Metformin: Taking away the candy for cancer?

Jalving, Mathilde; Gietema, Jourik A.; Lefrandt, Joop D.; Jong, Steven de; Reyners, Anna K.L.; Gans, Rijk O. B.; Vries, Elisabeth G.E. de

doi:10.1016/j.ejca.2010.06.012

Cited by 344 publications

(308 citation statements)

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“…Recent epidemiological evidence suggests that metformin can lower the risk of cancer and reduce cancer incidence and cancer-related deaths among diabetic patients (Decensi et al 2010). Furthermore, a retrospective cohort study of patients with early-stage endometrial cancer showed that patients receiving metformin and adjuvant chemotherapy had a higher response rate than those receiving adjuvant chemotherapy alone (Jalving et al 2010). These findings have prompted further research into the potential role of metformin in cancer treatment and prevention (Ben Sahra et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

et al. 2013

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Adenomyosis is a finding that is associated with dysmenorrhea and heavy menstrual bleeding, associated with PI3K/AKT signaling overactivity. To investigate the effect of metformin on the growth of eutopic endometrial stromal cells (ESCs) from patients with adenomyosis and to explore the involvement of AMP-activated protein kinase (AMPK) and PI3K/AKT pathways. Primary cultures of human ESCs were derived from normal endometrium (normal endometrial stromal cells (N-ESCs)) and adenomyotic eutopic endometrium (adenomyotic endometrial stroma cells (A-ESCs)). Expression of AMPK was determined using immunocytochemistry and western blot analysis. 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assays were used to determine the effects of metformin and compound C on ESCs and also to detect growth and proliferation of ESCs. AMPK and PI3K/AKT signaling was determined by western blotting. A-ECSs exhibited greater AMPK expression than N-ESCs. Metformin inhibited proliferation of ESCs in a concentration-dependent manner. The IC 50 was 2.45 mmol/l for A-ESCs and 7.87 mmol/l for N-ESCs. Metformin increased AMPK activation levels (p-AMPK/AMPK) by 2.0G0.3-fold in A-ESCs, 2.3-fold in A-ESCs from the secretory phase, and 1.6-fold in the proliferation phase. The average reduction ratio of 17b-estradiol on A-ESCs was 2.1G0.8-fold in proliferative phase and 2.5G0.5-fold in secretory phase relative to the equivalent groups not treated with 17b-estradiol. The inhibitory effects of metformin on AKT activation (p-AKT/AKT) were more pronounced in A-ESCs from the secretory phase (3.2-fold inhibition vs control) than in those from the proliferation phase (2.3-fold inhibition vs control). Compound C, a selective AMPK inhibitor, abolished the effects of metformin on cell growth and PI3K/AKT signaling. Metformin inhibits cell growth via AMPK activation and subsequent inhibition of PI3K/AKT signaling in A-ESCs, particularly during the secretory phase, suggesting a greater effect of metformin on A-ESCs from secretory phase.

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Section: Discussionmentioning

confidence: 99%

Metformin inhibits growth of eutopic stromal cells from adenomyotic endometrium via AMPK activation and subsequent inhibition of AKT phosphorylation: a possible role in the treatment of adenomyosis

et al. 2013

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“…Insulin, even if with lower affinity, binds and activates IGF1R, which is expressed at high levels in tumour cells. Insulin decreases circulating concentrations of IGFBP1 and IGFBP2 ( Jalving et al 2010). This can improve the bioactivity of IGF1, which activates IGF1R and IR/IGF1R hybrid receptors with a similar potency (Slaaby et al 2006).…”

Section: Insulin Action and Metformin: A Metabolic Point Of Viewmentioning

confidence: 99%

Metformin, cancer and glucose metabolism

Salani¹,

Río²,

Marini³

et al. 2014

Endocrine-Related Cancer

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Metformin is the first-line treatment for type 2 diabetes. Results from several clinical studies have indicated that type 2 diabetic patients treated with metformin might have a lower cancer risk. One of the primary metabolic changes observed in malignant cell transformation is an increased catabolic glucose metabolism. In this context, once it has entered the cell through organic cation transporters, metformin decreases mitochondrial respiration chain activity and ATP production that, in turn, activates AMP-activated protein kinase, which regulates energy homeostasis. In addition, metformin reduces cellular energy availability and glucose entrapment by inhibiting hexokinase-II, which catalyses the glucose phosphorylation reaction. In this review, we discuss recent findings on molecular mechanisms that sustain the anticancer effect of metformin through regulation of glucose metabolism. In particular, we have focused on the emerging action of metformin on glycolysis in normal and cancer cells, with a drug discovery perspective.

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“…Metformin is an AMPK-activating drug and is currently used for type-2 diabetes treatment. Epidemiological studies have shown reduced incidence of cancer in diabetic patients treated with metformin (Evans et al, 2005;Jalving et al, 2010;Libby et al, 2009). It is highly intriguing to test whether this clinically safe and known glucose metabolism modulating drug can enhance anti-cancer activity of cytotoxic chemotherapy and/or further lower the cancer recurrence following adjuvant chemotherapy.…”

Section: Targeting Glycolysis For Cancer Treatmentmentioning

confidence: 99%