the current worldwide diabetic epidemic is not only influencing the morbidity and mortality of the present generation , but with no doubt has a trans - generational epigenetic inheritance impact with increasing prevalence for cancer with type 2 diabetes mellitus ( t2 dm ) 1 - 3 . the raised risk of cancer in t2 dm 4 - 7 , and with a demographic shift in age towards the over 65 years old , translates into considerable financial and social burden on finite health care budgets . the link between t2 dm and raised incidence of colorectal cancer ( crc ) and prostate cancer ( pc ) , and mortality , has been related to a constellation of risk factors pertaining to metabolic syndromes , specifically insulin resistance , hyperinsulinemia , and hyperglycemia 8 - 11 . a significant point to note here is that excessive plasma concentration of insulin and glucose correlate with accelerated aging 12 . hence , there is an urgent need for targeted therapy for comorbid diabetes and cancer . one such medication is the old workhorse for t2 dm , metformin , which has generated considerable attention . therefore , our review primarily focuses on metformin use in diabetics with either colorectal or prostate cancers . the properties and biological mechanisms of metformin are further discussed in relation to diabetes and cancer , followed by its applications in in vitro , in vivo and clinical studies . the history of metformin , a biguanide derivative , dates back to the middle - ages , and its structural analogue galegine was isolated from galega officinalis ( goat 's rue , french lilac , italian fitch ) ; a plant native to the middle east that has been used for treatment of diabetes in europe 13 . accumulating evidence shows beneficial survival effects of therapeutic intervention with metformin for cancer patients with t2 dm ( fig . metformin , a cationic ( hydrophilic base ) drug , exerts its pleiotropic pharmacological effects beyond those of metabolic control 14 , and includes favorable anti - inflammatory outcomes 15 , 16 . information on the pharmacological response to metformin requires an understanding of both its pharmacokinetics and genetic variation of the different transporters for the di - directional movement of metformin across plasma membranes 17 ( fig.2 ) . metformin is absorbed from the lumen of the gastrointestinal tract ( gi ) through plasma membrane monoamine transporter ( pmat , or equilibrative nucleoside transporter - ent-4 ) 18 . by its passage through the organic cation transporter 1 ( oct1 ) , located in the basolateral membrane of human hepatocytes indeed , this was confirmed by investigations on oct1 gene - deficient mice , where the uptake of metformin in hepatic and intestinal tissues was lower , compared to control animals 19 . these studies implied that oct1 is pivotal for raising the intracellular concentration of metformin ; and as a corollary , there was a corresponding derangement in glucose metabolism 19 . interestingly , metformin is excreted unmetabolized through mutli - drug and toxin extrusion 1 ( mate1 ) and mate2 , located in the apical membrane of kidney proximal tubular cells , into urine 20 . recent studies suggest that substantial inter - individual heterogeneity in metformin pharmacokinetics exists , and this is recognized to be due to genetic variants of different metformin transporter proteins 20 - 22 . reduced expression or altered functionality of transporter proteins will result in less than optimum pharmacotherapy or undesirable toxic effects of metformin . due to the reduced uptake of glucose from the intestinal tract , metformin improves insulin sensitivity by increasing peripheral glucose absorption and utilization by adipose tissue and skeletal muscle . it reduces hyperinsulinemia and improves insulin resistance by enhancing the affinity of insulin receptor for insulin 23 . moreover , metformin - driven benefits negate dyslipidemia by creating a milieu to give rise to lower circulating levels of total cholesterol , low - density lipoprotein ( ldl ) and triglycerides 24 . in addition , administration of metformin to patients promotes lower body weight or at least weight neutrality 25 , 26 . importantly , metformin is a low cost drug with a well characterized safety profile in management of diabetes and cancer . metformin inhibits complex 1 of mitochondrial electron transport chain 27 - 29 , and thereby attenuates oxidative respiration resulting in atp / amp ratio imbalance , which in turn activates liver kinase b1 ( lkb1 ) and ampk 29 , 30 . dephosphorylation by protein phosphatase 2a ( pp2a ) reversibly decreases enzyme efficiency ( inactivation ) of ampk . interestingly , metformin interplay with cellular metabolic homeostasis extends to inhibition of amp deaminase to increase the pool of amp available for activation of ampk 31 . thus , ampk can choreograph a network of diverse molecular signaling routes depending on the contextual requirements for physiological cellular homeostasis and/or pathophysiological states ( fig . metformin acts cooperatively with the upstream kinase lkb1 to