Dipeptide γ‑secretase inhibitor treatment enhances the anti‑tumor effects of cisplatin against gastric cancer by suppressing cancer stem cell properties

Kato,Ryo; Iwamuro,Masaya; Shiraha,Hidenori; Horiguchi,Shigeru; Tanaka,Emi; Matsumoto,Ken; Ohyama,Atsushi; Sawahara,Hiroaki; Nagahara,Teruya; Uchida,Daisuke; Tsutsumi,Koichiro; Okada,Hiroyuki

doi:10.3892/ol.2018.9301

Dipeptide γ‑secretase inhibitor treatment enhances the anti‑tumor effects of cisplatin against gastric cancer by suppressing cancer stem cell properties

Authors:
- Ryo Kato
- Masaya Iwamuro
- Hidenori Shiraha
- Shigeru Horiguchi
- Emi Tanaka
- Ken Matsumoto
- Atsushi Ohyama
- Hiroaki Sawahara
- Teruya Nagahara
- Daisuke Uchida
- Koichiro Tsutsumi
- Hiroyuki Okada
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Affiliations: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700‑8558, Japan, Okayama University Medical School, Okayama 700‑8558, Japan, Department of Internal Medicine, Akaiwa Medical Association Hospital, Okayama 709‑0816, Japan, Department of Gastroenterology and Hepatology, Japanese Red Cross Okayama Hospital, Okayama 700‑8607, Japan
Published online on: August 13, 2018 https://doi.org/10.3892/ol.2018.9301
Pages: 5426-5432

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Abstract

The γ‑secretase inhibitor blocks Notch activity by preventing its cleavage at the cell surface. In the present study, the effect of the γ‑secretase inhibitor on the viability of gastric cancer cells when administered in combination with cisplatin was investigated, with particular focus on CD44highLgr‑5high cancer cells. The four gastric cancer cell lines, MKN45, MKN74, SC‑6‑JCK and SH‑10‑TC, were used for the experiments. In the MTT assay, treatment with 25 µM dipeptide γ‑secretase inhibitor (DAPT) alone did not affect cell proliferation in any of the four cell lines. Gastric cancer cells subjected to combination treatment with DAPT and cisplatin exhibited decreased viability when compared with those treated with cisplatin alone. Flow cytometry was performed to evaluate the expression of cluster of differentiation (CD)‑44 and leucine‑rich repeat‑containing G‑protein coupled receptor 5 (Lgr‑5), two cancer stem cell markers in gastric cancers. Treatment with cisplatin alone significantly increased the proportion of CD44highLgr‑5high cells. However, the addition of DAPT to cisplatin reduced the CD44highLgr‑5high fraction, suggesting that DAPT reduced the number of gastric cancer cells. In conclusion, the present study demonstrated the synergistic effects of DAPT in combination with cisplatin by decreasing the survival of gastric cancer cells. In addition, combination treatment with DAPT reduced the number of CD44highLgr‑5high cells, which are thought to exhibit cancer stem cell properties. These results highlight the therapeutic potential of DAPT in gastric cancer treatment.

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