Abstract
Accumulating evidence suggests that metformin, used as an antidiabetic drug, possesses anti-cancer properties. Metformin reduced the incidence and growth of experimental tumors in vivo. In a randomized clinical trial among nondiabetic patients, metformin treatment significantly decreased the number of aberrant crypt foci compared to the untreated group with a follow-up of 1 month. In our study, HT29 cells were treated with graded concentrations of metformin, 10 mM/25 mM/50 mM for 24/48 h. We performed immunofluorescence experiments by means of confocal microscopy and western blot analysis to evaluate a panel of factors involved in apoptotic/autophagic processes and oxidative stress response. Moreover, HT29 cells treated with metformin were analyzed by a flow cytometry assay to detect the cell apoptotic rate. The results demonstrate that metformin exerts growth inhibitory effects on cultured HT29 cells by increasing both apoptosis and autophagy; moreover, it affects the survival of cultured cells inhibiting the transcriptional activation of Nuclear factor E2-related factor 2 (NRF-2) and nuclear factor-kappa B (NF-κB). The effects of metformin on HT29 cells were dose- and time-dependent. These results are very intriguing since metformin is emerging as a multi-faceted drug: It has a good safety profile and is associated with low cost and might be a promising candidate for the prevention or the treatment of colorectal cancer.
Highlights
Colorectal cancer (CRC) is still a major neoplasm [1], and its prevalence and mortality have a high impact on human health [2]
In order to examine whether metformin affects human colorectal cancer cell proliferation, we investigated the effect of the drug on the cancer cell line HT29 cells
The first observation was made using an inverted microscope and raised concerns about the eventual changes of some features of the treated cells compared to controls; as shown in Figure 1 the phenotype of HT29 cells treated with metformin was preserved, the cell adhesion to the culture plates implied some changes in the characteristic rounded shape of untreated HT29 cells Figure 1
Summary
Colorectal cancer (CRC) is still a major neoplasm [1], and its prevalence and mortality have a high impact on human health [2]. Metformin (1, 1-dimethylbiguanide hydrochloride) is a biguanide derivative that has been extensively used for treating diabetes mellitus [11] It decreases basal glucose output by suppressing gluconeogenesis and glycogenolysis in the liver, and by increasing glucose uptake in muscle tissue. Patients with type 2 diabetes taking metformin might be at a lower risk of cancer (including CRC), compared with those who do not take metformin [14,15]. NF-κB plays an important role in type 2 diabetes mellitus (T2DM), as obesity activates the transcription factor NF-κB, which increases the risk for T2DM. The present study aims to assess whether metformin has the potential to suppress the growth of colorectal cancer cells and to evaluate its role in affecting the NRF-2/NF-κB pathways
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