Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells

Hanne-Line Rabben; Yosuke Kodama; Masahiko Nakamura; Atle Magnar Bones; Timothy Cragin Wang; Duan Chen; Chun-Mei Zhao; Anders Øverby

doi:10.3389/fphar.2021.613458

Chemopreventive Effects of Dietary Isothiocyanates in Animal Models of Gastric Cancer and Synergistic Anticancer Effects With Cisplatin in Human Gastric Cancer Cells

Front Pharmacol. 2021 Apr 8:12:613458. doi: 10.3389/fphar.2021.613458. eCollection 2021.

Authors

Hanne-Line Rabben^{1

2}, Yosuke Kodama¹, Masahiko Nakamura³, Atle Magnar Bones⁴, Timothy Cragin Wang^{1

5}, Duan Chen¹, Chun-Mei Zhao^{1

2}, Anders Øverby^{1

3}

Affiliations

¹ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
² The Central Norway Regional Health Authority, Stjørdal, Norway.
³ Center for Clinical Pharmacy and Clinical Sciences, School of Pharmacy, Kitasato University, Tokyo, Japan.
⁴ Cell, Molecular Biology and Genomics Group, Department of Biology, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
⁵ Division of Digestive and Liver Diseases, Columbia University College of Physicians and Surgeons, New York, NY, United States.

Abstract

Naturally occurring isothiocyanates (ITCs) from edible vegetables have shown potential as chemopreventive agents against several types of cancer. The aims of the present study were to study the potential of ITCs in chemoprevention and in potentiating the efficacy of cytotoxic drugs in gastric cancer treatment. The chemoprevention was studied in chemically induced mouse model of gastric cancer, namely N-methyl-N-nitrosourea (MNU) in drinking water, and in a genetically engineered mouse model of gastric cancer (the so-called INS-GAS mice). The pharmacological effects of ITCs with or without cisplatin were studied in human gastric cell lines MKN45, AGS, MKN74 and KATO-III, which were derived from either intestinal or diffused types of gastric carcinoma. The results showed that dietary phenethyl isothiocyanate (PEITC) reduced the tumor size when PEITC was given simultaneously with MNU, but neither when administrated after MNU nor in INS-GAS mice. Treatments of gastric cancer cells with ITCs resulted in a time- and concentration-dependent inhibition on cell proliferation. Pretreatment of gastric cancer cells with ITCs enhanced the inhibitory effects of cisplatin (but not 5-fluorouracil) in time- and concentration-dependent manners. Treatments of gastric cancer cells with PEITC plus cisplatin simultaneously at different concentrations of either PEITC or cisplatin exhibited neither additive nor synergetic inhibitory effect. Furthermore, PEITC depleted glutathione and induced G₂/M cell cycle arrest in gastric cancer cells. In conclusion, the results of the present study showed that PEITC displayed anti-cancer effects, particularly when given before the tumor initiation, suggesting a chemopreventive effect in gastric cancer, and that pretreatment of PEITC potentiated the anti-cancer effects of cisplatin, possibly by reducing the intracellular pool of glutathione, suggesting a possible combination strategy of chemotherapy with pretreatment with PEITC.

Keywords: cisplatin; dietary (or plant) isothiocyanates; gastric cancer; glutamine; glutathione; mice.