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Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain

Oncogene volume 39, pages 2345–2357 (2020)Cite this article

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Abstract

Systemic toxicity and tumor cell resistance still limit the efficacy of chemotherapy in colorectal cancer. Therefore, alternative treatments are desperately needed. The thiazolide Nitazoxanide (NTZ) is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea with a favorable safety profile. Interestingly, NTZ and the thiazolide RM4819—its bromo-derivative lacking antibiotic activity—are also promising candidates for cancer treatment. Yet the exact anticancer mechanism(s) of these compounds still remains unclear. In this study, we systematically investigated RM4819 and NTZ in 2D and 3D colorectal cancer culture systems. Both compounds strongly inhibited proliferation of colon carcinoma cell lines by promoting G1 phase cell cycle arrest. Thiazolide-induced cell cycle arrest was independent of the p53/p21 axis, but was mediated by inhibition of protein translation via the mTOR/c-Myc/p27 pathway, likely caused by inhibition of mitochondrial respiration. While both thiazolides demonstrated mitochondrial uncoupling activity, only RM4819 inhibited the mitochondrial respiratory chain complex III. Interestingly, thiazolides also potently inhibited the growth of murine colonic tumoroids in a comparable manner with cisplatin, while in contrast to cisplatin thiazolides did not affect the growth of primary intestinal organoids. Thus, thiazolides appear to have a tumor-selective antiproliferative activity, which offers new perspectives in the treatment of colorectal cancer.

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Fig. 1: Thiazolides induce G1 cell cycle arrest independent of apoptosis induction.
Fig. 2: Thiazolides induced G1 cell cycle arrest is independent of the p53/p21 axis.
Fig. 3: Thiazolide induce p27 stabilization via reduction of c-Myc protein translation.
Fig. 4: RM4819 and NTZ induce energy depletion by directly targeting mitochondrial oxidative phosphorylation.
Fig. 5: RM4819 but not NTZ strongly inhibits mitochondrial respiratory chain complex III.
Fig. 6: RM4819 and NTZ strongly inhibit the proliferation of intestinal tumoroids without altering intestinal organoids growth.

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Acknowledgements

This study has been supported by a research grants from the DFG-funded Konstanz Research School-Chemical Biology (KoRS-CB, GSC 2018), the BMBF (e:ToP program, NeuriTox), and the Projects from the European Union’s Horizon 2020 research and innovation program EU-ToxRisk (grant agreement No 681002) and ENDpoiNTs (grant agreement No 825759). PR received a fellowship from the Deutscher Akademischer Austauschdienst (DAAD), JD and KB from the Baden-Württemberg Ministry of Science, Research and Art–funded Co-operative research training school InViTe. The authors like to thank A. Ahmed for technical help.

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Authors and Affiliations

  1. Department of Biology, Biochemical Pharmacology, University of Konstanz, Konstanz, Germany

    P. Ripani, K. Bode, M. E. Delgado, L. Dietrich, V. M. Betzler & T. Brunner

  2. Konstanz Research School Chemical Biology KORS-CB, University of Konstanz, Konstanz, Germany

    P. Ripani, J. Delp, T. U. Mayer, M. Leist & T. Brunner

  3. Chair for In Vitro Toxicology and Biomedicine, inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany

    J. Delp & M. Leist

  4. Biotechnology Institute Thurgau, University of Konstanz, Konstanz, Germany

    V. M. Betzler

  5. Department of Medicinal Chemistry, Peking University Health Science Centre, Beijing, China

    N. Yan

  6. Department of Biology, Molecular Toxicology Group, University of Konstanz, Konstanz, Germany

    G. von Scheven

  7. Department of Biology, Molecular Genetics, University of Konstanz, Konstanz, Germany

    T. U. Mayer

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Ripani, P., Delp, J., Bode, K. et al. Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain. Oncogene 39, 2345–2357 (2020). https://doi.org/10.1038/s41388-019-1142-6

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