Metformin and cancer prevention -
One way that metformin works is by getting inside cells and hitting a molecular switch that turns the cells into little sugar sponges, soaking up molecules of the sugar glucose floating in the blood. This molecular switch is an enzyme called AMPK, a master controller of shuttling glucose molecules from the blood, into cells.
Thanks to work by researchers like Dario, we now know that AMPK also plays an important role in cancer. In many cancers, the cells have lost their ability to use AMPK as a master switch. This disruption to how the cells utilise energy contributes to their uncontrolled growth and proliferation — the underlying feature of all cancers.
We did an experiment and saw this massive activation of the enzyme. And we just knew that was it. The role of AMPK in cancer had not really been appreciated up to that point. This was a big step forward for cancer research but it took an even bigger leap in thinking to realise the potential for how this finding could positively affect the lives of people with cancer.
And then you start to realise the implications of the results. And then you remember that the drug metformin can switch on this enzyme, so maybe metformin could also be a way to counteract the development of tumours.
Dario knew that metformin was able to switch on AMPK to help people with diabetes so he reasoned that maybe the drug could also provide protection against cancer.
To test this, Dario and others based in Dundee dove into the clinical records of nearly 12, people diagnosed and treated for type 2 diabetes between and , and looked at how many of them went on to develop cancer during their lifetime. Their analysis of the data revealed that the people with type 2 diabetes who were treated with metformin were at a lower risk of developing cancer.
However, the incidence of other types of cancer e. Interestingly enough, it has been suggested that diabetes is associated with a lower risk for prostate cancer 2 , 3. According to the American Diabetes Association and the American Cancer Society consensus report the relative risks imparted by diabetes are greatest about two fold or higher for cancers of the liver, pancreas, and endometrium, and lesser about 1.
The association of diabetes and cancer was first reported as an incidental finding in 6. Nowadays, this coexistence is well recognized, however in spite of the intensive studies its mechanism still remains unclear.
There is a general agreement that T2DM and cancer share several common potential risk factors e. In T2DM, insulin resistance and hyperinsulinemia either endogenous due to insulin resistance or induced by administration of exogenous insulin formulations are considered to be independent risk factors for cancer development 1 , 2.
In addition, hyperglycemia-related oxidative stress, accumulation of advances glycation end products as well as low-grade inflammation may also enhance the risk of malignant transformation 7 , 8. Recent publications have also suggested the link between hypoglycemic medications and cancer 8 - The results of numerous preclinical, epidemiological and clinical studies suggested that metformin use is associated with inhibition of cancer cell growth and proliferation and reduction in all-cancer incidents in comparison with users of other hypoglycemic drugs.
In the present work we discuss the proposed mechanism s of anticancer effect of metformin as well as preclinical and clinical data suggesting this beneficial effect. The current proposed anticancer molecular action of metformin is mainly associated with the inhibition of the mammalian target of rapamycin complex 1 mTORC1.
The mTOR pathway plays a pivotal role in metabolism, growth and proliferation of cancer cell Metformin is thought to inhibit mTORC1 pathway Figure 1. It is believed that systemic effect of metformin manifested by the reduction of circulating level of insulin and insulin-like growth factor 1 IGF-1 might be associated with anticancer action The excessive food consumption insulin leads to increased liver production of IGF-1 that binds to IGF-1 receptor and insulin receptor.
Evidences indicate that these pathways play important role in changes of cellular metabolism that are typical feature of tumor cells Evidences suggest that the inhibition of mTOR pathway by metformin proceeds dependent and independent on AMP-activated protein kinase AMPK activation. AMPK phosphorylates tuberous sclerosis complex protein 2 TSC2 that inhibits mTORC1 leading to decrease in protein synthesis and cell growth Among the first studies that showed the participation of AMPK activation in antitumor action of metformin were researches performed on breast cancer cells 18 , Dowling et al.
showed that compound C, an inhibitor of AMPK, reversed inhibition of initiation of translation evoked by metformin More recently, Mohammed et al. showed reduction of carcinoma spread in pancreas of transgenic mice fed with metformin Additionally, pancreatic tissue of mice fed with metformin revealed a significant inhibition of mTOR, and an increase of phosphorylated AMPK and TSC2 However, Gwinn el al.
demonstrated that inhibition of mTOR could be independent on TSC2, since AMPK directly phosphorylates the rotor compartment of mTOR Several studies identified that liver kinase B1 LKB1 , a major upstream kinase of AMPK, may be involved in anticancer action of metfromin associated with inhibition of mTOR.
