• Journal of Digestive Cancer Reports
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• v.8 no.2
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• pp.97-101
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• 2020

Metformin is a widely used first-line anti-diabetic drug worldwide. Epidemiologic studies using the large population-based cohort database have shown the association between metformin uses and reduced risk of various type cancers including gastric cancer. In the gastric cancer prevention, metformin use was associated with the significant reduction of gastric cancer risk, especially for long-term metformin users. However, there is no well-designed randomized controlled clinical trial investigating the effect of metformin as a chemopreventive drug for gastric cancer. Therefore, further well-designed clinical trials will be needed to implement metformin for chemoprevention of gastric cancer.

• Development and Reproduction
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• v.27 no.2
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• pp.77-89
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• 2023

Metformin is the most widely used anti-diabetic drug that helps maintain normal blood glucose levels primarily by suppressing hepatic gluconeogenesis in type II diabetic patients. We previously found that metformin induces apoptotic death in H4IIE rat hepatocellular carcinoma cells. Despite its anti-diabetic roles, the effect of metformin on hepatic de novo lipogenesis (DNL) remains unclear. We investigated the effect of metformin on hepatic DNL and apoptotic cell death in H4IIE cells. Metformin treatment stimulated glucose consumption, lactate production, intracellular fat accumulation, and the expressions of lipogenic proteins. It also stimulated apoptosis but reduced autophagic responses. These metformin-induced changes were clearly reversed by compound C, an inhibitor of AMP-activated protein kinase (AMPK). Interestingly, metformin massively increased the production of reactive oxygen species (ROS), which was completely blocked by compound C. Metformin also stimulated the phosphorylation of p38 mitogen-activated protein kinase (p38MAPK). Finally, inhibition of p38MAPK mimicked the effects of compound C, and suppressed the metformin-induced fat accumulation and apoptosis. Taken together, metformin stimulates dysregulated glucose metabolism, intracellular fat accumulation, and apoptosis. Our findings suggest that metformin induces excessive glucose-induced DNL, oxidative stress by ROS generation, activation of AMPK and p38MAPK, suppression of autophagy, and ultimately apoptosis.

• Journal of Medicine and Life Science
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• v.17 no.2
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• pp.41-46
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• 2020

Metformin, a predominantly prescribed anti-diabetic drug for decades, has gained new insights for its anti-tumor activity in a variety of cancer cells. Our previous studies also showed the obvious pro-apoptotic activity of metformin and the underlying action mechanisms in hepatocellular carcinoma cells. Together with apoptosis, autophagy is a crucial intracellular process to determine the survival or death of cells under some stressful environments. The present study aimed to determine the role of autophagy in metformin-induced death of H4IIE hepatocellular carcinoma cells. Metformin blocked the formation of autophagosome and the expression of LC3A, generally described as a biomarker of autophagy. Inhibition of AMPK reversed the metformin-induced blockade of autophagy. Antioxidant (NAC) suppressed the metformin-induced cell death but not affected LC3A. The inhibition of protein kinase C totally restored the metformin-suppressed expression of LC3A. In summary, our present study suggests that autophagy is an anti-apoptotic player in metformin-induced apoptosis in H4IIE cells.

• Korean Journal of Clinical Pharmacy
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• v.13 no.2
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• pp.67-71
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• 2003

The purpose of this study was to investigate the effect of aspirin (5, 10, 20 mg/kg) on the pharmacokinetics of metformin $(15\;mg/kg)$ in rabbits. The plasma concentration of metformin was decreased significantly (p<0.05) by co-administration of aspirin (10, 20 mg/kg) compared with control. Area under the plasma concentration-time curve (AUC) of metformin was decreased significantly (p<0.05) by co-administration of aspirin (10, 20mg/kg) compared with control. Relative bioavailability $(R.B\%)$ of metformin by co-administration was 79.3 (5 mg/kg), 57.5 (10 mg/kg) and 62.5 (20 mg/kg). Peak plasma concentration of metformin was significantly (p<0.05) decreased by co-administration of aspirin (10, 20 mg/kg) compared with control. The elimination rate constant $(K_{el})$ of metformin was increased by co-administration of aspirin (10, 20 mg/kg) compared with control. The terminal half-lifes $(t_{1/2})$ and mean resident time (MRT) of metformin by co-administration of aspirin (10, 20 mg/kg) were decreased significantly (p<0.05) compared with control. It is considered that the significantly decreased plasma concentration and AUC of metrormin is due to increase of elimination in urine acidified by co-administration of aspirin. The results suggest that the dosage of metformin should be adjusted when metformin is co-administered with aspirin in the clinical situation.

