MBD4 frameshift mutation caused by DNA mismatch repair deficiency enhances cytotoxicity by trifluridine, an active antitumor agent of TAS-102, in colorectal cancer cells
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Satoshi Suzuki1, Moriya Iwaizumi1, Hidetaka Yamada2, Tomohiro Sugiyama1, Yasushi Hamaya1, Takahisa Furuta3, Shigeru Kanaoka4, Haruhiko Sugimura2,7, Hiroaki Miyajima1, Satoshi Osawa5, John M. Carethers6 and Ken Sugimoto1
1First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
2Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
3Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
4Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan
5Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
6Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
7International Mass Imaging Center, Hamamatsu University School of Medicine, Hamamatsu, Japan
Moriya Iwaizumi, email: [email protected]
Keywords: colorectal cancer; trifluridine; MBD4; microsatellite instability; frameshift mutation
Received: January 23, 2017 Accepted: October 02, 2017 Published: November 15, 2017
Backgrounds: Trifluridine is an active antitumor component of TAS-102 that resembles 5-fluorouracil. Although patients with advanced colorectal cancer (CRC) exhibiting a mismatch repair (MMR) deficiency reportedly do not benefit from 5-fluorouracil-based chemotherapy and we previously reported that truncated methyl-CpG binding domain protein 4 (MBD4) enhances 5-fluorouracil cytotoxicity in MMR-deficient CRC cells, little is known regarding the effect of MMR deficiency on trifluridine cytotoxicity in CRC.Aim: We investigated whether trifluridine induces cytotoxicity in a DNA MMR-dependent manner and evaluated how truncated MBD4 alters trifluridine cytotoxicity.Methods: We utilized the human CRC cell lines HCT116 (hMLH1-deficient cells) and HCT116+ch3 (hMLH1-restored cells) and compared their sensitivities to trifluridine. And we established 5-fluorouracil-refractory hMLH1-deficient cells and analyzed trifluridine cytotoxicity. Finally, we established truncated MBD4 overexpressed CRC cell lines, and compared trifluridine sensitivity.Results: The sensitivities of HCT116 and HCT116+ch3 to trifluridine were comparable. 5-Fluorouracil-refractory hMLH1-deficient cells treated with trifluridine showed an equal or greater sensitivity than non-5-fluorouracil-refractory cells. Moreover, MBD4tru cells were more sensitive than the control cells to trifluridine.Conclusions: Trifluridine induces cytotoxicity independently of the DNA MMR status as well as under 5-fluorouracil-refractory conditions, and the MBD4 frameshift mutation enhances trifluridine cytotoxicity.
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