activate ampk , the master regulator of metabolic homeostasis , resulting in the attenuation of plasma concentrations of risk factors , namely glucose , insulin , triglycerides and cholesterol 9 , 32 , 33 . metformin , via ampk , controls the activity and expression of key regulatory lipid enzymes that have been identified in metabolic reprogramming of cancers . phosphorylated ampk , by upstream metformin - mediated effect , markedly reduces the expression ( mrna and protein ) of lipogenic transcription factor sterol regulatory element - binding protein-1 ( srebp-1 ) and hence its targeted genes are also downregulated such as fatty acid synthase ( fas ) 30 , 34 , and 3-hydroxy-3-methyl glutaryl - coa reductase ( hmgr , membrane - bound enzyme ) , which is known to reduce hmg - coa to mevalonate 35 . in addition , ampk directly inactivates hmgr by phosphorylation at serine 872 , thus essentially abating cholesterol synthesis 36 . also , statins , which are reportedly used for anti - cancer therapy , lower cholesterol by inhibiting hmgr 37 - 39 , which is up - regulated in many forms of cancers 40 . moreover , the activated form of ampk alters the activity of another type of lipogenic enzyme , acetyl - coa carboxylase ( acc ) , which exists in two isoforms : acc1 ( acc- ) and acc2 ( acc- ) . phosphorylation of aac1 switches on fatty acid synthesis through its metabolite malonyl - coa , while acc2 controls fatty acid oxidation 41 . contextually of interest is the silencing by small interfering rna ( sirna ) of acc1 gene that leads to growth arrest and caspase - dependent apoptosis of the human lipogenic lncap prostate cancer cell line 42 . altogether , these inhibitory signaling arrays of metabolic activity mitigate the burden of cancer - promoting effect of high fat diets . cellular growth - retarding contributions of metformin occur downstream from activation of lkb1/ampk pathway , inhibition of mtor , stabilization of the transcription factor p53 ( its degradation is suppressed with downregulation of cyclin d1 43 and associated increases in the expression of cyclin - dependent kinase inhibitors p27 and p21 
 44 . the transcription factor p53 contributes to p21 gene transcription ; and up - regulates the expression of apoptotic genes ( bax , caspase-3 , 8 , 9 ) 45 . these molecular signaling events channel cells to latency and hence drive them to accumulate in the go / g1 cell cycle phase ; dna - damage and fragmentation ensues , leading to tumor suppression and further to autophagy and/or apoptosis 46 . in addition , metformin - activated ampk phosphorylates ulk1 at serines 317 and 777 to ultimately induce mitophagy , autophagy as well as cell death , and subsequently apoptosis and reduction of tumor size 47 , 48 . furthermore , nf-b is a transcription factor associated with apoptosis , inflammation , oxidative stress and neoplastic malignancy , which are all inhibited by metformin - stimulated ampk 48 - 51 . evidently all of this is reflected by the aforementioned investigations on cell lines , animal models and beneficial survival outcomes of therapeutic intervention studies with metformin for cancer - related patients with t2 dm . antiproliferative actions of ampk , activated by metformin , suppress the growth of human umbilical vein endothelial cells ( huvec ) 52 as well as human and rat aortic smooth muscle cells 16 , 53 , thus preventing tumor angiogenesis 54 . intuitively , this will lead to starving of the tumor of nutrients , thereby limiting biosynthetic processes for macromolecules and hence cell growth for malignancy . therefore , such multi - actions of ampk suppress tumors with greater efficacy . also , ampk directly phosphorylates tsc2 tumor suppressor ( phosphorylated at dual locations : threonine 1227 and serine 1345 55 and raptor ( regulatory - associated protein of mtor , phosphorylated at serines 722 and 792 ) 56 , a constituent subunit of mtorc1 ( mammalian target of rapamycin ) , to suppress mtorc1 activity 55 , 56 . moreover , metformin directly interacts with mtorc1 to inhibit its effects downstream , the ribosomal protein s6 , s6 kinase 1 ( s6k1 ) and the translation initiation factor 4e binding protein 1 ( 4e - bp1 ) , and again this induces cell cycle arrest and inhibits dna synthesis 57 . metformin arrests hyperinsulinemia - induced free radicals ( superoxide anion radical , hydroxyl radicals ) and reactive oxygen species ( ros , hydrogen peroxide ) , which are integral to oxidative stress ( imbalance between oxidants and antioxidants ) and play an active mechanistic role in most cancers , and cell death is associated with generation of ros 50 , 58 - 61 . ampk in conjunction with the transcription factor foxo3 lessens the fatty acid - induced generation of intracellular ros by up - regulating the expression of the antioxidant thioredoxin 62 - 64 , and the reduction in nadph oxidase activity 65 . in contrast , reactive oxygen species , such as hydrogen peroxide , significantly activates the ampk sub - unit to inhibit mtorc1 signaling and induce apoptosis 66 . taken together , this implies