced mice. mRNA expression of TNF-α, IL-6 and IL-1β in colon tissue was found higher in DSS + CA-4P group than DSS-stimulated ulcerative colitis model group [34]. A study examining the mechanisms underlying the effects of 4,5-diarylimidazole brimamin which is water-soluble and a derivative of the vascular-disrupting agent CA-4, on endothelial and carcinoma cells has been conducted.…”

“…CA-4P has been shown to give rise to increase in cellular necrosis in different tumor models and delay tumor growth. Single use of CA-4P as a vascular disrupting agent in several cancers such as ovarian, pancreatic neuroendocrine tumors, non-small cell lung cancer and glioma is well tolerated and adverse effects during the treatment are not serious [34].…”

“…CA-4P is a cis-stilbene while resveratrol is a trans-stilbene. According to the results, use of CA-4P for human cancer treatment is effective but the presence of ulcerative colitis or the risk of developing ulcerative colitis should be considered [34].…”

Dandelion polysaccharide treatment protects against dextran sodium sulfate‐induced colitis by suppressing NF‐κB/NLRP3 inflammasome‐mediated inflammation and activating Nrf2 in mouse colon

“…When the experiment was finished, the model group was 3.61 ± 0.15, while the DSS + DP (L) and DSS + DP (H) groups were 2.60 ± 0.16 and 1.82 ± 0.16, respectively. Colorectal shortening also reflected the extent of colon damage during acute DSS‐induced colitis (Tang et al, 2020 ). DSS‐treated mice showed shorter colons than the control group (6.05 ± 0.60 vs 9.58 ± 0.54 cm, p < .01), whereas the colon length in the DSS + DP(L) and DSS + DP(H) groups as well as the DP group (6.89 ± 0.49, 7.59 ± 0.75, 8.02 ± 0.48) had a dramatic increase compared with the DSS group ( p < .01) (Figure 1d,e ).…”