Therapeutic Effects Of Dihydroartemisinin In Multiple Stages Of Colitis-associated Colorectal Cancer

Objective:Colorectal cancer(CRC)is one of the malignant tumors that is globally associated with high morbidity and mortality rates.Inflammatory bowel diseases(IBD),including ulcerative colitis(UC)and Crohn’s disease(CD),are likely to develop into cancer,namely colitis-associated colorectal cancer(CAC).The mechanisms involved in the pathogenesis of CAC have not been established.However,inflammatory responses involving various immune cells such as macrophages,dendritic cells,and T lymphocytes(including CD4+and CD8+T cells)have been implicated in the pathogenesis of CAC.In the early CAC stages macrophages differentiate into the Ml-type to promote inflammation and eliminate pathogens.In the late CAC stages,macrophages proliferate into the M2 type to inhibit immune responses against tumors and enhance the growth as well as tumor infiltration.Since CAC is a stepwise process from inflammation to cancer,the prevention of CAC occupies a crucial position.Dihydroartemisinin(DHA),a derivative of artemisinin,is the active metabolite of artemisinin compounds.It is effective against both inflammatory responses and cancer development.During colitis treatment,DHA has also been shown to regulate PI3K/AKT and NF-κB signaling pathways.Furthermore,through multiple mechanisms including but not limited to apoptosis,cell migration inhibition,ferroptosis and cell cycle arrest,DHA has been reported to exhibit anti-tumor effect in various cancers,such as ovarian cancer,gastric cancer,liver cancer and other solid tumors.In addition,DHA is an effective enhancer for Chemotherapy and immunotherapy.Therefore,we established a CAC model to determine the role of DHA on inflammation and tumorigenesis.We have found that DHA could decrease inflammatory response in the early stage of CAC by the inhibition of TLR4 signal pathway in macrophage.Moreover,DHA promoted the apoptosis of colon cancer cells in the late stage of CAC.These results indicated that CAC could serve as a potent agent for the prevention and treatment of CAC.Methods:Mice were challenged with azoxymethane(AOM)and dextran sulfate sodium(DSS)to establish CAC models.DHA was administered by oral gavage.Colon and tumor tissues were obtained from the AOM/DSS models to investigate inflammatory responses and tumor development.Inflammatory cytokines in the murine models were detected by qRT-PCR and ELISA.TLR4 signaling-related proteins were detected by western blot.Macrophage infiltration were measured by Immunohistochemistry and immunofluorescence while apoptosis in the colon cancer cells were determined by flow cytometry and western blot.Result:DHA inhibited inflammatory responses in the early stages of AOM/DSS model and inhibited the subsequent tumor formation.In addition,DHA was shown to:reverse macrophage infiltration in colon mucosa and suppress their activation;suppress pro-inflammatory cytokines such as TNF-α,IL-6 and IL-β by inhibiting the activation of TLR4 signal pathway as well as inhibit tumor growth in the late stages of CAC by enhancing cell cycle arrest and apoptosis in tumor cells.Administration of DHA during the whole period of AOM/DSS model was also shown to generate an addictive effect with regards to the inhibition of inflammation and tumor growth,therefore,improving the therapeutic effect of DHA on CAC.Conclusion:The present study indicated that DHA could be a potent agent in the management of the initiation and development of CAC without obvious side effect,which warranted further clinical translation of DHA for CAC treatment.Figure[16]table[3]reference[100]...