Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

Higurashi, Takuma; Hosono, Kunihiro; Takahashi, Hirokazu; Komiya, Yasuhiko; Umezawa, Shotaro; Shimizu, Eiji; Uchiyama, Takashi; Taniguchi, Leo; Hata, Yasuo; Uchiyama, S.; Hattori, Akiko; Nagase, Hajime; Kessoku, Takaomi; Arimoto, Jun; Matsuhashi, Nobuyuki; Inayama, Yoshiaki; Yamanaka, Shōji; Taguri, Masataka; Nakajima, Atsushi

doi:10.1016/s1470-2045(15)00565-3

Cited by 268 publications

(238 citation statements)

References 31 publications

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“…A systematic review of observational studies suggested that diabetic patients on metformin have a reduction in the rate of CRC compared to their diabetic counterpart not on metformin [53, 62–64]. Furthermore, a multicenter double-blind, randomized controlled phase III trial found that non-diabetic patients who received metformin 250 mg daily were less likely to have metachronous adenomas 1 year after polypectomy compared to those who received placebo (RR 0.67; 95% CI 0.47–0.97) [65]. Despite this association between DM and CRC, the screening guidelines remain the same as that for the general population.…”

Section: Treatment Considerations In Diabetes-related Enteropathic DImentioning

confidence: 99%

Diabetes Mellitus and the Colon

Piper

Saad

2017

Curr Treat Options Gastro

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Opinion statement Diabetes mellitus (DM) can affect the structure and function of the colon promoting commonly encountered lower gastrointestinal symptoms such as constipation, diarrhea, abdominal distention, bloating, and abdominal pain. Specific colonic disorders for which adults with DM are at greater risk include chronic constipation, enteropathic diarrhea, colorectal cancer (CRC), inflammatory bowel disease, microscopic colitis, and Clostridium difficile colitis. Smooth muscle structure and function, density of the interstitial cells of Cajal, and the health and function of the autonomic and enteric nerves of the colon are all potential affected by DM. These effects can in turn lead to alterations in colon motility, visceral sensation, immune function, endothelial function, and the colonic microbiome. The evaluation and treatment for slow transit constipation as well as pelvic floor dysfunction should be considered when constipation symptoms are refractory to initial treatment measures. DM-related medications and small bowel conditions such as celiac disease and small intestinal bowel overgrowth should be considered and excluded before a diagnosis of enteropathic diarrhea is made. Given the higher risk of CRC, adults with DM should be appropriately screened and may require a longer bowel preparation to ensure an adequate evaluation.

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Section: Treatment Considerations In Diabetes-related Enteropathic DImentioning

confidence: 99%

Diabetes Mellitus and the Colon

Piper

Saad

2017

Curr Treat Options Gastro

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“…There is clear clinical evidence that even low-dose oral metformin reduces colon polyp formation (Higurashi et al, 2016), although evidence that patients with diabetes treated with metformin have reduced cancer burden is controversial (Farmer et al, 2017; Nie et al, 2016). It is unclear whether the clinical and experimental antineoplastic actions of metformin are attributable to systemic effects, such as reduction of circulating insulin levels; to direct effects on neoplastic cells; or to both mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

et al. 2018

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SUMMARY Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.

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“…Recently, increasing evidence has shown that metformin is capable of reducing risk of and/or improving prognosis of some types of cancer in patients with or without type II diabetes [2][3][4][5][6][7]. Experimental studies have shown the antitumor activities of metformin in multiple cancers such as liver [8], lung [9], pancreas [10], ovary [11] and gastric cancer [12].…”

Section: Introductionmentioning

confidence: 99%

“…Experimental studies have shown the antitumor activities of metformin in multiple cancers such as liver [8], lung [9], pancreas [10], ovary [11] and gastric cancer [12]. Moreover, metformin has entered into clinic trails as a chemopreventive or chemotherapeutic agent against tumors [6,7,13,14] and has shown promise in several tumors [6,7,13].…”

Section: Introductionmentioning

confidence: 99%

Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

Feng

Wang

2018

Cell Physiol Biochem

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Background/Aims: This study aimed at investigating the effects of metformin on the growth and metastasis of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo. Methods: Two human ESCC cell lines EC9706 and Eca109 were selected and challenged with metformin in this study. Western blot assay was performed to detect th level of Bcl-2, Bax and Caspase-3. Scratch wound assay, transwell assay and Millicell invasion assay were used to assay the invasion and migration of EC9706 and Eca109 cells. Nude mice tumor models were used to assay the growth and lung metastasis of ESCC cells after metformin treatment. The plasma glucose level was also assayed. Results: We found that metformin significantly inhibited proliferation and induced apoptosis of both ESCC cell lines in a dose- and time-dependent manner, and the expression of Bcl-2 was down-regulated and Bax and Caspase-3 were up-regulated. Metformin significantly inhibited the invasion and migration of EC9706 and Eca109 cells (p < 0.05). mRNA and protein levels of MMP-2 and MMP-9 decreased significantly upon treatment with metformin of 10mM for 12, 24 and 48h in a time-dependent manner (p < 0.05). In line with in vitro results, in vivo experiments demonstrated that metformin inhibited tumorigenicity, inhibited lung metastasis and down-regulated the expression of MMP-2 and MMP-9. Moreover, we showed that metformin treatment did not cause significant alteration in liver and renal functions and plasma glucose level. Conclusion: Our study for the first time demonstrated the anti-invasive and anti-metastatic effects of metformin on human ESCC cells both in vitro and in vivo, which might be associated with the down-regulation of MMP-2 and MMP-9. As a whole, our results indicate the potential of metformin to be developed as a chemotherapeutic agent for patients with ESCC and might stimulate future studies on this area.

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Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial

Cited by 268 publications

References 31 publications

Diabetes Mellitus and the Colon

Diabetes Mellitus and the Colon

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer

Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

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