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Ruthenium–dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation

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Abstract

Background

Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies.

Methods

To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium–dihydroartemisinin complex (D–Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties.

Results

Compared with its parent compound, ART, D–Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D–Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D–Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D–Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation.

Conclusions

Our results demonstrated that D–Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound’s anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D–Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity.

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Data availability

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

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Acknowledgements

Not applicable.

Funding

This work was supported in part by the Tang Foundations, and the NIH/NIDDK grant 5P30DK042086.

Author information

Author notes

  1. Chong-Zhi Wang, Chunping Wan and Cang-Hai Li are co-first authors, who contribute equally to this study.

Authors and Affiliations

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

    Chong-Zhi Wang, Chunping Wan, Yun Luo, Qinge Ma, Angela H. Wang, Mallory Lager & Chun-Su Yuan

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

    Chong-Zhi Wang & Chunping Wan

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

    Cang-Hai Li, Guo-Gang Liang & Ting-Liang Jiang

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

    Chun-Feng Zhang

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

    Qi-Hui Zhang

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

    Lifei Hou

  7. 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: CHL, CFZ, QHZ, TLJ, LH. Conducted experiment: CZW, CW, GGL, YL, QM, AHW. 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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The experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Chicago.

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Wang, CZ., Wan, C., Li, CH. et al. Ruthenium–dihydroartemisinin complex: a promising new compound for colon cancer prevention via G1 cell cycle arrest, apoptotic induction, and adaptive immune regulation. Cancer Chemother Pharmacol 93, 411–425 (2024). https://doi.org/10.1007/s00280-023-04623-7

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