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Original article
Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice
  1. Benedikt Kortüm1,
  2. Christoph Campregher1,
  3. Michaela Lang1,
  4. Vineeta Khare1,
  5. Matthias Pinter2,
  6. Rayko Evstatiev1,2,
  7. Gerald Schmid1,
  8. Martina Mittlböck3,
  9. Theresa Scharl4,
  10. Melanie H Kucherlapati5,
  11. Winfried Edelmann6,
  12. Christoph Gasche1,2
  1. 1Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
  2. 2Division of Gastroenterology and Hepatology, Department of Medicine 3, Medical University of Vienna, Vienna, Austria
  3. 3Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
  4. 4Institute for Applied Statistics and IT, University of Natural Resources and Life Sciences, Vienna, Austria
  5. 5Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York, USA
  1. Correspondence to Professor Christoph Gasche, Division of Gastroenterology and Hepatology, Department of Medicine 3, Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Währinger Gürtel 18-20, Vienna 1090, Austria; christoph.gasche{at}meduniwien.ac.at

Abstract

Objective Lynch syndrome is caused by germline mutations in DNA mismatch repair genes leading to microsatellite instability (MSI) and colorectal cancer. Mesalazine, commonly used for the treatment of UC, reduces MSI in vitro. Here, we tested natural compounds for such activity and applied mesalazine and thymoquinone in a Msh2loxP/loxP Villin-Cre mouse model for Lynch syndrome.

Design Flow cytometry was used for quantitation of mutation rates at a CA13 microsatellite in human colon cancer (HCT116) cells that had been stably transfected with pIREShyg2-enhanced green fluorescent protein/CA13, a reporter for frameshift mutations. Mice were treated for 43 weeks with mesalazine, thymoquinone or control chow. Intestines were analysed for tumour incidence, tumour multiplicity and size. MSI testing was performed from microdissected normal intestinal or tumour tissue, compared with mouse tails and quantified by the number of mutations per marker (NMPM).

Results Besides mesalazine, thymoquinone significantly improved replication fidelity at 1.25 and 2.5 µM in HCT116 cells. In Msh2loxP/loxP Villin-Cre mice, tumour incidence was reduced by mesalazine from 94% to 69% (p=0.04) and to 56% (p=0.003) by thymoquinone. The mean number of tumours was reduced from 3.1 to 1.4 by mesalazine (p=0.004) and to 1.1 by thymoquinone (p<0.001). Interestingly, MSI was reduced in normal intestinal tissue from 1.5 to 1.2 NMPM (p=0.006) and to 1.1 NMPM (p=0.01) by mesalazine and thymoquinone, respectively. Thymoquinone, but not mesalazine, reduced MSI in tumours.

Conclusions Mesalazine and thymoquinone reduce tumour incidence and multiplicity in Msh2loxP/loxP Villin-Cre mice by reduction of MSI independent of a functional mismatch repair system. Both substances are candidate compounds for chemoprevention in Lynch syndrome mutation carriers.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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