Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Hanna, Rabbie K.; Zhou, Chunxiao; Malloy, Kimberly; Sun, Li; Zhong, Yan; Gehrig, Paola A.; Bae‐Jump, Victoria L.

doi:10.1016/j.ygyno.2012.01.009

Cited by 122 publications

(90 citation statements)

References 53 publications

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“…A subsequent study found that metformin in combination with paclitaxel resulted in mainly G 2 arrest and decreased human telomerase reverse transcriptase mRNA expression. Metformin was demonstrated to potentiate the effects of paclitaxel in endometrial cancer cells by inhibiting cell proliferation and modulating the mTOR pathway (24). In another study, metformin was found to decrease high-fat-induced cardiac cell death by inhibiting ceramide synthesis.…”

Section: Discussionmentioning

confidence: 96%

Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

et al. 2015

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Abstract. Metformin is commonly used to treat type II diabetes, although it may also reduce the risk of cancer and improve the associated prognosis. However, its mode of action in cancer remains unclear. The present study evaluated the effects of metformin on lung adenocarcinoma A549 cells and identified molecular mechanisms of metformin activity. The A549 cells were treated with metformin at different concentrations and cell viability was assayed by using an MTT assay. The cell cycle and the apoptosis rate were assayed by flow cytometry. Nude mice were transplanted with A549 cells and the tumor growth inhibition rate was detected. Once the A549 cells had been treated with 20 mM metformin for 48 h, the cell cycle was arrested in the G 0 /G l phase and the apoptosis rate was 20.57±3.16%. The expression of the B-cell lymphoma (Bcl)-2 and Bcl-extra large proteins was downregulated following metformin treatment, while Bax protein expression was significantly increased. Tumor size in the high-dose metformin and cisplatin plus metformin groups was significantly smaller, and the inhibition rates were 41.3 and 72.9%, respectively, compared with the control group. These results indicated that metformin displays anticancer activity against lung adenocarcinoma by causing G 1 arrest of the cell cycle and subsequent cell apoptosis through the mitochondria-dependent pathway in A549 cells. Furthermore, it was found that metformin dramatically inhibited lung adenocarcinoma tumor growth in vivo. These data suggest that metformin may become a potential cytotoxic drug in the prevention and treatment of lung adenocarcinoma.

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Section: Discussionmentioning

confidence: 96%

Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

et al. 2015

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“…As previous reports revealed, AMPK is upstream of the PI3K/AKT pathway (Hanna et al 2012). The researchers wanted to know whether AMPK is upstream of the PI3K/AKT pathway in A-ESCs.…”

Section: Ampk Activation Inhibits the Pi3k/akt Pathway In A-escsmentioning

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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“…odds ration (OR), 0.86; 95% CI, 0.63-1. In vitro cell system analyses have demonstrated that metformin: i) inhibits the growth of various endometrial cancer cell lines; ii) attenuates the invasion and metastasis of endometrial cancer cell lines by modifying the nuclear factor-κB, matrix metalloproteinase-2/9/Akt and Erk 1/2 pathways; and iii) enhances endometrial cancer cell chemosensitivity to cisplatin and paclitaxel by reducing glyoxalase I expression and regulating the mTOR signaling pathway (23,(50)(51)(52). At the molecular level, the fundamental activity of metformin inhibits mitochondrial oxidative phosphorylation, and may exert energy-associated stress on neoplastic cells (23).…”

Section: Metformin and Endometrial Cancermentioning

confidence: 99%

Clinical benefits of metformin in gynecologic oncology

2015

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Metformin potentiates the effects of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

Cited by 122 publications

References 53 publications

Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

Metformin inhibits growth of lung adenocarcinoma cells by inducing apoptosis via the mitochondria-mediated pathway

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

Clinical benefits of metformin in gynecologic oncology

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