1. Academic Validation
  2. Induction of endoplasmic reticulum stress and inhibition of colon carcinogenesis by the anti-helmintic drug rafoxanide

Induction of endoplasmic reticulum stress and inhibition of colon carcinogenesis by the anti-helmintic drug rafoxanide

  • Cancer Lett. 2019 Oct 10:462:1-11. doi: 10.1016/j.canlet.2019.07.014.
Federica Laudisi 1 Antonio Di Grazia 1 Veronica De Simone 2 Fabio Cherubini 1 Alfredo Colantoni 1 Angela Ortenzi 1 Eleonora Franzè 1 Vincenzo Dinallo 1 Davide Di Fusco 1 Ivan Monteleone 3 Eric R Fearon 4 Giovanni Monteleone 1 Carmine Stolfi 5
Affiliations

Affiliations

  • 1 Department of Systems Medicine, University of "Tor Vergata", Rome, Italy.
  • 2 Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.
  • 3 Department of Biomedicine and Prevention, University of "Tor Vergata", Rome, Italy.
  • 4 Department of Internal Medicine, Human Genetics and Pathology, University of Michigan, Ann Arbor, USA.
  • 5 Department of Systems Medicine, University of "Tor Vergata", Rome, Italy. Electronic address: carmine.stolfi@uniroma2.it.
Abstract

Colorectal Cancer (CRC) remains one of the leading causes of mortality worldwide. Drug repositioning is a promising approach for new Cancer therapies, as it provides the opportunity to rapidly advance potentially promising agents into clinical trials. The FDA-approved anti-helminthic drug rafoxanide was recently reported to antagonize the oncogenic function of the BRaf V600E mutant protein, commonly found in CRCs, as well as to inhibit the proliferation of skin Cancer cells. These observations prompted us to investigate the potential anti-cancer effects of rafoxanide in CRC models. We found rafoxanide inhibited proliferation in CRC cells, but not in normal colonic epithelial cells. Rafoxanide's anti-proliferative action was associated with marked reduction in cyclin D1 protein levels and accumulation of cells in the G0/G1 phase. These effects relied on selective induction of the endoplasmic reticulum stress (ERS) response in CRC cells and were followed by caspase-dependent cell death. Systemic administration of rafoxanide to APCmin/+ mice induced to develop CRCs caused ERS activation, proliferation inhibition and Apoptosis induction in the neoplastic cells. Collectively, our data suggest rafoxanide might be repurposed as an anti-cancer drug for the treatment of CRC.

Keywords

Apc(min/+) mice; Apoptosis; Cyclin D1; Drug repurposing; UPR; eIF2α.

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