a Department of Pharmacology , School of Basic Medical Sciences, Capital Medical University , Beijing , China.
b Beijing Key Laboratory of Environmental Toxicology, Department of Toxicology and Sanitary Chemistry , School of Public Health, Capital Medical University , Beijing , China.
Cancer Biol Ther. 2019;20(3):338-348. doi: 10.1080/15384047.2018.1529108. Epub 2018 Oct 25.
Although a mountain of papers have showed that metformin plays a role in inhibiting cancers, but the mechanism underpinning this has not yet fully elucidated. Herein, we used AOM/DSS model, the clinicopathological features are similar to those found in humans, to investigate the effects of metformin as well as combination with 5-FU in the prevention of colitis and colitis associated cancer (CAC). Oral metformin significantly inhibited DSS-induced ulcerative colitis and AOM/DSS-induced CAC. Metformin also ameliorated 5-FU-induced colorectal gastrointestinal symptoms in mice. Metformin combination with 5-FU strongly inhibited colorectal cancer. Metformin reduced levels of the NFκB signaling components p-IKKα/β, p-NFκB, p-IκBα in colorectal mucosal cells. Transmission electron microscopy analysis suggested that the inhibition of metformin on colitis and CAC might associate with its biological activity of protecting mitochondrial structures of colorectal epithelial cells. Further analysis by Mito Tracker Red staining assay indicated that metformin prevented HO-induced mitochondrial fission correlated with a decrease of mitochondrial perimeter. In addition, metformin increased the level of NDUFA9, a Q-module subunit required for complex I assembly, in colorectal epithelial cells. These observations of metformin in the inhibition of colitis and CAC might associate with its activity of activating the LKB1/AMPK pathway in colorectal epithelial cells. In conclusion, metformin inhibited colitis and CAC through protecting the mitochondrial structures of colorectal epithelial cells.
尽管大量文献表明二甲双胍在抑制癌症方面发挥作用，但这一作用的机制尚未完全阐明。在此，我们使用 AOM/DSS 模型，该模型的临床病理特征与人类相似，来研究二甲双胍以及与 5-FU 联合在预防结肠炎和结肠炎相关癌症（CAC）中的作用。口服二甲双胍可显著抑制 DSS 诱导的溃疡性结肠炎和 AOM/DSS 诱导的 CAC。二甲双胍还改善了 5-FU 诱导的小鼠结直肠胃肠道症状。二甲双胍与 5-FU 联合强烈抑制结直肠癌。二甲双胍降低了结直肠黏膜细胞中 NFκB 信号成分 p-IKKα/β、p-NFκB 和 p-IκBα 的水平。透射电子显微镜分析表明，二甲双胍抑制结肠炎和 CAC 可能与其保护结直肠上皮细胞线粒体结构的生物学活性有关。进一步通过 MitoTracker Red 染色分析表明，二甲双胍预防 HO 诱导的与线粒体周长减少相关的线粒体裂变。此外，二甲双胍增加了结直肠上皮细胞中复合物 I 组装所需的 Q 模块亚基 NDUFA9 的水平。二甲双胍在抑制结肠炎和 CAC 中的这些观察结果可能与其在结直肠上皮细胞中激活 LKB1/AMPK 通路的活性有关。总之，二甲双胍通过保护结直肠上皮细胞的线粒体结构抑制结肠炎和 CAC。
