A. Human Studies on Pancreatic Cancer Risk and Mortality with Metformin Use Among Diabetics, B. Human Studies on Overall Cancer Risk and Mortality with Metformin Use Among Diabetics
1. Introduction
Numerous epidemiological studies have reported that metformin, a well-known and widely used anti-diabetic drug, may provide protective benefits in decreasing pancreatic cancer risk among the diabetic population. Following a brief introduction regarding metformin’s history and pharmacological properties, this book chapter presents epidemiological findings showing how metformin is associated with protection against pancreatic cancer. We also introduce the anti-cancer effects of metformin through AMPK-independent and AMPK-dependent manners [1-6]. These mechanisms include its inhibitory effects on the insulin growth factor-1 (IGF-1), G protein-coupled receptor (GPCR) and mTORC1 signaling pathways [3-10]. We then discuss the metabolic effects of metformin in cancer. For example, metformin has been shown to inhibit glycolysis in various cancer cell lines [11-13]. Metformin is a known inhibitor of complex I of the electron transport chain [14-18], potentially limiting the intact oxidative respiration capabilities of the cancer cell. We also discuss in depth the anti-cancer mechanisms of action of metformin in the context of lipid metabolism as reported in numerous models. These include metformin’s ability to increase fatty acid β-oxidation in adipocytes [19] and its ability to inhibit hepatic lipogenesis [2]. As shown by numerous studies [20-23], metformin also possesses anti-lipogenic properties, potentially limiting this critical metabolic pathway that confers cancer pancreatic cell survival advantage.
We provide preclinical and clinical evidences of the potential utility of metformin in pancreatic cancer. For example, a very recent report has shown tumor growth inhibition
We conclude this chapter by discussing our most recent findings that show how metformin inhibits glucose-derived fatty acid synthesis in the context of available acetyl-CoA and the presence of K-
However, an important question remains on whether or not metformin really has chemopreventive and/or therapeutic use for pancreatic cancer. This chapter argues that metformin does have anti-cancer properties by examining numerous experimental studies on metformin’s potential mechanisms of action along with the metabolic and genetic context by which metformin may act as an anti-cancer drug.
2. The history behind metformin
3. Synthesis, structure and pharmacology of metformin
Metformin has an oral bioavailability of 50-60% under fasting conditions and the peak plasma concentration is reached within a couple of hours. The plasma protein binding is negligible. Metformin is not metabolized but it is accumulated in tissues such as the liver, the kidneys, the salivary glands and the gastrointestinal tract [34]. Eighty percent of the elimination of metformin occurs by the urinary tract. The average elimination half-life in plasma is 6.2 hours. The half-life of biguanides is approximately 2 hours [34]. Interestingly, metformin is distributed to (and appears to accumulate in) red blood cells with a much longer elimination half-life: 17.6 hours.
4. Chemopreventive properties of metformin
Numerous observational studies show that metformin use, when compared against other diabetic agents such as insulin and sulfonylureas, decreases cancer risk and overall cancer mortality among the diabetic population. These protective associations have been reported across different cancer types and among various diabetic populations.
Table 1A summarizes epidemiological studies that show pancreatic cancer risk and cancer mortality associated with metformin use while Table 1B presents observational studies and clinical trials on overall cancer risk and mortality in relation to metformin use. While some studies show a reduction in pancreatic cancer [35-39] and overall cancer risk [37, 39-45] among diabetic metformin users, there are also studies that report no significant difference in cancer risk among diabetics who take metformin compared to patients who take other anti-diabetic treatments [36, 46-51]. These conflicting results may be explained by differences in the study population, the confounding factors accounted for during statistical analysis and the selected study design (e.g., cohort
5. Chemotherapeutic properties of metformin
Experimental studies show that metformin possesses anti-cancer effects in various cancer types. As the metabolic effects of metformin are discussed in the section “Metformin as an Anti-lipogenic Drug,” figure 2 provides a summary of metformin’s effects exclusively on cancer signaling pathways. Overall, we present metformin’s effects on cancer cells as AMPK-dependent (pathways 2, 4, 5, 6 and 10) and independent (pathways 1, 3, 7- 9 and 11). Although there is an overlap between cell signaling and metabolic alterations due to metformin treatment (e.g., via ETC complex I and ATP production, AMPK/mTORC1 axis and metabolic control), metformin’s anti-cancer effects can be grouped into: a) inhibition of ATP and ROS production, b) inhibition of IRS-1/Akt/mTORC1 axis, c) anti-inflammatory effects, d) cell cycle arrest and e) inhibition of general transcription factors.
