Abstract | OBJECTIVE: 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 Msh2(loxP/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:
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Authors | 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 |
Journal | Gut
(Gut)
Vol. 64
Issue 12
Pg. 1905-12
(Dec 2015)
ISSN: 1468-3288 [Electronic] England |
PMID | 25429050
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ |
Chemical References |
- Anti-Inflammatory Agents, Non-Steroidal
- Benzoquinones
- Mesalamine
- Msh2 protein, mouse
- MutS Homolog 2 Protein
- thymoquinone
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Topics |
- Animals
- Anti-Inflammatory Agents, Non-Steroidal
(pharmacology, therapeutic use)
- Benzoquinones
(pharmacology, therapeutic use)
- Cell Proliferation
(drug effects)
- Colorectal Neoplasms, Hereditary Nonpolyposis
(genetics, pathology, prevention & control)
- Disease Models, Animal
- Female
- Frameshift Mutation
- HCT116 Cells
- Humans
- Intestinal Mucosa
(metabolism)
- Male
- Mesalamine
(pharmacology, therapeutic use)
- Mice
- Microsatellite Instability
(drug effects)
- MutS Homolog 2 Protein
(genetics, metabolism)
- Mutation Rate
- Tumor Burden
(drug effects)
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