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Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation

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Abstract

Background

Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared.

Methods

Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4+ T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17.

Results

Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation.

Conclusions

As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects.

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Data availability

The analyzed data sets generated during the study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported in part by the NIH/NCCAM Grants P01 AT004418, K01 AT005362, and 5P30DK042086.

Author information

Author notes

  1. Chong-Zhi Wang and Chunping Wan are co-first authors, who contributed equally to this study.

Authors and Affiliations

  1. Central Laboratory, The No. 1 Affiliated Hospital of Yunnan University of Traditional Chinese Medicine, Kunming, 650021, China

    Chong-Zhi Wang & Chunping Wan

  2. Tang Center for Herbal Medicine Research, and Department of Anesthesia and Critical Care, University of Chicago, 5841 South Maryland Avenue, MC 4028, Chicago, IL, 60637, USA

    Chong-Zhi Wang, Chunping Wan, Yun Luo, Zhi Liu, Daniel H. Wang, Mallory Lager & Chun-Su Yuan

  3. School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China

    Chun-Feng Zhang

  4. School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400044, China

    Qi-Hui Zhang

  5. School of Pharmacy, Nanjing Medical University, Nanjing, 211166, Jiangsu, China

    Lina Chen

  6. Tang Center for Traditional Chinese Medicine Research, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Cang-Hai Li & Ting-Liang Jiang

  7. Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, 02115, USA

    Lifei Hou

  8. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, IL, 60637, USA

    Chun-Su Yuan

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  1. Chong-Zhi Wang
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Contributions

Project administration: CZW, CSY. Participated in research design: CFZ, QHZ, LC, ZL, LH. Conducted experiment: CZW, CW, YL, DHW. Wrote an original draft preparation: CZW, ML, CSY. Performed data analysis: CW, YL. Edited and reviewed: CZW, CHL, TLJ, CSY.

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Correspondence to Chong-Zhi Wang.

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All procedures for experimental protocols of the present study involving animals and cells were performed in accordance with the ethical standards of the institution of practice at which the studies were conducted. The need for ethics approval for human fecal-related study was waived by the local medical ethics committee and is deemed unnecessary according to local guidelines. It did not pertain to any (clinical/biological) investigation of any human tissue at any level. Verbal and written consent was obtained from all participants. Ethics approval was not required by the local medical ethics committee, as it was deemed unnecessary according to the committee’s requirements.

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Wang, CZ., Wan, C., Luo, Y. et al. Effects of dihydroartemisinin, a metabolite of artemisinin, on colon cancer chemoprevention and adaptive immune regulation. Mol Biol Rep 49, 2695–2709 (2022). https://doi.org/10.1007/s11033-021-07079-1

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