氨基二硫代甲酸酯类化合物IC5抑制结直肠癌细胞增殖及干预炎症性肠病相关结直肠癌发展（英文）

IC5, a dithiocarbamate derivative, inhibits colon cancer cell proliferation in vitro and colitis-associated colorectal carcinogenesis in vivo

结直肠癌是发病率和死亡率较高的癌症之一,炎症性肠病和异常的细胞增殖在结直肠癌发展过程中发挥重要作用,所以,抗炎和抑制细胞增殖已成为结直肠癌化学预防的主要策略。本文发现氨基二硫代甲酸酯类化合物IC5可剂量依赖性抑制人结直肠癌细胞LoVo增殖,IC50约为22μM?同时,IC5显著诱导细胞G2/M期周期阻滞。进一步研究发现,在LoVo细胞中,IC5可以显著抑制NF-κB信号,因此推测IC5可能抑制炎症响应。利用氧化偶氮甲烷(AOM)/葡聚糖硫酸钠(DSS)诱导小鼠结直肠癌模型研究发现,IC5可显著抑制结直肠癌发展。AOM/DSS小鼠模型结直肠癌发生率为58.3%,口服给予IC5 50 mg/kg和100 mg/kg可显著降低小鼠结肠癌发生率,分别降至37.5%和25.0%。此外,IC5可降低血浆中丙氨酸转氨酶(ALT)及天冬氨酸转氨酶(AST)的水平。综上所述,IC5可干预炎症相关结直肠癌的发生发展,作为癌症预防试剂值得继续研究。

Colorectal cancer （CRC） is one of the leading causes of cancer-related deaths, and inflammatory bowel diseases and dysregulated cell proliferation play important roles in colorectal carcinogenesis. Therefore, inhibition of inflammatory signaling and cell proliferation is used as a major strategy for chemoprevention of CRC. In the present study, it was found that IC5, a dithiocarbamate derivative, could inhibit the proliferation of LoVo human colon cancer cells in a concentration-dependent manner, with an IC50 of 22 gM. The anti-proliferation effect of IC5 was accompanied by a significant cell cycle arrest in G2/M phase. Further study revealed that IC5 significantly inhibited NF-~B signaling in LoVo cells, suggesting that IC5 could inhibit inflammatory responses. We then evaluated the in vivo efficacy of IC5 to inhibit colitis-associated colorectal carcinogenesis using an azoxymethane （AOM）/dextran sodium sulfate （DSS） mouse model. AOM/DSS treatment resulted in a CRC incidence of 58.3%, while the incidences were decreased to 37.5% and 25% in mice orally administered with 50 and 100 mg/kg IC5, respectively. In addition, IC5 also reduced the plasma levels of alanine aminotransferase and asparatate aminotransferase. Taken together, these results suggested that IC5 could prevent colitis-associated colorectal carcinogenesis, and more attention should be paid to it as a cancer chemopreventive agent in further investigation.