Metformin inhibited colitis and colitis-associated cancer (CAC) through protecting mitochondrial structures of colorectal epithelial cells in mice

Abstract

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 H 2 O 2-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.

Oral Administration of Microencapsulated B. Longum BAA-999 and Lycopene Modulates IGF-1/IGF-1R/IGFBP3 Protein Expressions in a Colorectal Murine Model

“…On the contrary, metformin administration was effective in reducing number of tumors, the composition of resident inflammatory cells and other inflammatory scores, and the incidence of adenocarcinomas in the colon of AOM + DSS treated mice after 16-weeks. Similarly, the chemopreventive effect of metformin has been previously demonstrated [22] and the effects of IGFBP3 knockout and metformin were observed in a murine model of ulcerative colitis, showing significantly reduced colitis [30].…”

“…As IGF-binding proteins (IGFBPs) modulate the amount of bioavailable IGFs in a positive or negative manner [21,22], both the positive rate and expression grade of IGFBPs are shown in the lower panel of Figure 3. In the Normal group, the positive rates of IGF2BP1 and IGFBP2 expression in colonic samples were significantly lower (33 and 40%, respectively), whereas IGFBP3 expression was significantly higher (by 43%, p < 0.05) than that of the AOM + DSS control group.…”

“…LYC was extracted from softgels and homogenized with NaCl 0.9% to provide the corresponding concentration; groups 6–7 (LYC 20 and LYC 50, n = 7) received 20 and 50 mg kg −1 of LYC, respectively. Metformin (1, 1-dimethylbiguanide hydrochloride) has been reported to provide in vivo and in vitro anti-inflammatory effects through inhibition of NF-κB signaling [22,30,44]; thus, a positive control group was included, and animals in group 8 (Metformin, n = 7) received 600 mg·kg −1 of metformin (Merck company, Naucalpan de Juárez, Edo de México, MEX), dissolved in NaCl 0.9%. The corresponding treatments were prepared daily and gavaged every morning (0.2 mL total volume) to all mice throughout the 16 weeks, with the exceptions of weeks 5 and 6.…”

Gut bacteria signaling to mitochondria in intestinal inflammation and cancer

“… 142 Additionally, numerous studies suggest the mechanism by which the diabetic drug metformin inhibits cancer cells might correlate with its mitochondrial-targeting activity to inhibit the ETC. 143 Population studies such as that of Seo et al have shown that diabetic patients treated with metformin, which inhibits ETC Complex I, present an approximately 30% reduced overall cancer incidence and mortality rate. 144 Therefore, mitochondrial-targeted therapeutics are emerging as an exciting opportunity for cancer therapy.…”

Is Metformin a Treatment Opportunity for Colorectal Cancer?

“…(50) In a study, metformin prevented inflamed colorectal epithelial cells and cancer cells by activating the LKB1/AMPK pathway. (51) On the other hand, metformin can inhibits the mTOR pathway in an AMPKindependent pathway by inactivating Rag GTPases. (52)…”