Repurposing inactive as well as, greater people

Repurposing Metformin For Use In Cancer Therapy
Introduction 
There are two types of diabetes type 1 and type 2. Type 1 diabetes is an autoimmune disease and is caused by the loss of the function beta-cells. Type 2 diabetes is whereby the body needs more insulin, due to insulin resistance caused by weight gain and physical inactivity. Both types of diabetes have environmental and genetic factor links (Tuomi, 2005).  
The prevalence of diabetes is dramatically increasing in the United states and worldwide. In 1985 there were 30 million people suffering from diabetes around the world, in 1995 this had increased to 135 million of the worldwide population. By 2025 it is estimated that the occurrence of diabetes is set to increase by 42% affecting 300 million people. (Winer and Sowers, 2004) 90% of the incidence of diabetes is suspected to be type 2 diabetes. (Winer and Sowers, 2004). In the UK according to the NICE 2015 guidelines Metformin (see figure 1) is the first line of drug treatment for type 2 diabetics. (Nice Guideline 2015)  

Cancer is a devastating illness that can have devastating affects on society globally. The number of people diagnosed with cancer is increasing this is due to; an increase in the ageing population, an increasing number of people who are overweight and physically inactive as well as, greater people smoking. In 2012 according to GLOBOCAN it was estimated that 14.1 million cancer cases were raised, and 8.2 million deaths happened world-wide. 57% of worldwide cancer cases and 65% of worldwide deaths occur in developing countries. Globally lung cancer is the most prevalent amongst males. The incidence rates of cancer for males and females are twice as high in developed countries than developing countries. However, mortality rates from cancer are only 8-15% higher in developed countries. This disproportionality reflects availability of treatment, lifestyle factors and the detection of cancer. The biggest risk factors for cancer are smoking obesity, physical inactivity and infection. Smoking is particularly linked with cancers such as lung, liver and stomach cancer. Obesity and physical inactivity are risk factors for breast and colorectal cancer. Infection is a risk for stomach and liver cancer. Many cancers could have been prevented by applying the correct prevention strategies for example, stop smoking, vaccination, and detecting cancer at an early stage. (Torre et al., 2015)
This paper will be focusing on the relationship between diabetes and cancer and on metformin’s ability to treat cancer. The main research aims of this paper are. To see if metformin alone is an effective agent in treating cancer. To see if metfromin is able to be used long term to treat cancer in doses that are within the safe therapeutic rang to treat type 2 diabetes. To see if metformin is more likely to have an increased anti-cancer effect on cancers which are associated with hyperinsulinmia. To see if metformin is able to be used along side traditional cancer treatments, in order to increase the efficiency of the traditional cancer treatment and to lower the doses.   
Metformin and Diabetes 
Metformin primarily works by reducing serum glucose levels. Metformin is named an insulin sensitiser as it stimulates the effect of insulin. It stops the liver producing glucose, which is because of a decrease in the production of gluconeogenesis as well as an effect on glycogenolysis. Metformin triggers an enzyme called adenosine monophosphate kinase (AMPK) which stops the synthesis of gluconeogenesis and glycogen synthesis in the liver by enzyme inhibition involved in these processes. Simultaneously, it transports glucose to the muscles and encourages insulin signalling. (Nasri and Rafieian-Kopaei, 2014). 