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Oliveria et al., 2007 [46] | United States | Cohort | Pancreatic cancer risk | Metformin vs no Metformin | RR: 1.26 (0.80-1.99) | Age, gender, gastrectomy, chronic pancreatitis, deep venous thrombosis, dermatomyositis/polymyositis, alcoholism, hepatitis B/C, history of polyps |
Currie et al., 2009 [47] | United Kingdom | Cohort | Progression to pancreatic cancer | Sulfonylureas vs Metformin Metformin + Sulfonylureas vs Metformin Insulin-based therapies |
HR: 0.38 (0.13-1.12) |
Age, sex, smoking status, diagnosis of a previous cancer |
Li et al., 2009 [35] | United States | Case-control | Pancreatic cancer risk | Metformin |
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Age, sex, race smoking, alcohol, BMI, family history of cancer, diabetes duration, use of insulin |
Bodmer et al., 2011 [36] | United Kingdom | Case-control | Pancreatic cancer risk | Metformin (both sexes) Metformin (females only) Sulfonylureas Insulin |
OR: 0.87 (0.59-1.29) |
BMI, smoking, alcohol consumption, diabetes duration |
Ferrara et al., 2011 [48] | United States | Cohort | Pancreatic cancer risk | Metformin and pioglitazone |
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Age, ever use of other diabetes medications, year of cohort entry, sex, race/ethnicity, income, current smoking, baseline HbA1c, diabetes duration, new diabetes diagnosis, creatinine, and congestive heart failure |
Liao et al., 2011 [49] | Taiwan | Cohort | Pancreatic cancer risk | Metformin | HR: 0.85 (0.39-1.89) | Crude/ Unadjusted |
Lee et al., 2011 [37] | Taiwan | Cohort | Pancreatic cancer risk | Metformin vs. potential use of other oral anti-hyperglycemic medications |
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Age, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index score, time-dependent metformin use |
Morden et al., 2011 [50] | United States | Cohort | Pancreatic cancer risk | Metformin | HR: 1.25 (0.89-1.75) | Age category, race/ethnicity, diabetes complications, obesity diagnosis, oral estrogen use, Part D low income subsidy (a poverty indicator), 14 Charlson comorbidities, and tobacco exposure diagnosis |
Ruiter et al., 2012 [38] | Netherlands | Cohort | Pancreatic cancer risk | Metformin vs. sulfonylureas |
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Age at first oral glucose-lowering drug (OGLD) prescription, sex, year in which the first OGLD prescription was dispensed, number of unique drugs used in the year, number of hospitalizations in the year before the start of OGLD |
Sadeghi et al., 2012 [52] | United States | Cohort | Median survival in pancreatic cancer, prognostic factors of overall survival in pancreatic cancer | Metformin vs. Non-metformin Univariate Analysis: Metformin Multivariate Analysis: Metformin |
15.2 months vs. 11.1 months |
No significant differences in BMI, age, sex, race, diabetes duration, disease stage, tumor size, performance status, serum CA-19-9 between metformin and non-metformin group |
Nakai et al., 2013 [51] | Japan | Cohort | Prognostic factors of overall survival in pancreatic cancer | Univariate Analysis: Biguanide Sulfonylureas Insulin Thiazolidine-dione |
HR: 0.61 (0.19-1.44) |
Age (G65 or Q65 years old), sex (male or female), performance status (PS; 0Y1 or 2Y3), primary tumor size (G30 or Q30 mm), distant metastasis (yes or no), body mass index (G22 or Q22 kg/m2), chemotherapy (combination therapy with gemcitabine and S-1 vs others), DM (yes or no), insulin (yes or no), sulfonylurea (yes or no), biguanide (yes or no), thiazolidine (yes or no), hypertension (yes or no), ACEI or ARB (yes or no), Ca-blocker (yes or no), A-blocker (yes or no), and statin (yes or no) |
Singh et al., 2013 [53] | Various | Meta-analysis | Pancreatic cancer risk | Metformin use | OR: 0.76 (0.57-1.03) |
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Zhang et al., 2013 [39] | Various | Meta-analysis | Cancer incidence and mortality | Metformin (and in combination with other drugs) vs. non-users | SRR: Incidence |
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Bold type under “Risk” column indicates statistical significance using 95% confidence interval. HR, hazard ratio; OR, odds ratio, SRR, summary relative risk. | ||||||
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Evans et al., 2005 [41] | Scotland | Case-control | Cancer incidence | Metformin vs. no metformin | OR: 0.77 (0.64-0.92) | Smoking, body mass index, blood pressure, and postcode rank for material deprivation |
Libby et al., 2009 [40] | Scotland | Nested case-control | Cancer deaths | Metformin vs. no metformin | HR: 0.63 (0.53-0.75) | Sex, age, BMI, A1C, deprivation, smoking, other drug use |
