Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt

Janjetović, Kristina; Vučićević, Ljubica; Misirkić, Maja; Vilimanovich, Urosh; Tovilović, Gordana; Zogović, Nevena; Nikolić, Zoran; Jovanović, Svetlana; Bumbaširević, Vladimir; Trajkovič, Vladimir; Harhaji-Trajković, Ljubica

doi:10.1016/j.ejphar.2010.11.005

Cited by 96 publications

(64 citation statements)

References 54 publications

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“…Metformin action is mainly mediated by AMPK activation; however, several recent reports indicate that some effects of metformin in cancer cell lines could be mediated by an AMPK-independent pathway (13,(27)(28)(29). In our model, AMPK inactivation by AMPK dominant-negative construct (30) or inhibition of AMPK expression by siRNA (data not shown) inhibits the effect of metformin on melanoma invasion, suggesting that the effects of this drug are mediated through an AMPKdependent mechanism.…”

Section: Discussionmentioning

confidence: 73%

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Cerezo

Tichet

Abbe

et al. 2013

Molecular Cancer Therapeutics

182

139

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Metformin was reported to inhibit the proliferation of many cancer cells, including melanoma cells. In this report, we investigated the effect of metformin on melanoma invasion and metastasis development. Using different in vitro approaches, we found that metformin inhibits cell invasion without affecting cell migration and independently of antiproliferation action. This inhibition is correlated with modulation of expression of proteins involved in epithelial-mesenchymal transition such as Slug, Snail, SPARC, fibronectin, and Ncadherin and with inhibition of MMP-2 and MMP-9 activation. Furthermore, our data indicate that this process is dependent on activation of AMPK and tumor suppressor protein p53. Finally, we showed that metformin inhibits melanoma metastasis development in mice using extravasation and metastasis models. The presented data reinforce the fact that metformin might be a good candidate for clinical trial in melanoma treatment.

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Section: Discussionmentioning

confidence: 73%

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Cerezo

Tichet

Abbe

et al. 2013

Molecular Cancer Therapeutics

182

139

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“…According to the research conducted by Gotlieb et al (11) and Rattan et al (13), metformin with cisplatin synergistically killed ovarian cancer cells. In contrast, Janjetovic et al (18) reported an antagonistic interaction between metformin and cisplatin in human glioma, rat glioma, human neuroblastoma, mouse fibrosarcoma, and human leukemia cell lines, possibly via an AMP kinase-independent upregulation of the Akt survival pathway. However, they also found augmented cisplatin sensitivity by metformin in a mouse melanoma cell line.…”

Section: Discussionmentioning

confidence: 86%

“…Despite these findings, the precise mechanisms of the metformin-induced effects are not fully understood. In particular, controversy remains about whether metformin is apoptotic (6,10) or just cytostatic (5,9) and whether it kills cancer cells synergistically with cytotoxic agents including cisplatin (11,13), paclitaxel (8), and doxorubicin (17), or if it is antagonistic to cisplatin (18,19).…”

Section: Introductionmentioning

confidence: 99%

Antiproliferative action of metformin in human lung cancer cell lines

et al. 2012

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Abstract. The oral antidiabetic agent metformin has anticancer properties, probably via adenosine monophosphate-activated protein kinase activation. In the present study, growth inhibition was assessed by a clonogenic and by a cell survival assay, apoptosis induction was assessed by Hoechst staining and caspase activities and cell cycle alteration after exposure to metformin, and the interaction of metformin with cisplatin in vitro were elucidated in four human lung cancer cell lines representing squamous, adeno-, large cell and small cell carcinoma. Clonogenicity and cell proliferation were inhibited by metformin in all the cell lines examined. This inhibitory effect was not specific to cancer cells because it was also observed in a non-transformed human mesothelial cell line and in mouse fibroblast cell lines. Inhibition of clonogenicity was observed only when the cells were exposed to metformin for a long period, (10 days) and the surviving fraction, obtained after inhibiting proliferation by increasing the dose, reached a plateau at approximately 0.1-0.3, indicating the cytostatic characteristics of metformin. Metformin induced significant apoptosis only in the small cell carcinoma cell line. A tendency of cell cycle accumulation at the G0/G1 phase was observed in all four cell lines. Cisplatin, in a dose-dependent manner, severely antagonized the growth inhibitory effect of metformin, and even reversed the effect in three cell lines but not in the adenocarcinoma cell line. The present data obtained using various histological types of human lung cancer cell lines in vitro illustrate the cytostatic nature of metformin and its cytoprotective properties against cisplatin.

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“…Studies in vivo demonstrated that metformin can, at least to some extent, cross the blood-brain barrier (BBB) through an organic cation transporter-dependent mechanism and exert pharmacological effects, including AMPK activation, in intact brain (8,14) and glioma cells in vitro (4). Notably, the AMPK pathway appears to be critical for the growth of epidermal growth factor receptor-dependent glioblastoma multiforme (GBM), and the activation of AMPK by its agonist significantly reduces GBM proliferation (15).…”

Section: Introductionmentioning

confidence: 99%

“…The key mechanism of metformin action is the activation of its major effector molecule, the adenosine monophosphateactivated protein kinase (AMPK), a sensor of cellular energy that is normally activated under conditions of starvation (3)(4)(5). The upregulation of AMPK inhibits several anabolic/mitogenic pathways activated by growth factors and nutrients, including the phosphatidylinositol-3-kinase (PI-3K) pathway, the mammalian target of rapamycin (mTOR) and extracellular signal-regulated kinases 1 and 2 (ERK1/2) (6).…”

Section: Introductionmentioning

confidence: 99%

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

2012

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Abstract. Metformin, a derivative of biguanide, is a first-line therapy for type 2 diabetes mellitus. Since the drug has been shown to significantly reduce the risk of various cancers and cancer mortality in diabetic patients, it is being considered as a potential anticancer therapeutic or preventive agent. In cellular models, metformin inhibits the growth of many types of cancer cells; however, its effects on glioblastoma multiforme (GBM) are not well characterized. Here, we analyzed the effects of metformin on the growth and migration of LN18 and LN229 GBM cells cultured under basal conditions or exposed to leptin, a cytokine that has recently been implicated in GBM development. We found that 2-16 mM metformin reduced basal and leptin-stimulated growth of GBM cells in a dose-dependent manner. Furthermore, the drug significantly inhibited the migration of GBM cells. The action of metformin was mediated through the upregulation of its main signaling molecule, the adenosine monophosphate-activated protein kinase (AMPK), as well as through the downregulation of the signal transducer and activator of transcription 3 (STAT3) and the Akt/PKB serine/threonine protein kinase. In leptin-treated cells, the drug reversed the effects of the cytokine on the AMPK and STAT3 pathways, but modulated Akt activity in a cell-dependent manner. Our results suggest that metformin or similar AMPK-targeting agents with optimized bloodbrain-barrier penetrability could be developed as potential treatments of GBM and could be used in conjunction with other target drugs such as leptin receptor antagonists.

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Metformin reduces cisplatin-mediated apoptotic death of cancer cells through AMPK-independent activation of Akt

Cited by 96 publications

References 54 publications

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Metformin Blocks Melanoma Invasion and Metastasis Development in AMPK/p53-Dependent Manner

Antiproliferative action of metformin in human lung cancer cell lines

Metformin inhibits leptin-induced growth and migration of glioblastoma cells

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