Article

Metformin Amplifies Chemotherapy-Induced AMPK Activation and Antitumoral Growth

Departments of Internal Medicine and Clinical Pathology, FCM, Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil.
Clinical Cancer Research (Impact Factor: 8.72). 06/2011; 17(12):3993-4005. DOI: 10.1158/1078-0432.CCR-10-2243
Source: PubMed

ABSTRACT

Metformin is a widely used antidiabetic drug whose anticancer effects, mediated by the activation of AMP-activated protein kinase (AMPK) and reduction of mTOR signaling, have become noteworthy. Chemotherapy produces genotoxic stress and induces p53 activity, which can cross-talk with AMPK/mTOR pathway. Herein, we investigate whether the combination of metformin and paclitaxel has an effect in cancer cell lines.
Human tumors were xenografted into severe combined immunodeficient (SCID) mice and the cancer cell lines were treated with only paclitaxel or only metformin, or a combination of both drugs. Western blotting, flow cytometry, and immunohistochemistry were then used to characterize the effects of the different treatments.
The results presented herein show that the addition of metformin to paclitaxel leads to quantitative potentialization of molecular signaling through AMPK and a subsequent potent inhibition of the mTOR signaling pathway. Treatment with metformin and paclitaxel resulted in an increase in the number of cells arrested in the G(2)-M phase of the cell cycle, and decreased the tumor growth and increased apoptosis in tumor-bearing mice, when compared with individual drug treatments.
We have provided evidence for a convergence of metformin and paclitaxel induced signaling at the level of AMPK. This mechanism shows how different drugs may cooperate to augment antigrowth signals, and suggests that target activation of AMPK by metformin may be a compelling ally in cancer treatment.

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Available from: Guilherme Z. Rocha, Jan 04, 2016
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    • "Metformin (N0, N0-dimethylbiguanide) belongs to the biguanide class of oral hypoglycemic agents and is a widely used antidiabetic drug, now prescribed to almost 120 million people in the world for the treatment of type II diabetes [3]. Metformin also displays significant growth-inhibitory and proapoptotic effects in several cancer models, alone4567 or in combination with chemotherapeutic drugs [8, 9]. A recent study showed that metformin prevents tobacco-induced carcinogenesis in mice with 72% decrease in tumor burden [10]. "
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    • "Metformin is commonly considered as an insulin sensitizer as it enhances signaling through the insulin receptor, resulting in an decrease in insulin resistance and subsequent reduction in circulating insulin levels (18). Recent studies have reported that metformin use is associated with a significant reduction in the incidence of cancer (18,19). A preliminary study suggested that metformin inhibits cancer cell growth by activating adenosine monophosphate protein kinase (AMPK), inactivating mTOR and eventually reducing the activity of the mTOR effector S6K1 (20). "
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    ABSTRACT: Obesity, diabetes and insulin resistance are marked risk factors that promote the development of type I endometrial cancer. Previous studies have demonstrated that insulin-like growth factor 1 (IGF-1) and IGF-2 promote cell proliferation in endometrial cancer cells, while metformin reverses this effect and inhibits cell proliferation. However, the effects of metformin on the regulation of the IGF signaling pathway are unclear. The aim of this study was to investigate the regulation of IGF signaling by metformin in endometrial cancer cells, and to determine the effects of metformin combined with IGF-1 receptor (IGF-1R) inhibitor on cell proliferation and apoptosis. Cell proliferation was assessed following exposure of Ishikawa and HEC-1B endometrial cancer cell lines to metformin and/or the IGF-1R inhibitor, PPP. Apoptosis was assessed by TdT-mediated dUTP nick end labeling assay. Metformin was observed to downregulate IGF-1R and upregulate IGF binding protein-1 (IGFBP-1) mRNA and protein expression, while compound C, an adenosine monophosphate protein kinase inhibitor, reversed this effect. Metformin administered with PPP inhibited endometrial cancer cell proliferation to a greater degree than treatment with either agent alone. At high concentrations (1 or 2 mM), metformin induced apoptosis in endometrial cancer cells. Metformin combined with IGF-1R axis inhibitors may act synergistically to kill tumor cells, as metformin was shown to delay and prevent IGF-1R feedback. In conclusion, this study supported the results of animal studies and subclinical studies, demonstrating the feasibility of metformin combined with IGF-1R axis inhibitors in the treatment of endometrial cancer.
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    • "However, whether AMPK is pro-apoptotic or pro-survival is dependent on the type and/or severity of stresses. Severe stresses including vincristine [7] [8], taxol [9] [10] and temozolomide [11]-activated AMPK appears proapoptotic . While in conditions like starvation [12], hypoxia [13] and oxidative stress [14], AMPK activation could promote cell survival . "
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