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.
Highlights
Gastric cancer is one of the leading causes of cancer in the world with over one million new cases reported in 2018 (GLOBOCAN) (Ferlay et al, 2013; Bray et al, 2018)
The aromatic ITCs displayed a higher potential in inhibiting cell proliferation in both MKN45 and AGS compared to AITC
It is unlikely that phenethyl isothiocyanate (PEITC) interacts directly with MNU on one hand, but on the other hand, PEITC may act on gastric epithelial cells to prevent the initiation of tumorigenesis as it has been suggested that PEITC induce apoptosis, inhibits cell cycle progression and inhibits angiogenesis (Mitsiogianni et al, 2019)
Summary
Gastric cancer is one of the leading causes of cancer in the world with over one million new cases reported in 2018 (GLOBOCAN) (Ferlay et al, 2013; Bray et al, 2018). A challenge for improving patient care of gastric cancer in terms of survival and quality of life appears to be ineffective cytotoxic chemotherapy. These facts indicate that there are still great needs for improvement in the prevention and treatment of gastric cancer. We have showed that denervation (surgically, pharmacologically or genetically) suppressed the tumorigenesis of gastric cancer, which was associated with a decrease in WNT/β-catenin signaling, the suppression of stem cell expansion through M3 receptor-mediated cholinergic signaling and the reversion of metabolic reprogramming, and that the combination of denervation and mono-chemotherapy led to an enhanced effect on tumor growth and survival in an animal model of gastric cancer (Zhao et al, 2014; Rabben et al, 2016). We wanted to explore the potential of a class of anti-cancer agents, isothiocyanates (ITCs) for chemoprevention and enhancement of chemotherapy as they are shown to interfere with tumor metabolism (Conaway et al, 2002; Lv et al, 2020)
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