Monami et al., 2009 [42] | Italy | Case-control | Cancer incidence | 36 mo metformin vs no metformin | OR: 0.28 (0.13-0.57) | Concomitant therapies, exposure to metformin and gliclazide |
Bowker et al., 2010 [44] | Canada | Cohort | Cancer death | Metformin vs. sulfonylurea | HR: 0.80 (0.65-0.98) | Age, sex and chronic disease score |
Home et al., 2010 [54] | Various | Randomized control trials | Cancer incidence | Metformin vs. rosiglitazone Metformin vs. glibenclamide Metformin + sulfonylurea vs. Rosiglitazone + sulfonylurea |
HR: 0.92 (0.63-1.35) HR: 0.78 (0.53-1.14) HR: 1.22 (0.86-1.74) |
Not reported |
Landman et al., 2010 [45] | Netherlands | Cohort | Cancer mortality | Metformin vs. no metformin | HR: 0.43 (0.23-0.80) | Smoking (yes or no), age, sex, diabetes duration, A1C, serum creatinine, BMI, blood pressure, total cholesterol–to–HDL ratio, albuminuria, insulin use, sulfonylurea use, and macrovascular complications (yes or no) |
Lee et al., 2011 [37] | Taiwan | Cohort | Cancer incidence | Metformin vs. no metformin | HR: 0.12 (0.08-0.19) | age, gender, other oral anti-hyperglycemic medication usage, CCI score and dose and duration of metformin exposure |
Monami et al., 2011 [43] | Italy | Case-control | Cancer incidence | Metformin vs. no metformin in patients under insulin treatment, | OR: 0.46 (0.25-0.85) | Charlson comorbidity score (CCS), glargine mean daily dose (MDD), and total MDD of insulin |
Zhang et al., 2013 [39] | Various | Meta-analysis | Cancer incidence and mortality | Metformin (and in combination with other drugs) vs. non-users | SRR: Incidence 0.73 (0.64-0.83) Mortality 0.82 (0.76-0.89 |
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Bold type under “Risk” column indicates statistical significance using 95% confidence interval. HR, hazard ratio; OR, odds ratio, SRR, summary relative risk. |
6. Overall physiological and cellular effects of metformin in cancer models
Contrary to sulfonylureas, which act at the level of the pancreatic secretion of insulin, biguanides act at the level of sensitivity of the target tissues for insulin. Moreover, the biguanides can reduce the hyperglycemia without leading to incidental hypoglycemia. Hence, the term “anti-glycemic” agent was coined for metformin.
In the late 90s, amongst many studies published on the cellular effects of metformin, we showed that metformin is able to modulate the insulin receptor (IR) in cholesterol (chol)-treated human hepatoma cells, HepG2 [69]. In that study, we used a cellular model in which insulin sensitivity was altered by supplementing the culture medium of HepG2 cells with a derivative of CHOL, cholesteryl hemisuccinate (CHS) [70, 71]. Overall, metformin did not affect IR phosphorylation in control cells. However, metformin affected IR autophosphorylation in CHS-treated cells. At 1 and 5 min of insulin stimulation, metformin increased IR phosphorylation in these cells, restoring IR phosphorylation in CHS-treated cells towards control levels. As mentioned earlier, metformin is a charged biguanide, requiring cell surface transport protein for its influx [72] and exhibits membrane effects as well as cellular effects [73]. Pertinent to our early work, recent studies from Algire et al. [74] demonstrated that a high energy diet promotes tumor growth and that metformin decreases tumor volume only in high-energy fed animals. The authors suggest that,
After nearly two decades of research and approval of metformin by the FDA in 1994, the target of the compound has yet to be identified. Arguably, as mentioned above, metformin is a charged biguanide, requiring cell surface transport protein for its influx [75] and exhibits membrane effects as well as cellular effects [73]. While Algire et al found that the anti-tumor effect of metformin was limited in animals on high-energy diets using
Finally, the fact that metformin prevents tumor development and growth in nude mice [5], supports a potential priming effect of metformin on the host potentially limiting the availability of ‘onco’ metabolites for which the tumor is ‘addicted’. These types of studies investigating the processes of carcinogenesis, may address important gaps in current knowledge regarding the role of tumor metabolism in drug response. We strongly believe that mechanistic insight on these issues will have exceptionally high impact and potentially re-shape current paradigms about anti-metabolic drugs, pancreatic cancer treatment and personalized medicine. Indeed, we speculate that the efficacy of metformin – and possibly drugs with similar mechanism – depends on the metabolic context in which the tumor exists. This is potentially, a paradigm-changing concept as it suggests that host/tissue metabolic factors play a role in tumor conditioning and influence treatment response; a hypothesis that has not previously been considered in the clinical evaluation of metformin.
