The Effect Of Ivermectin On The Development Of AOM/DSS Induced Colitis-associated Cancer In Mice

BackgroundWith the continuous improvement of national living standards,dietary structure and lifestyle have undergone great changes,which virtually leads to an increase in the incidence of colorectal cancer(CRC)year by year,resulting in a serious social burden.Inflammatory bowel disease(IBD)is a multifactorial chronic inflammatory disease,which is related to the imbalance of interaction between the host immune system and gastrointestinal environment.Chronic inflammation of the intestinal epithelium is positively correlated with cancer development.With the severity of the disease,the duration of the disease,and the extent of the damage,about 15% of IBD patients will eventually develop colorectal cancer,which we call colitis associated cancer(CAC).Although new treatment methods for colorectal cancer continue to be developed,such as radiotherapy and chemotherapy,targeted therapy,and biological therapy,the cost is relatively high,so the current clinical treatment is still mainly surgical resection.In addition,the mechanism of occurrence,development,and metastasis of colon cancer is very complex,which leads to the lack of specific drugs for the treatment of colorectal cancer in clinical practice.Therefore,an in-depth search for an inexpensive and effective drug for the prevention or treatment of colorectal cancer has become an urgent problem to be solved.Ivermectin(IVM)is a 16-membered ring macrocyclic antiparasitic drug derived from Avermectin.IVM has a strong killing effect on parasites and has a potent antiviral effect.In particular,recent studies have found that IVM has anticancer effects,including breast cancer,renal cell carcinoma,nasopharyngeal carcinoma,glioma,and leukemia.Our previous experimental results in vitro have shown that IVM can inhibit the proliferation of colorectal cancer cells,but whether it has a similar effect in vivo and its possible mechanism need to be further studied.ObjectiveIn this study,the tumor model of CAC mice induced by azomethane oxide(AOM)/ sodium dextran sulfate(DSS)was used to explore the protective effect and possible molecular mechanism of IVM on the occurrence and development of colorectal cancer cells,to provide the theoretical basis for the development of new drugs for the treatment of CAC.MethodsCAC mouse model induced by AOM/DSS: female C57BL/6 mice were injected intraperitoneally with the dose of 10mg/kg on the first day,and then the drinking water was replaced with 2.5% DSS solution for 7 days,and then the mice were continuously fed with ordinary drinking water for 14 days as a cycle.This method was repeated for three cycles.From the second day of intraperitoneal injection of AOM,mice were given different doses of IVM(0,2,5mg/kg)every 2days.During the experiment,the general status,diet,body weight,and clinical signs of mice in each group were monitored and recorded every day.At the end of the third cycle,the mice were killed,the colon tissue was obtained and the size and number of tumors were recorded,and the pathological changes in the colon were detected by pathology.In addition,the mice were sacrificed at the end of the second cycle of model construction,and their colorectal specimens were obtained.The above contents were also observed and related indicators such as cytokines and apoptotic proteins were measured,so as to preliminarily explore the mechanism of IVM inhibiting the formation and development of CAC.Results1.The high dose of IVM alleviated the weight loss at the tumor stage in CAC model mice(P< 0.05),and reduced the disease activity index score of CAC model mice at the end of the third cycle from 2.4 points to 1.5 points(P < 0.05).2.The low dose of IVM reduced the number of tumors from 4.2 to 1.8(P < 0.05),the mean tumor size from 2.9mm to 2.0mm(P < 0.05),and the high dose of IVM reduced the tumor load from10 mm to 3.5mm(P < 0.05).3.Histopathological analysis showed that IVM could reduce the degree of intestinal epithelial dysplasia in mice.4.IVM can reduce weight loss and intestinal length loss caused by inflammation.Compared with the original body weight,it increased from 96.3% in the model group to 101.2% in the IVM high-dose group(P < 0.01),and the disease activity index score of reduced mice decreased from 2.2points to 1.1 points(P < 0.05).In addition,the degree of intestinal shortening was decreased from7.1cm to 8.7cm(P < 0.01).5.IVM inhibited the production of IL-6,TNF-α,IL-17 A,IFN-γ,and up-regulated IL-2 in the inflammatory stage(P < 0.05),and the effect of high dose of IVM was more obvious.6.IVM increased the ratio of apoptosis-related protein Bax/Bcl-2 in intestinal tissues of mice,upregulated the expression of caspase-3,and promoted the hydrolysis of PARP to Cleaved PARP.ConclusionIVM intervention can reduce the degree of intestinal epithelial dysplasia in the AOM/DSSinduced colorectal cancer mouse model,improve its clinical symptoms,delay or prevent the transformation from colitis to colon cancer in mice.On the one hand,its mechanism may be through down-regulating the production of inflammatory factors TNF-α,IL-6,IFN-γ,IL-17 A and upregulating the level of IL-2 in the intestinal tissue of mice to improve inflammation,on the other hand,by inducing the expression of Caspase-3,Bax/Bcl-2,and Cleaved-PARP,the key molecules of the apoptosis pathway.