In vitro and in vivo studies revealed that deletion of LKB1 function accelerated proliferation of tumor cell and sensitized them to activators of AMPK such as biguanide 22 - Due to the fact that p53 expression and phosphorylation is regulated by AMPK and p53 is involved in cell metabolism and control of cell cycle its participation in metformin action is discussed.
However, others researches indicated that inhibitory effect on cancer cell growth of metformin was associated with p53 activity 28 - Taking together the results of preclinical studies are inconclusive whether antitumor action of metformin is associated with p Some investigators hypothesize that the dose of metformin may determine the effect of metformin.
Yi et al. demonstrated on hepatoma cells that low concentration of metformin induced pdependent senescence, whereas higher doses induced apoptotic cell death Inhibition of mTOR by metformin independent on AMPK activation was demonstrated by Memmott et al.
in mice lung cancer cells Kalender et al. demonstrated in Drosophilla cells that inhibition of mTOR signaling induced by metformin occurred in the absence of AMPK. Metformin was found to inhibit breast carcinoma cell growth through decreasing level of epidermal growth factor receptor 2 HER2.
This effect was mediated by inhibition of the mTOR effector, p70S6K1 p70S6K is responsible for the phosphorylation of S6 ribosomal protein and thereby protein synthesis at the ribosome Antiproliferative action of metformin related to enhancement of DNA-damage-inducible transcript 4 protein DDIT4, REDD1 expression, a negative regulator of mTOR, was reported in prostate cancer cells by Ben Sahra et al.
This effect of metformin was also independent on AMPK activation The results of preclinical studies undoubtedly confirm the efficacy of metformin to inhibit cancer cell growth in vitro and to reduce tumor spread in animal models of various cancers.
Metformin-induced AMPK activation may downregulate CD39 and CD79 gene expression thereby reducing myeloid-derived suppressor cell-driven immunosuppression [ 47 ]. Tumour-associated macrophages have been shown to be immunosuppressive through production of specific immunomodulatory cytokines promoting tumour growth.
Metformin and its role in cancer prevention is an area that has been underexplored in prospective studies. Indeed, the epidemiological data provide a strong rationale for testing this hypothesis in selected groups of patients, for example, obese or insulin-resistant individuals and now early clinical trial data is emerging in support.
Metformin has been shown to suppress intestinal polyp growth in a murine model of familial adenomatous polyposis coli [ 51 ] and a subsequent randomised clinical trial showed that metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy following 12 months of treatment with metformin [ 52 ].
However, prevention studies designed to identify differences in cancer incidence are notoriously difficult to execute given the numbers of patients needed to properly power such a trial and the length of time it takes to complete adequate follow-up.
However, opportunity lies in investigating the potential of metformin as cancer preventative for patients with cancer predisposition syndromes which will allow for smaller studies and shorter follow-up. LFS is caused by germline pathogenic variants in the TP53 tumour suppressor gene [ 53 ] and in studies of mice carrying a knock-in missense mutation of TP53 , metformin increases their cancer-free survival [ 54 , 55 ].
On this basis, randomised clinical trials are now moving forward to evaluate whether metformin can reduce cancer incidence in this high-risk population. In summary, outcomes from late-phase efficacy studies testing metformin as a repurposed cancer therapeutic have been disappointing.
In a rush to establish its potential utility, such trials were designed prior to due diligence with regard to patient selection, mechanism of action and appropriate combination.
New avenues of investigation in selected populations including the assessment of combination with immunotherapy, and potential as a cancer preventative agent still warrant well-designed clinical investigation. Prasad V, Mailankody S. Research and development spending to bring a single cancer drug to market and revenues after approval.
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Journal of Healthy cauliflower dishes Medicine volume 21Mstformin number: Cite this article. Metrics details. Metformin is a well-known anti-diabetic drug that has preventtion repurposed for Megformin Metformin and cancer prevention applications, Recovery supplements as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Mstformin Metformin has been Mdtformin to Metforminn anti-cancer properties in addition to glucose-lowering activity and Healthy cauliflower dishes systematic reviews and meta-analyses have studied Metformin and cancer prevention association between metformin use Metfkrmin cancer incidence or Cardiovascular training for beginners outcomes. We performed an umbrella review to assess Metforjin robustness of these Metformin and cancer prevention to facilitate proper interpretation of these results to inform clinical and policy decisions. Methods: We searched PubMed and Embase systematic reviews and meta-analyses investigating the effect of metformin use on cancer incidence or survival outcomes published from inception to September 2, Results: We included 21 systematic reviews and meta-analyses covering 11 major anatomical sites and 33 associations. There was strong evidence for the association between metformin use and decreased pancreatic cancer incidence. The association between metformin use and improved colorectal cancer overall survival OS was supported by highly suggestive evidence.
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