6.1. Metformin as a glucose lowering drug
Metformin works by decreasing hepatic gluconeogenesis [81], activating insulin receptor tyrosine phosphorylation [82], decreasing intestinal glucose absorption and increasing skeletal and adipose tissue glucose uptake [82]. One mechanistic study conducted in mice demonstrates that metformin (250 mg/kg/day for three consecutive days) increases the association of the glycolytic enzymes hexokinase to the mitochondria and phosphofuctokinase to F-actin in mice hearts [83]. These associations result in their activation and up-regulation in glycolysis, increasing cardiac glucose utilization which may partly explain the cardio protective effects of the drug [84, 85]. Since 1995, metformin has been a widely prescribed glucose lowering agent in the United States for type 2 diabetic and polycystic ovary syndrome patients. It is a well-tolerated drug with lactic acidosis as a reported serious side effect [86]. However, the link between lactic acidosis and metformin use has recently been questioned [87].
6.2. Metformin as an anti-lipogenic drug
Dating back to the 1920’s, Otto Warburg published his observations on the metabolic aberrations of cancer cells. In the seminal paper entitled “The Metabolism of Tumors in the Body,” Warburg and colleagues showed the absence of lactic acid accumulation in the blood of normal animals (no cancer) [88]. Whereas, animals with tumors accrued greater concentration of lactic acid in venous compared to arterial blood as well as in the tumor cavity, indicating the formation of lactic acid from glucose fermentation as blood goes through the tumor [88].
The reliance of cancer cells on glucose metabolism stems from their need to generate metabolites and reducing equivalents that are used to support crucial biosynthetic reactions that make lipids, nucleotides and amino acids. These biomolecules are rate-limiting for cell proliferation and survival. Glycolysis yields glucose-6-phosphate that enters the oxidative arm of the Pentose Phosphate Pathway (PPP). The oxidative PPP produces NADPH which, together with acetyl-CoA, fuels lipid synthesis in the cytosol. The non-oxidative branch of the PPP yields ribose-5-phosphate that is the precursor for nucleotides. In fact, as early as 1998, it has been argued that the both PPP branches (but primarily the non-oxidative branch) serve to produce ribose to sustain the increased needs of the cancer cell for DNA and RNA [89]. Fructose-6-phosphate and glyceraldehyde-3-phosphate are by-products of the glycolytic and the non-oxidative pentose phosphate pathways, providing an intimate link between glucose metabolism and nucleotide generation. Acetyl-CoA produced from the pyruvate dehydrogenase reaction enters the tricarboxylic acid (TCA) cycle in the mitochondria. Citrate can be exported from the mitochondria into the cytosol and converted back to acetyl-CoA (catalyzed by ATP citrate lyase) for lipid synthesis. Malate, an intermediate in the TCA cycle, can be converted into pyruvate by malic enzyme with the production of NADPH, a reducing equivalent that is used to generate reduced glutathione, allowing cancer cells greater tolerance to free radical-induced damage [90]. Glutaminase catalyses the hydrolysis of the amine group of glutamine to form glutamate and ammonia. Glutamate equilibrates with α-ketoglutarate via glutamate dehydrogenase. In a process termed reductive carboxylation, glutamine-derived citrate provides the acetyl-CoA for lipid synthesis and TCA cycle intermediates [91]. Hence, the glutamine addiction of cancer cells is another mechanism by which the metabolism is rewired to support biosynthesis [90, 91]. Please refer to Figure 3 for an integrated visual of cancer metabolism.