that metformin may lower cancer risk owing to its inherent properties of improving an altered metabolic picture , which is reflected by a fall in plasma glucose and insulin concentrations 32 . evidence from a panel of cancer cell lines 43 , 67 , 68 , animal models 43 , 68 , 69 and epidemiological studies 70 - 73 suggests that metformin not only improves the life style and well - being , but lowers the rates of mortality in crc 74 and pc 75 . multi - ethnic epidemiological studies have revealed disparity between ethnic groups of patients with pc risk due to diabetes and/or different medication ( metformin ) 6 , 73 , 75 . however , in one of the latter meta - analysis studies on pc , the authors added a caveat that additional long - term investigations on the use of metformin for pc must be forthcoming for concrete confirmation of the available data 75 . appropriately , triggered by these promising anti - tumorigenic benefits of metformin , epidemiologists have initiated clinical trials centered on a variety of tumors , including colorectal ( 5 ongoing clinical trials ) and prostate ( 3 ongoing clinical trials ) cancers with diabetes , and these can be located at http://www.clinicaltrials.gov/ website . continuing from above , recent evidence has commenced a debate on whether ampk is a suppressor of cancer or an oncogenic member of signaling cascade 76 , 77 . this is perhaps an issue of the extent of ampk activation , where at low activity it may not be a potent anti - cancer agent , but sustained high activation may be critical for inhibition on growth and survival of tumors . in the same context , it is not clear from the literature if any dose response curves for metformin as a chemotherapeutic agent have been performed on ampk activity . consideration must be given to the subject of genetic polymorphism of organic cation transporters ( oct1 and oct2 ) , which may affect the population - based individual variability and hence clinical efficacy of metformin 78 . therefore , this necessitates further studies to ensure and to consolidate that the thesis on metformin - activated ampk is water - tight as an inhibitor of proliferative growth in cancers . to conclude , recent advances in pinpointing the molecular control points that orchestrate the myriad of transduction pathways is pivotal to personalized therapy for cancer and other treatments , and the metformin research has rightly focused on ampk , the master metabolic sensor . on a cautionary note , tumors are heterogeneous by character , and as mother nature has its own surprises , therefore it may be prudent to target more than one molecule as this approach may be more efficacious . overall though , the preceding statements confirm that metformin is as a mono - therapeutic agent with multi - fold targets ( table 1 and 2 ) . although an arsenal of therapeutic drugs is available for the management of different categories of cancer with type 2 diabetes mellitus , metformin remains the most widely used medication for t2 dm . recently , ampk has received considerable attention regarding its central role as a metabolic homeostasis sustaining rheo - transducer as well as an inter - link between signaling routes between diabetes and cancer . further preclinical and clinical investigations are ongoing to evaluate the therapeutic benefits of metformin on ampk activation as an anti - diabetic , anti - proliferative , hypoinsulinemic , apoptotic and hence anti - carcinogenic agent . indeed , results with metformin demonstrate that ampk is an ideal target for activation in both crc and pc , and moreover metformin has other beneficial pleotropic targets in addition to metabolic control . in this context , and considering the afore - mentioned paragraphs , its effects on aberrant homeostasis in t2 dm , crc and pc are truly remarkable . hence , it potentially holds substantial promise as a positive dual modifier of deranged metabolic homeostasis and as an anti - neoplastic agent .
both diabetes and cancer are prevalent diseases whose incidence rates are increasing worldwide , especially in countries that are undergoing rapid industrialization changes . apparently , lifestyle risk factors including diet , physical inactivity and obesity play pivotal , yet preventable , roles in the etiology of both diseases . 
 epidemiological studies provide strong evidence that subjects with diabetes are at significantly higher risk of developing many forms of cancer and especially solid tumors . 
 in addition to pancreatic and breast cancer , the incidence of colorectal cancer and prostate cancer is increased in type 2 diabetes . while diabetes ( type 2 ) and cancer share many risk factors , the biological links between the two diseases are poorly characterized . in this review , 
 we highlight the mechanistic pathways that link diabetes to colorectal and prostate cancer and the use of metformin , a diabetes drug , to prevent and/or treat colorectal and prostate cancer . 
 we review the role of ampk activation in autophagy , oxidative stress , inflammation , apoptosis , and cell cycle progression .