• YAKHAK HOEJI
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• v.54 no.6
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• pp.455-460
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• 2010

We evaluated the inappropriateness of metformin use in patients with type 2 diabetes and chronic medical conditions to identify the frequency of the prescription metformin in violation of the food and drug administration (FDA) black box warning. We reviewed medical records of 307 outpatients who received metformin at endocrinology department in a hospital setting between January 1, 2005 and August 30, 2009. Of the 307 outpatients, 25 discontinued treatment of metformin due to elevated serum creatinine level (Scr${\geq}$1.5 mg/dl in male, Scr${\geq}$1.4 mg/dl in female), cancers, and/or liver disease. 5 were lost to follow-up. 89 (29.0%) of the patients had cardiovascular disease, 54.1% for hypertension, 9.8% for liver disease, and 60 (20.8%) for chronic kidney disease. 12 patients (3.9%) with chronic kidney disease and/or elevated serum creatinine level, and 1 patient (0.3%) with lactic acidosis were contraindicated to metformin use. Metformin should be avoided in 7 outpatients (2.3%) with active hepatitis and 1 patient (2.6%) with liver cirrhosis. Of the 307 outpatients, 13 (4.2%) patients who received metformin at the first visit and 16 (8.7%) patients who received metformin at the last visit violated to black box warning. 8 (2.6%) of the patients were in precautionary conditions to metformin use. Adjusted mean difference of serum creatinine was -0.16 mg/dl [95% CI: -0.22 to -0.11 (p<0.05)] and adjusted mean difference of alanine aminotransferase was 4.46 IU/l [95% CI: 2.47 to 6.44 (p<0.05)] between the first visit and the last visit. Critical number of elderly patients who are at the high risks of drug-disease and drug-laboratory interaction is exposed to the inappropriate metformin use in violation of black box warning. The periodic evaluation of metformin use and monitoring prescription through drug utility review (DUR) system is needed to improve patients' safety and to reduce adverse drug events.

• Korean Journal of Clinical Pharmacy
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• v.32 no.1
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• pp.13-19
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• 2022

Background: The use of combination therapy and fixed-dose combination therapy is increasing for the treatment of type 2 diabetes. Sodium glucose cotransporter-2 inhibitor (SGLT2i) is a drug class used in combination with metformin. Methods: Type 2 diabetes patients on SGLT2i/metformin combination therapy were extracted from the 2019 Health Insurance Review & Assessment Service-National Patients Sample. On July 1, 2019, SGLT2i and metformin fixed-dose combination (SGLT2i/metformin FDC) and two-pill combination (TPC) groups were identified, and a chi-square test and multiple logistic regression were performed. Results: Of total 2,992 patients, 1,077 (36%) were prescribed SGLT2i/metformin FDC and 1,915 (64%) were prescribed TPC. We found that the most common comorbidities were in the order of dyslipidemia, gastrointestinal disease, and hypertension. Multiple logistic regression analysis showed that the use of SGLT2i/metformin FDC was lower than TPC in patients with diabetic neuropathy (OR=0.76, p=0.008). Clinic (OR=2.09, p<0.001) and general hospital (OR=1.40, p=0.019) showed higher tendency to prescribe SGLT2i/metformin FDC compared to tertiary hospital. The tendency of prescribing SGLT2i/metformin FDC was lower in Kyeonggi (OR=0.79, p=0.037), Gyeongsang (OR=0.77, p=0.025) and Chungcheong (OR=0.68, p=0.007) than Seoul. Conclusion: Factors related to the use of SGLT2i/metformin FDC in patients with type 2 diabetes were complication, medical institution and region. The tendency to prescribe SGLT2i/metformin FDC was relatively higher in clinics than in tertiary general hospitals and in Seoul than in other regions.