Metformin is a hydrophilic base which is existent as a cationic species at a pH of 7.4. As a result transport through cell membranes via passive diffusion should be controlled. Metformin is absorbed from the small intestine and has an oral bioavailability of 55±16%. (Graham et al., 2011)    
Metformin and Cancer 
Recent studies have shown that metformin can be used for cancer treatment, as metformin has shown to have cancer preventative properties in patients with diabetes. As well as having a better prognosis of cancer in patients who have diabetes. Epidemiological studies have been conducted to observe the effect of metformin on cancer. A cohort study where 4,085 type 2 diabetic patients took metformin and 4,085 patients did not take metformin were compared. The patients who took metformin had a reduced risk of cancer. 7.3% of people who took metformin were diagnosed with cancer compared to 11.6% of those who did not. (Chae et al., 2016) 
Metformin belongs to a group of drugs called Biguanides, it is the most common biguanide that is prescribed and is now emerging as a possible cancer drug. Clinical and epidemiological studies have shown evidence that metformin can be suitable as a therapeutic cancer agent. Metformin’s primary affect of lowering circulating insulin may be crucial for cancers related to hyperinsulinemia such as breast and colon cancer. However, metformin’s main mechanism of inhibiting the growth of cancer cells is through inhibiting the mammalian target of rampamycin (Mtor) signalling including protein synthesis. (Dowling, Goodwin and Stambolic, 2011)   
Metformin can also exert an anti-cancerous affect by its ability to reduce the circulatory level of insulin in the blood and insulin-like growth factor 1 (IGF-1). Insulin and IGF-1 are also involved in carcinogenesis, through the balance of the insulin/IGF receptor signalling pathway. Insulin leads to an increase in the liver producing IGF-1 which binds to the IGF-1 receptor and the insulin receptor. Through the insulin receptor substrate (IRS) the signal is dispatched to phosphoinositide 3-kinase (PI3K), as well as AKt/protein kinase B (PKB) this then activates Mtorc1. Also, the insulin receptor through growth factor receptor-bound protein 2 (GR B2) propagates signal to Ras/Raf/ERK pathway that urges cell growth. Evidence suggests that these pathways play a pivotal role in carrying out changes of cellular metabolism which are identifiable of tumour cells. A lot of cancers are associated with an increased level of circulating insulin/IGF1 as well as, upregulation of insulin/IGF receptor signalling pathways. Metformin has been found to lower insulin levels, change cellular metabolism and stop signalling pathways in cancerous cells and non-cancerous cells. (Kasznicki, et al 2014).           
Pre-clinical evidence is indicating that metformin has anti-cancer properties against colorectal cancer. The study was conducted on cancer cell lines and xenografts therefore, they will need more than normal amounts of metformin. Patient derived xenografts were generated from two colorectal cancer patients in order to examine the effects of 5-fluorouracil and metformin. 150mg/kg of orally administered metformin, administered for 24 days inhabited the growth of patient derived xenografts tumours by 50%. In a different patient derived xenografts model metformin given simultaneously with 25mg/kg 5-Fluorouracil lead to an 85% growth inhibition. (Mohamed Suhaimi et al., 2017) This shows that metformin can be used along side cancer drugs to exert an increased anti-cancerous affect. 
Algire et al demonstrated the efficacy of metformin in a Clinical study of repurposing metformin for lung cancer treatment and management, on two lung cancer animal models. Cell lines and xenograft cells of prostate, breast and lung cancer the anticancerous effects were observed. Metformin worked on the cancer stem cells by increasing CD44 and decreasing CD24. Metformin was given 200/ml (15mg/kg) in an oral intake in drinking water. The results were that metformin reduced the dose of doxorubicin the chemotherapy agent. (Chen et al 2017) This shows that metformin can be used along side cancer agents to be able to reduce the dose of usual cancer treatments this could save money, time and reduce side effects most importantly.      
