Metformin: Its emerging role in oncology

Micić, Dragan; Cvijović, Goran; Trajkovič, Vladimir; Duntas, Leonidas H.; Polovina, Snežana

doi:10.14310/horm.2002.1288

Cited by 42 publications

(27 citation statements)

References 86 publications

(87 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…AICAR is converted to its metabolite ZMP (AICAR monophosphate) [29], which mimics the effects of AMP on AMPK kinase while the cellular levels of AMP, ADP and ATP remain unaffected [30,31]. Metformin can activate AMPK via its upstream kinase LKB1, mitochondrial respiratory chain block and reduction of the intracellular ATP concentration [32,33], or inhibition of AMP-deaminase [34], which leads to increased levels of AMP and reduced ATP. This lowering of intracellular ATP might impede insulin secretion by keeping K ATP channels in the open state, thereby overcoming a possible inhibitory action of AMPK on these channels under metformin [14].…”

Section: Discussionmentioning

confidence: 99%

Effect of the AMP-Kinase Modulators AICAR, Metformin and Compound C on Insulin Secretion of INS-1E Rat Insulinoma Cells under Standard Cell Culture Conditions

Langelueddecke

Jakab

Ketterl

et al. 2012

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: The function of β-cells is regulated by nutrient uptake and metabolism. The cells′ metabolic state can be expressed as concentration ratios of AMP, ADP and ATP. Relative changes in these ratios regulate insulin release. An increase in the intracellular ATP concentration causes closure of K_ATP channels and cell membrane depolarization, which triggers stimulus-secretion coupling (SSC). In addition to K_ATP channels, the AMP-dependent protein kinase (AMPK), a major cellular fuel sensor in a variety of cells and tissues, also affects insulin secretion and β-cell survival. In a previous study we found that the widely used AMPK inhibitor compound C retards proliferation and induces apoptosis in the rat β-cell line INS-1E. We therefore tested the effects of AMPK activators (AICAR and metformin), and compound C on AMPK phosphorylation, insulin secretion, K_ATP channel currents, cell membrane potential, intracellular calcium concentration, apoptosis and cell cycle distribution of INS-1E cells under standard cell culture conditions (11 mM glucose). Methods: Western blotting, ELISA, patch-clamp, calcium imaging and flow cytometry. Results: We found that basal AMPK phosphorylation is enhanced by AICAR (1 mM) and metformin (1 mM) but remained unaffected by compound C (10 µM). Both AICAR and compound C stimulated basal insulin secretion whereas metformin had no effect. Pre-incubation with AICAR (1 mM) caused an inhibition of K_ATP currents but did not significantly alter the average cell membrane potential (Vm) or the threshold potential of electrical activity. Acute administration of AICAR (300 µM) led to a depolarization of Vm, which was not due to an inhibition of the basal- or glucose-induced chloride conductance, and was not accompanied by elevations of intracellular calcium (Ca_i). AICAR had no additive blocking effect on K_ATP currents when applied together with tolbutamide. Compound C applied over 24 hours induced an increase in the percentage of cells positive for caspase activity, whereas AICAR (1 mM) applied for 48 hours was without effect. Medium glucose concentration <3 mM caused cell cycle arrest, caspase activation and an increase of cell granularity. Conclusion: We conclude that under standard cell culture conditions the AMPK modulators AICAR and compound C, but not metformin, stimulate insulin secretion by AMPK-independent mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

Effect of the AMP-Kinase Modulators AICAR, Metformin and Compound C on Insulin Secretion of INS-1E Rat Insulinoma Cells under Standard Cell Culture Conditions

Langelueddecke

Jakab

Ketterl

et al. 2012

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4)(5)(6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7).…”