Diabetes and cancer are both metabolic diseases. It is therefore, not surprising that the mechanisms of action of metformin against type 2 diabetes and cancer include the drug’s ability to alter critical metabolic circuits that lead to the normalization of blood glucose in diabetes and the impairment of biosynthetic pathways in cancer cells. For example, it is well-established that metformin is an inhibitor of complex I of the ETC. In 2000, two research groups have independently shown that dimethylbiguanide selectively blocks complex I of the ETC [14, 15]. In intact isolated hepatocytes, dimethylbiguanide has been reported to dose-dependently (0.1 to 10mM) inhibit oxygen consumption maximally at 20-30min [15]. The inhibition of respiration only occurred when glutamate-malate (complex I substrates) were used as substrates versus when succinate (complex II substrate)-rotenone or
Besides inhibition of complex I and effects on glucose metabolism, numerous studies also show metformin-induced metabolic changes in non-cancer and cancer cells. One of the most notable effects of metformin is inhibition of lipogenesis, a metabolic pathway that is critical for a cancer cell’s survival advantage. Under lipogenic conditions, surplus glucose in the cell is converted to pyruvate via glycolysis in the cytoplasm. Pyruvate is converted to acetyl-CoA and transported as citrate from the mitochondria into the cytoplasm. ATP citrate lyase (ACLY) converts citrate back to acetyl-CoA. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA in an ATP-dependent manner. Acetyl-CoA and malonyl-CoA are then used as substrates for the production of palmitate by the seven enzymatic reactions catalyzed by FAS. In cancer,
Suppression of anabolic pathways (metformin is anti-lipogenic) is in keeping with the expected consequences of AMPK activation [1]. HMGCR may also play an important role in human malignancies. Indeed, recent transcriptional profiling demonstrated that cholesterol and lipid metabolisms are linked to cellular transformation [96]. Interestingly, high HMGCR mRNA levels correlated with poor patient prognosis and reduced survival. The levels of additional mevalonate (MVA) pathway genes were also significantly correlated with poor prognosis of breast cancer patients, suggesting the entire pathway may be deregulated in these cases [97]. It is interesting to note that the metformin-induced inhibition of respiration is blocked by the addition of palmitate in 3T3-L1 adipocytes [19]. Adipocytes treated with palmitate complexed to albumin in the presence of carnitine had comparable oxygen consumption rates when compared to control. These results indicate that the metformin-induced inhibition of respiration can be reversed by the addition of fatty acids, which led the authors to conclude that the mechanism of action of metformin may be linked to fatty acid metabolism [19]. Although indirect, this article presented a link between metformin and its effects on lipid metabolism or
The normoglycemic effects of metformin has also been attributed to its ability to prevent fatty acid oxidation which decreases acetyl-CoA, ATP and reducing equivalents’ availability for hepatic gluconeogenesis [98], an effect likely mediated by a reduction in the expression of the carnitine palmitoyltransferase I gene [99] and eventually, a decrease in protein expression and activity of the enzyme resulting in impairment in long fatty acid chain transport from the mitochondrial outer membrane into the matrix where β-oxidation takes place. Current publications also render support to the lipid-inhibitory effects of metformin. Metformin (0.2 to 1.0 mM for 16 h) has been shown to activate AMPK and decrease the mRNA, nuclear translocation and consequent activation via cleavage of the nuclear portion and the promoter activity of SREBP-1c in rat hepatoma McA-RH7777 cells [22, 23]. The mRNA and nuclear protein levels of SREBP-2 were also reduced after metformin treatment. This AMPK-mediated suppression of SREBP-1c has also been reported to prevent lipogenesis in an insulin resistant mouse model [20] and is consistent with a decrease in hepatic SREBP-1 expression in mice fed a high fat (60% lipids) diet for 10 weeks and then metformin (0.48mg% of the diet) for another six weeks [100]. Since SREBP-1c and SREBP-2 are transcription factors that promote the expression of enzymatic genes involved in fatty acid and cholesterol synthesis, respectively [101] we would expect diminished lipid synthesis as a biological endpoint of their down-regulation. In accordance, MRC5 human fetal lung fibroblasts incubated for 72 h with metformin (5 x 10-5 to 5 x 10-4 M) decreased 1-14acetate incorporation into sterols, fatty acids and triglycerides compared to control, accompanied by a reduction in the activities of HMGCR and ACAT, enzymes that catalyze the formation of mevalonic acid from HMGCoA and the esterification of cholesterol, respectively [102]. Also, metformin has been shown to induce the phosphorylation (Ser-351) of the nuclear receptor TR4 via AMPK, leading to decreased TR4 transactivation and a decrease in the gene expression of its target, steroyl-CoA desaturase 1 (
The role of SCD1 in cancer has been gaining more attention as a potential pharmacological target in cancer interventions [104]. SCD is an endoplasmic reticulum-bound protein encoded by the
In support of the anti-lipogenic effects of metformin, Bhalla and others [2] have reported that metformin decreased the gene and protein expression of enzymes involved in fatty acid synthesis namely, ACC, FAS and ACLY which was accompanied by a reduction in hepatic triglycerides in a mouse model of hepatocellular cancer fed metformin at a dose of 250 mg/kg for 24-36 weeks.