A study has investigated the effects of metformin on the cancer cells of the glioma, ovarian, endometrial, breast and colon. For metformin to have an anti-cancer affect on its own, extremely high doses are required which are out of the type 2 diabetes therapeutic range. These high does of metformin can cause fatal side effects in particular lactic acidosis. Therefore it is crucial to develop the efficacy of the anticancer properties of metformin to lower the dose to prevent fatal side effects. (Yoo et al., 2017)
Future Directions
In order for metformin to be given alone as an anticancer treatment at doses which are used to treat type 2 diabetics, metformin should be given over a prolonged time period or be given with another therapeutic method such as radiotherapy, chemotherapy or hyperthermia. These are an alternative to receiving metformin at extreme high doses. (Yoo et al., 2017) Chemotherapy drugs do not have specific affects on cancerous cells causing toxicity, and weakening of the immune system. Nanotechnology based chemotherapies have the ability to precisely target cancerous cells with a low amount of toxicity and intensified efficacy. (Gao et al., 2014) Lee et al proposed that putting metformin onto multi-walled carbon nanotubes (MWNTs-Met/PEG) (see figure 2) beneath near-infrared radiation would increase the results of cancerous cells to metformin as well as reducing the dose. The carbon nanotubes provide precise drug targeting and localised heating to the cancerous cells. The cytotoxicity of metformin was increased via the photo thermal condition rather than then hyperthermia condition. (Yoo et al., 2017)

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Figure 2 Diagram of MWNTs-Met/PEG synthesis 
(This image is has been licensed under a Creative Commons Attribution 4.0 International License, permitting sharing and replication). Copy of The license https://creativecommons.org/licenses/by/4.0/legalcode  (Yop et al., 2017) 
Colorectal cancer is a cancer that is common worldwide, its treatment has server adverse effects and the drug treatment is non selective. Therefore, a better option would be to develop a safe drug with good bioavliability and a good drug targeting profile. Metformin loaded solid nanoparticles were created and were specified for the size of the particle, thermal behaviour, zeta potential, structure, crystallinity, drug entrapment, structure, drug release and morphology. The ideal solid lipid nanoparticles were the size 195.01 ±6.03nm, the surface charge was -17.08 ±0.95mv, they were amorphous, the shape was fibrous and the release of metformin was controlled. This ideal optimised charge, shape and size indicate that the solid lipid nanoparticles will drift and gather in the colon tumour, inhibiting tumour cell proliferation and lead to cell death and inhibit tumour growth. (Ngwuluka, Kotak and Devarajan 2016)
Hirsh et al has demonstrated that low doses of metformin 0.1mM or 0.3mM eliminate cancer stem cells. Cancer stem cells are resistant to chemotherapy therefore, cancer relapse takes place. (Yoo et al., 2017) This shows metrormin can be used at low doses which do not cause lactic acidosis. 
Lee et al have researched that metformin’s anti-cancerous effects on breast cancer are increased under hyperthermia conditions however, the concentration of metformin is very low at 30µ. This is the concentration of metformin in blood plasma of type 2 diabetics under metformin treatment (Yoo et al., 2017). Therefore, metformin can be used for cancer treatment at therapeutic doses used to treat diabetes.  
Eikaura et al established that the anti-cancer effect of metformin is because it exerts an immune-mediated anti tumour effect by protecting the CD8+ tumour-infiltrating lymphocytes from apoptosis as well as, unavoidable functional exhaustion in the cancerous cells small scale environment, preventing cancerous cells from growing. Metformis anti cancerous effect on CD8+ tumour-infiltrating lymphocytes are recognisable at low concentrations of 10µ. (Yoo et al., 2017) This is also indicative that Metformin can be used at low doses that are not going to cause adverse effects.
A study established a relationship between boswellic acid nano-particles and metformin. The metformin was kept at a constant dose of 20mM but there were different doses of boswellic acid nanoparticles. The effect of boswellic acid nanoparticles was increased with metformin. There was an 80% retardation of cell proliferation, this was with 20mM metformin and a mixture of 0.3g/mL and 0.4g/mL of boswellic acid nanoparticles. The retardation effect on pancreatic cell lines (MiaPaCa-2) was dependent upon time, with relation to combination therapy. There was a great rate of induction apopotsis along DNA fragmentation in the pancreatic cells that have cancer. The in-vitro lysis confirmed the compatibility of the blood with the combination therapy. Cell death via apoptosis was verified by proteinase apoptosis. The cells were considered in great detail under the TMRE-Mitochondrial membrane potential assay kit. The results were that there was a decrease of mitochondrial membrane potential because of apoptosis after combination dug treatment. (Snima et al., 2015) 
Conclusion
In conclusion, the research aims of the paper have been answered. Metformin alone was not effective in treating cancer as, extremely high doses were required. Combination therapy with radiotherapy or chemotherapy will exert the efficacy of metformin’s anti-cancerous properties. Metformin is also able to lower the doses of conventional treatments used to treat cancer.