Section: Introductionmentioning

confidence: 92%

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Zhang

Wei

et al. 2017

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The traditional anti-diabetic drug, metformin, has been found to have anticancer effects. The Sonic hedgehog (Shh) signaling pathway is involved in the on cogenesis of gastric cancer. The aim of the present study was to investigate whether metformin has an effect on the Shh signaling pathway in gastric cancer cells. HGC-27 and MKN-45 human gastric cancer cells were treated with metformin at different concentrations and for different durations. Subsequently the mRNA and protein levels of Shh, Smoothened (SMO), and Glioma-associated oncogene (Gli)-1, Gli-2 and Gli-3 were examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses. RNA interference was used to detect whether the effects of metformin treatment on the Shh signaling pathway were dependent on AMP-activated protein kinase (AMPK). The results revealed that the protein and mRNA levels of Shh and Gli-1 were decreased by metformin treatment in the two cell lines in a dose-and time-dependent manner. Metformin also significantly inhibited the gene and protein expression levels of SMO, Gli-2 and Gli-3. The small interfering RNA-induced depletion of AMPK reversed the suppressive effect of metformin on recombinant human Shh-induced expression of Gli-1 in HGC-27 gastric cancer cells. Therefore, metformin inhibited the Shh signaling pathway in the gastric cancer cell lines and the inhibitory effect of metformin on the Shh pathway was AMPK-dependent. IntroductionGastric cancer is one of the most common types of malignant cancer worldwide (1). In addition tosurgery, chemotherapy and radio chemotherapy, there is a demand for novel treatment approaches for gastric cancer due to its poor prognosis (2).Metformin is a widely used anti-diabetic drug, which has been reported to exhibit potential anticancer activity (3). Previous studies have shown that metformin administration significantly reduces the incidence and mortality rates of various types of cancer, including gastric cancer (4-6). According to the findings reported by a previous study, patients who were treated with metformin hada lower incidence of gastric cancer, compared with those who did not receive metformin treatment (7). However, the mechanism underlying the anticancer effects of metformin is complex and remains to be fully elucidated. Activation of the AMP-activated protein kinase (AMPK) pathway has been recognized as a key aspect of the anticancer effects of metformin (8).The Sonic hedgehog (Shh) signaling pathway is one of the most common signal transduction pathways in human cells (9). It is critical in normal cell differentiation and embryonic development (10). However, abnormal activation of the Shh pathway has been identified in several types of human cancer (11). Substantial evidence has shown that the Shh pathway is crucial to the development and homeostasis of gastric glands. In addition, abnormal activation of the Shh pathway has been found toresult in gastric cancer (12)(13)(14).The aim of the present study was to investigate the effects of m...

show abstract

“…This causes reduction in lipogenesis and synthesis of the acetyl-CoA carboxylase product malonyl-CoA resulting in increased fatty acid oxidation. Moreover, AMPK activation may result in p53 activation, which is a tumor suppressor that is often mutated in other type of cancer [19,20] . There have been several in vitro and in vivo studies on papillary, medullary, and anaplastic thyroid cancer cell lines evaluating the effects of metformin on the suppression of clonal growth, self-renewal, and proliferation of cancer stem cells [9,10,21,22] .…”

Section: Metformin and Thyroid Cancermentioning

confidence: 99%

Metformin Is Associated with a Favorable Outcome in Diabetic Patients with Cervical Lymph Node Metastasis of Differentiated Thyroid Cancer

Jang¹,

Kim

Kwon

et al. 2015

Eur Thyroid J

View full text Add to dashboard Cite

years) was associated with longer DFS than the nonmetformin subgroup (8.6 years) (HR 0.16, p = 0.021); metformin treatment was also associated with longer DFS in this subgroup in multivariate analysis after adjusting age, BMI, duration of diabetes, presence of tumor at resection margin, and serum thyroglobulin level at ablation (HR 0.03, p = 0.035). Conclusions: Metformin treatment is associated with low recurrence in diabetic patients with cervical LN metastasis of DTC.

show abstract

Metformin: Its emerging role in oncology

Cited by 42 publications

References 86 publications

Effect of the AMP-Kinase Modulators AICAR, Metformin and Compound C on Insulin Secretion of INS-1E Rat Insulinoma Cells under Standard Cell Culture Conditions

Effect of the AMP-Kinase Modulators AICAR, Metformin and Compound C on Insulin Secretion of INS-1E Rat Insulinoma Cells under Standard Cell Culture Conditions

Metformin suppresses the expression of Sonic hedgehog in gastric cancer cells

Metformin Is Associated with a Favorable Outcome in Diabetic Patients with Cervical Lymph Node Metastasis of Differentiated Thyroid Cancer

Contact Info

Product

Resources

About