• Clinical and Experimental Reproductive Medicine
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• v.32 no.4
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• pp.347-352
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• 2005

Objective: The purpose of this study was to evaluate and compare the effects of metformin and rosiglitazone in overweight or obese women with polycystic ovarian syndrome. Methods: Twenty Six overweight or obese patients with polycystic ovarian syndrome were randomly treated with either metformin (500 mg three times daily, n=13) or rosiglitazone (4 mg once daily, n=13) for 6 months. Hormonal studies were performed before and after treatment. Insulin resistances were calculated by computerized HOMA 2 Calculator v2.2. Results: Testosterone decreased while SHBG increased after 6 months treatment in both metformin and rosiglitazone treatment groups. Fasting glucose decreased after metformin or rosiglitazone treatment. HOMA insulin resistance improved after treatment with either drug. There was no differences in hormonal changes and insulin resistance between 2 treatment groups. Conclusions: This study shows that metformin and rosiglitazone are effective in improving insulin sensitivity and ameliorating hyperandrogenism in overweight/obese polycystic ovarian syndrome women.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3937-3940
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• 2015

Background: Pancreatic cancer risk is increased in patients with type 2 diabetes, while being reduced by metformin treatment. However, it is unclear whether metformin could be associated with clinical outcomes of patients with pancreatic cancer and concurrent type 2 diabetes. Materials and Methods: A pooled analysis of 4 publications including 1,429 patients was performed to investigate the association of metformin and overall survival(OS) in patients with pancreatic cancer and concurrent type 2 diabetes. Results: A borderline significant relative survival benefit was found in metformin treated patients compared with non-metformin treated patients (hazard ratio 0.80; 95% CI: 0.62-1.03). Conclusions: These results suggest that further investigation is warranted of whether metformin may benefit the survival of patients with pancreatic cancer and concurrent type 2 diabetes.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3275-3279
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• 2012

Recently, population-based studies of type 2 diabetes patients have provided evidence that metformin treatment is associated with a reduced cancer incidence and mortality, but its mode of action remains unclear. Here we report effects of metformin on hepatocellular carcinoma (HCC) Hep-G2 cells and details of molecular mechanisms of metformin activity. Our research indicates that metformin displays anticancer activity against HCC through inhibition of the mTOR translational pathway in an AMPK-independent manner, leading to G1 arrest in the cell-cycle and subsequent cell apoptosis through the mitochondrion-dependent pathway. Furthermore, we showed that metformin strongly attenuated colony formation and dramatically inhibited Hep-G2 tumor growth in vivo. In conclusion, our studies suggested that metformin might have potential as a cytotoxic drug in the prevention and treatment of HCC.

• Development and Reproduction
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• v.24 no.2
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• pp.113-123
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• 2020

Metformin has been widely used as an antidiabetic drug, and reported to inhibit cell proliferation in many cancers including non-small cell lung cancer (NSCLC). In NSCLC cells, metformin suppresses PI3K/AKT/mTOR signaling pathway, but effect of metformin on RAS/RAF/MEK/ERK signaling pathway is controversial; several studies showed the inhibition of ERK activity, while others demonstrated the activation of ERK in response to metformin exposure. Metformin-induced activation of ERK is therapeutically important, since metformin could enhance cell proliferation through RAS/RAF/MEK/ERK pathway and lead to impairment of its anticancer activity suppressing PI3K/AKT/mTOR pathway, requiring blockade of both signaling pathways for more efficient antitumor effect. The present study tested the combination therapy of metformin and trametinib by monitoring the alterations of regulatory effector proteins of cell signaling pathways and the effect of the combination on cell viability in NCI-H2087 NSCLC cells with NRAS and BRAF mutations. We show that metformin alone blocks PI3K/AKT/mTOR signaling pathway but induces the activation and phosphorylation of ERK. The combination therapy synergistically decreased cell viability in treatment with low doses of two drugs, while it gave antagonistic effect with high doses. These findings suggest that the efficacy of metformin and trametinib combination therapy may depend on the alteration of ERK activity induced by metformin and specific cellular context of cancer cells.