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Theranostics 2021; 11(13):6225-6239. doi:10.7150/thno.55939 This issue Cite

Research Paper

Therapeutic effects of dihydroartemisinin in multiple stages of colitis-associated colorectal cancer

Bingjun Bai^1#, Fei Wu^3#, Kangkang Ying², Yuzi Xu⁴, Lina Shan¹, Yiming Lv¹, Xing Gao⁵, Dengyong Xu¹, Jun Lu⁶, Binbin Xie^2✉

1. Department of Colorectal Surgery; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou 310016, PR China.
2. Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou 310016, PR China.
3. School of Medicine, Anhui University of Science and Technology, Huainan 232001, PR China.
4. Department of Oral Implantology and Prosthodontics, The Affiliated Hospital of Stomatology, School of Stomatology, Zhejiang University School of Medicine, and Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, 310006, PR China.
5. Department of Oncology; The Second Affiliated Hospital of Soochow University, Suzhou 215000, PR China.
6. Department of Clinical Laboratory, First Affiliated Hospital of Anhui University of Science and Technology, First People's Hospital of Huainan, Huainan 232001, PR China.
#These authors contributed equally to this work.

✉ Corresponding author: Binbin Xie, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, 3# East Qinchun Road, Hangzhou, Zhejiang, China, 310016. Phone: +86-571-86006926; E-mail: xieBBedu.cn.

Abstract

Colitis-associated colorectal cancer (CAC) develops from chronic intestinal inflammation. Dihydroartemisinin (DHA) is an antimalarial drug exhibiting anti-inflammatory and anti-tumor effects. Nonetheless, the therapeutic effects of DHA on CAC remain unestablished.

Methods: Mice were challenged with azoxymethane (AOM) and dextran sulfate sodium (DSS) to establish CAC models. DHA was administered via oral gavage in different stages of CAC models. 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 through qRT-PCR and ELISA. Toll-like receptor 4 (TLR4) signaling-related proteins were detected by western blot. Macrophage infiltration was measured using immunostaining analysis, and apoptosis in the colon cancer cells was detected by flow cytometry and western blot.

Results: DHA inhibited inflammatory responses in the early stage of the AOM/DSS model and subsequent tumor formation. In the early stage, DHA reversed macrophage infiltration in colon mucosa and decreased the expression of pro-inflammatory cytokines. DHA inhibited the activation of macrophage by suppressing the TLR4 signal pathway. In the late stage of CAC, DHA inhibited tumor growth by enhancing cell cycle arrest and apoptosis in tumor cells. Administration of DHA during the whole period of the AOM/DSS model generated an addictive effect based on the inhibition of inflammation and tumor growth, thereby improving the therapeutic effect of DHA on CAC.

Conclusion: Our study indicated that DHA could be a potent agent in managing the initiation and development of CAC without obvious side effects, warranting further clinical translation of DHA for CAC treatment.

Keywords: Dihydroartemisinin, colitis-associated colorectal cancer, macrophage, anti-inflammation, anti-tumor

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