Metformin prevents DMH‐induced colorectal cancer in diabetic rats by reversing the warburg effect

Abstract

Epidemiologic studies have shown that the treatment of diabetics with metformin reduced the risk of cancer-related mortality. Here, we investigated the chemopreventive effects of metformin on dimethylhydrazine (DMH)-induced colorectal carcinogenesis in diabetic SD rats following metformin treatment and the effect on Warburg effect involved in this process. Diabetic rat models were induced with high-fat feeding in combination with a low dose of Streptozotocin (STZ) and then induce colorectal cancer with a low dose of DMH. The formation of colorectal Aberrant crypt foci (ACF) and the incidence, number and size of the tumor were measured. The proliferation indices of colonic tissues were determined through Proliferating cell nuclear antigen (PCNA) immunostaining. Then detect the expression of PK and IDH in colonic tissues using immunohistochemistry and Western blot. The enzyme activities of HK and PDH in colonic tissues were measured. The growth and expression of PK and IDH and activity of HK and PDH in cell lines LoVo and HT-29 were measured after metformin treatment. The results showed that metformin treatment significantly inhibited the formation of ACF and tumors. The proliferation index of colonic tissues was significantly decreased following metformin treatment. In addition, metformin inhibited cell growth and decreased the imbalance in the expression of the enzymes involved in glycolysis and the TCA cycle. These findings suggested that metformin might produce a synergistic colon cancer-preventative effect in diabetic patients through the regulation of the enzymes expression involved in glucose metabolism.

Metformin prevents hormonal and metabolic disturbances and 1,2-dimethylhydrazine-induced colon carcinogenesis in non-diabetic rats

“…We observed increased levels of glucose, insulin, IGF-1, total cholesterol, triglycerides, MDA, glycated hemoglobin, and VEGF in serum of rats with DMH-induced colon tumors compared with the group without DMH ( Figure 1 ). These findings agree with available data 12,13,26,27 . Furthermore, we observed the normalizing effects of both MF doses on these parameters in DMH-exposed rats ( Figure 1 ).…”

“…Meanwhile, the anti-diabetic biguanide, metformin (MF), lowers elevated insulin levels in type 2 diabetes 3,9 , significantly reduces various cancer risks in humans with the condition, and prevents tumor development in numerous rodent tissues and organs 10,11 . Furthermore, MF inhibits some chemically induced colon carcinogenesis in diabetic, obese 12 , and non-diabetic rats 13 . In this work, we showed the inhibitory effects of MF on DMH-induced colon carcinogenesis in non-diabetic rats.…”

NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase

“…The inhibition of Warburg effect deprives the generation of ATP, decreasing cancer cells growth and proliferation [10, 11]. Thus, Warburg effect has received substantial attention as a novel therapeutic target in cancers including lung cancer [12, 13], leukemia [14], breast cancer [15–18], pancreatic cancer [19, 20], colorectal cancer [21, 22], bladder cancer [23], and multiple myeloma [24, 25]. In multiple myeloma, dichloroacetate, which is an inhibitor of aerobic glycolysis, has been reported to increase myeloma cell sensitivity to bortezomib [24].…”

Endothelial cell metabolism inhibition: A new approach to the treatment of resistant metastatic colorectal carcinoma

“…Hence, targeting the convergence of angiogenic signals on endothelial metabolism would be an effective alternative to anti-VEGF in metastatic CRC therapy. Drugs targeting the Warburg effect are under pre-clinical and clinical investigations [15][16][17][18][19] . These include GLUT1-targeted therapeutic agents such as small chemical entities, as well as GLUT1-mediated target drug delivery for anticancer agents such as fluorine-substituted platinum(II)-sugar conjugates.…”