Obesity is a known risk factor for cancers of the pancreas, colon and rectum, esophagus, kidney, prostate, breast, uterus and ovaries [119-123]. In order to recapitulate this condition in the preclinical setting, animal models are fed high energy (HE), high fat (HF) diets to induce the metabolic syndrome and/or obesity. In an
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Metformin Hydrochloride in Treating Patients With Pancreatic Cancer That Can be Removed by Surgery | Not yet recruiting | No Results Available | Stage IA Stage IB Stage IIA Stage IIB |
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Metformin Combined With Chemotherapy for Pancreatic Cancer | Recruiting | No Results Available | Locally Advanced Pancreatic Cancer/ Metastatic Pancreatic Cancer |
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Metformin Plus Modified FOLFOX 6 in Metastatic Pancreatic Cancer | Recruiting | No Results Available | Acinar Cell Adenocarcinoma of the Pancreas, Duct Cell, Adenocarcinoma of the Pancreas, Recurrent Pancreatic Cancer, Stage IV Pancreatic Cancer |
laboratory biomarker analysis |
Combination Chemotherapy With or Without Metformin Hydrochloride in Treating Patients With Metastatic Pancreatic Cancer | Recruiting | No Results Available | Pancreatic Cancer | |
Treatment of Patients With Advanced Pancreatic Cancer After Gemcitabine Failure | Recruiting | No Results Available | Pancreatic Adenocarcinoma Advanced or Metastatic | |
Gemcitabine+Nab-paclitaxel and FOLFIRINOX and Molecular Profiling for Patients With Advanced Pancreatic Cancer | Recruiting | No Results Available | Stage IV Pancreatic Cancer |
We recently found that the
In summary, metformin’s anti-cancer properties rest on its ability to impair cancer cell lipogenesis, a critical mechanism by which cancer cells maintain their survival advantage over normal cells. Metformin is able to control lipogenesis through inhibition of the transcription factors SREBP-1 and SREBP-2, inhibition of activities and/or expression of enzymes involved in cholesterol and fatty acid synthesis. We have shown that metformin’s anti-cancer role is effective in select metabolic phenotype and likely, a particulate cancer genotype. Thus, it is important to understand the metabolic context by which metformin exerts anti-cancer effects so that the correct patient population can be selected for therapeutic purposes.
7. Ongoing clinical trials on metformin as a chemotherapeutic drug for pancreatic cancer
There is considerable interest in the anti-tumor action of the commonly used anti-diabetic drug metformin for the treatment and management of patients with pancreatic cancer. Enthusiasm for metformin has been significantly strengthened by
8. Conclusions and perspectives
Metformin is an inexpensive and well-tolerated drug and its utility as a chemopreventive and/or chemotherapeutic agent can be harnessed when we identify the drug’s target/s, optimal dosage, and the correct patient sub-population who will benefit from metformin treatment. Until then, metformin remains the most widely prescribed anti-diabetic drug in the world with an unknown mechanism of action. In the era of targeted cancer therapy, one may cautiously link gene mutations and oncogenes up and down-regulation to cancer and involve metabolic phenotyping of the patient for better selection and truly personalized medicine.
Acknowledgments
MJC was supported by the USDA National Needs Fellowship training grant (Grant 2010-38420-20369). Part of the work presented in this chapter was supported by the Hirshberg Foundation for Pancreatic Cancer Research to EJM and LGB.
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