Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice

Benedikt Kortüm, Christoph Campregher, Michaela Lang, Vineeta Khare, Matthias Pinter, Rayko Evstatiev, Gerald Schmid, Martina Mittlböck, Theresa Scharl, Melanie H. Kucherlapati, Winfried Edelmann, Christoph Gasche

Research output: Contribution to journalArticle

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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 (ploxP/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.

Original languageEnglish (US)
Pages (from-to)1905-1912
Number of pages8
JournalGut
Volume64
Issue number12
DOIs
StatePublished - Dec 1 2015

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Mesalamine
Microsatellite Instability
Hereditary Nonpolyposis Colorectal Neoplasms
HCT116 Cells
Neoplasms
DNA Mismatch Repair
Frameshift Mutation
Mutation
Germ-Line Mutation
Incidence
Chemoprevention
Mutation Rate
Microsatellite Repeats
Colonic Neoplasms
Intestines
thymoquinone
villin
Tail
Colorectal Neoplasms
Flow Cytometry

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Kortüm, B., Campregher, C., Lang, M., Khare, V., Pinter, M., Evstatiev, R., ... Gasche, C. (2015). Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice. Gut, 64(12), 1905-1912. https://doi.org/10.1136/gutjnl-2014-307663

Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice. / Kortüm, Benedikt; Campregher, Christoph; Lang, Michaela; Khare, Vineeta; Pinter, Matthias; Evstatiev, Rayko; Schmid, Gerald; Mittlböck, Martina; Scharl, Theresa; Kucherlapati, Melanie H.; Edelmann, Winfried; Gasche, Christoph.

In: Gut, Vol. 64, No. 12, 01.12.2015, p. 1905-1912.

Research output: Contribution to journalArticle

Kortüm, B, Campregher, C, Lang, M, Khare, V, Pinter, M, Evstatiev, R, Schmid, G, Mittlböck, M, Scharl, T, Kucherlapati, MH, Edelmann, W & Gasche, C 2015, 'Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice', Gut, vol. 64, no. 12, pp. 1905-1912. https://doi.org/10.1136/gutjnl-2014-307663
Kortüm B, Campregher C, Lang M, Khare V, Pinter M, Evstatiev R et al. Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice. Gut. 2015 Dec 1;64(12):1905-1912. https://doi.org/10.1136/gutjnl-2014-307663
Kortüm, Benedikt ; Campregher, Christoph ; Lang, Michaela ; Khare, Vineeta ; Pinter, Matthias ; Evstatiev, Rayko ; Schmid, Gerald ; Mittlböck, Martina ; Scharl, Theresa ; Kucherlapati, Melanie H. ; Edelmann, Winfried ; Gasche, Christoph. / Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2loxP/loxP Villin-Cre mice. In: Gut. 2015 ; Vol. 64, No. 12. pp. 1905-1912.
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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 (ploxP/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.",
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AU - Khare, Vineeta

AU - Pinter, Matthias

AU - Evstatiev, Rayko

AU - Schmid, Gerald

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AU - Edelmann, Winfried

AU - Gasche, Christoph

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N2 - 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 (ploxP/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.

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