Rabben Hanne-Line, Kodama Yosuke, Nakamura Masahiko, Bones Atle Magnar, Wang Timothy Cragin, Chen Duan, Zhao Chun-Mei, Øverby Anders
Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
The Central Norway Regional Health Authority, Stjørdal, Norway.
Front Pharmacol. 2021 Apr 8;12:613458. doi: 10.3389/fphar.2021.613458. eCollection 2021.
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 G/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.
食用蔬菜中天然存在的异硫氰酸盐（ITCs）已显示出作为多种癌症化学预防剂的潜力。本研究的目的是研究ITCs在化学预防以及增强细胞毒性药物治疗胃癌疗效方面的潜力。在化学诱导的胃癌小鼠模型（即饮用水中添加N-甲基-N-亚硝基脲（MNU））和基因工程胃癌小鼠模型（即所谓的INS-GAS小鼠）中研究了化学预防作用。在源自肠型或弥漫型胃癌的人胃癌细胞系MKN45、AGS、MKN74和KATO-III中研究了ITCs联合或不联合顺铂的药理作用。结果表明，当PEITC与MNU同时给药时，饮食中的苯乙基异硫氰酸盐（PEITC）可减小肿瘤大小，但在MNU给药后或INS-GAS小鼠中给药时均无此效果。用ITCs处理胃癌细胞会导致细胞增殖受到时间和浓度依赖性的抑制。用ITCs预处理胃癌细胞可增强顺铂（而非5-氟尿嘧啶）的抑制作用，且呈时间和浓度依赖性。用不同浓度的PEITC和顺铂同时处理胃癌细胞，在PEITC或顺铂的不同浓度下均未表现出相加或协同抑制作用。此外，PEITC可消耗胃癌细胞中的谷胱甘肽并诱导G/M期细胞周期阻滞。总之,本研究结果表明，PEITC具有抗癌作用，尤其是在肿瘤起始前给药时，提示其在胃癌中有化学预防作用，且PEITC预处理可增强顺铂的抗癌作用，可能是通过减少细胞内谷胱甘肽池实现的，提示PEITC预处理可能是一种化疗联合策略。
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