MBD4 frameshift mutation caused by DNA mismatch repair deficiency enhances cytotoxicity by trifluridine, an active antitumor agent of TAS-102, in colorectal cancer cells
2017
// Satoshi Suzuki 1 , Moriya Iwaizumi 1 , Hidetaka Yamada 2 , Tomohiro Sugiyama 1 , Yasushi Hamaya 1 , Takahisa Furuta 3 , Shigeru Kanaoka 4 , Haruhiko Sugimura 2, 7 , Hiroaki Miyajima 1 , Satoshi Osawa 5 , John M. Carethers 6 and Ken Sugimoto 1 1 First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan 2 Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan 3 Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan 4 Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu, Japan 5 Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan 6 Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA 7 International Mass Imaging Center, Hamamatsu University School of Medicine, Hamamatsu, Japan Correspondence to: Moriya Iwaizumi, email: iwaizumi@hama-med.ac.jp Keywords: colorectal cancer; trifluridine; MBD4; microsatellite instability; frameshift mutation Received: January 23, 2017 Accepted: October 02, 2017 Published: November 15, 2017 ABSTRACT 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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