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

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Oncogene. Springer Science and Business Media. 2020, 39(11), pp. 2345-2357. ISSN 0950-9232. eISSN 1476-5594. Available under: doi: 10.1038/s41388-019-1142-6
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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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ISO 690RIPANI, Paola, Johannes DELP, Konstantin J. BODE, M. Eugenia DELGADO, Lea DIETRICH, Verena M. BETZLER, Gudrun VON SCHEVEN, Thomas U. MAYER, Marcel LEIST, Thomas BRUNNER, 2020. Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain. In: Oncogene. Springer Science and Business Media. 2020, 39(11), pp. 2345-2357. ISSN 0950-9232. eISSN 1476-5594. Available under: doi: 10.1038/s41388-019-1142-6
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@article{Ripani2020-03Thiaz-48078,
  year={2020},
  doi={10.1038/s41388-019-1142-6},
  title={Thiazolides promote G1 cell cycle arrest in colorectal cancer cells by targeting the mitochondrial respiratory chain},
  number={11},
  volume={39},
  issn={0950-9232},
  journal={Oncogene},
  pages={2345--2357},
  author={Ripani, Paola and Delp, Johannes and Bode, Konstantin J. and Delgado, M. Eugenia and Dietrich, Lea and Betzler, Verena M. and von Scheven, Gudrun and Mayer, Thomas U. and Leist, Marcel and Brunner, Thomas}
}
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