RT Journal Article SR Electronic T1 Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 1905 OP 1912 DO 10.1136/gutjnl-2014-307663 VO 64 IS 12 A1 Benedikt Kortüm A1 Christoph Campregher A1 Michaela Lang A1 Vineeta Khare A1 Matthias Pinter A1 Rayko Evstatiev A1 Gerald Schmid A1 Martina Mittlböck A1 Theresa Scharl A1 Melanie H Kucherlapati A1 Winfried Edelmann A1 Christoph Gasche YR 2015 UL http://gut.bmj.com/content/64/12/1905.abstract AB 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.