4-Methylthio-3-butenyl isothiocyanate (raphasatin) exerts chemopreventive effects against esophageal carcinogenesis in rats

Abstract

To examine the effects of 4-methylthio-3-butenyl isothiocyanate on esophageal carcinogenesis, male 6-week-old F344 rats were subcutaneously injected with 0.5 mg/kg body weight N-nitrosomethylbenzylamine three times per week for 5 weeks and fed a diet supplemented with 80 ppm 4-methylthio-3-butenyl isothiocyanate, equivalent to 6.05 mg/kg body weight/day for the initiation stage, 4.03 mg/kg body weight/day for the promotion stage, or 4.79 mg/kg body weight/day for all stages. Although the incidence of lesions was not affected by 4-methylthio-3-butenyl isothiocyanate treatment, the multiplicity of squamous cell papilloma in the esophagus was significantly decreased in rats in the 4-methylthio-3-butenyl isothiocyanate initiation stage group (1.13 ± 0.74), 4-methylthio-3-butenyl isothiocyanate promotion stage group (1.47 ± 0.99), and 4-methylthio-3-butenyl isothiocyanate all stage group (1.47 ± 1.13) as compared with rats treated with N-nitrosomethylbenzylamine alone (3.00 ± 1.46). Immunohistochemical analysis revealed that 4-methylthio-3-butenyl isothiocyanate induced apoptosis, suppressed cell proliferation, and increased p21 expression when administered in the promotion phase. These modifying effects were not observed in the rats treated with 4-methylthio-3-butenyl isothiocyanate alone. Our results indicated that 4-methylthio-3-butenyl isothiocyanate may exert chemopreventive effects against N-nitrosomethylbenzylamine-induced esophageal carcinogenesis in rats.

Toxic effects of 4‐methylthio‐3‐butenyl isothiocyanate (Raphasatin) in the rat urinary bladder without genotoxicity

“…However, it is more important that MTBITC had no toxic effects at lower doses, which may ensure the safety of low‐dose MTBITC applied as a chemopreventive usage, e.g . , 80 ppm in the previous chemopreventive studies (Okamura et al, ; Suzuki et al, ). Based on the previously reported concentrations of MTBITC in heirloom daikon varieties, such as Karami, Momoyama and Sabaga (67, 44 and 36 mg 100 g −1 , respectively) (Nakamura et al, ), the estimated daily dose of MTBITC exerting toxic effects in the present study was equal to approximately 130–250 g kg −1 BW day −1 daikon.…”

“…Furthermore, PEITC binds to protein targets more strongly than SFN (because the phenethyl group in PEITC is more hydrophobic and the sulfonyl group in SFN is more soluble, allowing PEITC to bind easily to cysteines), whereas SFN induces the greater generation of ROS than PEITC in vitro (Mi and Chung, ). In different in vivo studies, 80 ppm MTBITC was shown to inhibit NMBA‐induced rat esophageal carcinogenesis during both the initiation and promotion phases (Suzuki et al, ), whereas 500 ppm PEITC exerted chemopreventive effects only during the initiation phase, i.e. failed to inhibit carcinogenesis during the promotion phase in the same rat model (Siglin et al, ).…”

“…Notably, it is unlikely that the toxicity of MTBITC would also be observed in humans because this amount of daikon (8–15 kg day −1 for a 60‐kg human) is much higher than the normal dietary consumption. Therefore, daily consumption of daikon containing MTBITC can provide beneficial effects, as reported previously (Nakamura et al, ; Okamura et al, ; Suzuki et al, ). Further studies of the efficacy and the effective dose of MTBITC and the relevance of these findings to humans are needed.…”

“…Karami, Momoyama and Sabaga), which are more pungent than conventional Aokubi daikon, are a rich source of MTBITC (Nakamura et al, ). Additionally, we recently reported that MTBITC effectively suppresses N ‐nitrosomethylbenzylamine (NMBA)‐induced rat esophageal carcinogenesis when given during the initiation and/or promotion phases (Suzuki et al, ). Therefore, MTBITC may be a promising agent for cancer preventive strategies.…”

4-Methylthio-3-butenyl isothiocyanate (MTBITC) induced apoptotic cell death and G2/M cell cycle arrest via ROS production in human esophageal epithelial cancer cells

“…ITCs generated from glucosinolates are effective inhibitors of carcinogenesis, and many studies have evaluated the effects of ITCs on the prevention of various cancers in animals and the associated mechanisms of action in vitro (Xu et al, 2006;Navarro et al, 2011;IARC, 2004). Our previous studies showed that MTBITC may provide chemoprevention against esophageal carcinogenesis in rats and may activate Nrf2, the transcription factor related to cancer prevention in human esopha-geal cells (Hirata et al, 2018;Suzuki et al, 2016). The inhibitory effect of MTBITC on N-nitrosomethylbenzylamine (NMBA)-induced esophageal carcinogenesis in rats was observed when administered in both the initiation and promotion phases.…”