Article

Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice

University of Bologna, Bolonia, Emilia-Romagna, Italy
Experimental Gerontology (Impact Factor: 3.53). 08/2005; 40(8-9):685-93. DOI: 10.1016/j.exger.2005.07.007
Source: PubMed

ABSTRACT Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. Insulin/insulin-like growth factor 1 (IGF-1) signaling molecules that have been linked to longevity include DAF-2 and InR and their homologues in mammals, and inactivation of the corresponding genes is followed by increased life span in nematodes, fruit flies and mice. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. The chronic treatment of female transgenic HER-2/neu mice with metformin (100 mg/kg in drinking water) slightly decreased the food consumption but failed in reducing the body weight or temperature, slowed down the age-related rise in blood glucose and triglycerides level, as well as the age-related switch-off of estrous function, prolonged the mean life span by 8% (p < 0.05), the mean life span of last 10% survivors by 13.1%, and the maximum life span by 1 month in comparison with control mice. The demographic aging rate represented by the estimate of respective Gompertz's parameter was decreased 2.26 times. The metformin-treatment significantly decreased the incidence and size of mammary adenocarcinomas in mice and increased the mean latency of the tumors.

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    • "Recent retrospective analyses indicate that metformin inhibits cell proliferation in several human malignancies, including gastric carcinoma [10], pancreatic cancer [11], medullary thyroid cancer [12] and endometrial carcinoma [13]. It is also described that metformin suppresses tumor growth in animal models of ovarian cancer [14], melanoma [15], prostate cancer [16] and breast carcinoma [17]. Furthermore, this drug was also found to be associated with improved overall survival among diabetic patients with breast, prostate, colorectal or head and neck cancer [9,18–21]. "
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    ABSTRACT: Conventional therapeutic approaches for head and neck squamous cell carcinoma (HNSCC) are associated with many adverse effects that reduce quality of life. Therefore, identification of new less cytotoxic treatments is highly important. Metformin, which is commonly used for type 2 diabetes, may reduce cancer risk. A few clinical studies have examined the association between HNSCC and metformin. Therefore, the aim of this systematic review was to synthesize the available literature of the potential effect of metformin on HNSCC. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Studies were gathered by searching PubMed, MEDLINE, EMBASE, LILACS, and the Cochrane database before June 28, 2014, with no time or language restrictions. Studies that evaluated individuals of any age that underwent metformin and had HNSCC and compared with patients without treatment or patients that use other kind of treatment for HNSCC (drugs or radiotherapy) were considered. Selected articles were evaluated according to the Critical Appraisal Skills Programs. Of 313 identified citations, 3 studies met the inclusion criteria and were used for qualitative analysis. These studies demonstrated that individuals taking metformin had decreased rates of locoregional recurrence and metastasis and improved overall survival and disease-free survival rates. Individuals taking metformin had a lower incidence of HNSCC than those not taking metformin. Though there are only a few studies on the topic, currently available evidence suggests an association between HNSCC and metformin use. Metformin reportedly improves the overall survival of HNSCC patients. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Oral Oncology 01/2015; 51(5). DOI:10.1016/j.oraloncology.2015.01.007 · 3.03 Impact Factor
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    • "Indeed, clinical trials using metformin alone or in combination with other therapies in breast cancer are now underway including in the neoadjuvant (Hadad et al, 2011) and adjuvant setting (Goodwin et al, 2009). This enthusiasm for metformin has been supported by models of mouse mammary adenocarcinoma in which metformin treatment significantly decreased the incidence and size of the tumours (Anisimov et al, 2005) and inhibited the growth of transplantable HER2 mammary carcinoma in mice by 46% (Anisimov et al, 2010). There is some controversy regarding efficacy of metformin against triple-negative breast cancer, with reports of growth inhibition of tumour (Liu et al, 2009), but also triple-negative breast cancer resistance to metformin (Zhuang and Miskimins, 2008, 2011). "
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    ABSTRACT: Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. We sought to determine the efficacy of the biguanide phenformin in the chemoprophylaxis and in the treatment of oestrogen receptor (ER)-positive MCF7 and receptor triple-negative MDAMB231 xenografts in immunocompromised mice. We also compared the efficacy of phenformin and metformin in the treatment of MDAMB231. Immunocompromised mice were divided into groups: (1) phenformin administered for 2 weeks prior to cell injection; (2) established tumours treated with phenformin; (3) established tumours treated with metformin (only for MDAMB231 tumours); (4) untreated controls. Post-treatment tumours, liver and spleen were harvested for further analysis. Phenformin significantly inhibited both the development and growth of MCF7 and MDAMB231 tumours, and for MDAMB231 at greater efficacy than metformin without murine toxicity. The number of mitotic figures was significantly fewer in xenografts treated with phenformin compared with controls. Results suggested that the mechanism of action of phenformin in vivo is consistent with AMPK activation. Phenformin has clinical potential as an antineoplastic agent and should be considered for clinical trials both in ER-positive and triple-negative breast cancer.
    British Journal of Cancer 02/2012; 106(6):1117-22. DOI:10.1038/bjc.2012.56 · 4.82 Impact Factor
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    • "In addition to its antidiabetic properties, metformin has also been shown to exert beneficial effect in the treatment of polycystic ovary syndrome (Moll et al., 2007) and is currently being considered for anticancer therapy (Gonzalez-Angulo and Meric-Bernstam, 2010). Namely, it has been shown that metformin inhibits in vitro growth of various types of cancer cells, including breast cancer, prostate cancer and glioma cells (Zakikhani et al., 2006; Ben Sahra et al., 2008; Isakovic et al., 2007), as well as tumourigenesis and tumour progression in vivo (Ben Sahra et al., 2008; Buzzai et al., 2007; Huang et al., 2008; Anisimov et al., 2005). Moreover, population studies have suggested that metformin decreases the incidence of cancer and cancer-related mortality in diabetic patients (Evans et al., 2005; Bowker et al., 2006), while a recent report revealed that metformin improves the response to chemotherapy in diabetic patients with breast cancer (Jiralerspong et al., 2009). "
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    ABSTRACT: Metformin is an antidiabetic drug with anticancer properties, which mainly acts through induction of AMP-activated protein kinase (AMPK). In the present study we investigated the influence of metformin on the in vitro anticancer activity of the well-known chemotherapeutic agent cisplatin. Cell viability was determined by MTT and LDH release assay, oxidative stress and apoptosis (caspase activation, DNA fragmentation, and phosphatidylserine exposure) were assessed by flow cytometry, while activation of AMPK and Akt was analyzed by immunoblotting. Although metformin reduced the number of tumour cells when applied alone, it surprisingly antagonized the cytotoxicity of cisplatin towards U251 human glioma, C6 rat glioma, SHSY5Y human neuroblastoma, L929 mouse fibrosarcoma and HL-60 human leukemia cell lines. Only in B16 mouse melanoma cells metformin augmented the cytotoxicity of cisplatin. In U251 glioma cells metformin suppressed cisplatin-induced apoptotic cell death through inhibition of oxidative stress and caspase activation. The observed cytoprotection was apparently AMPK-independent, as metformin did not further increase cisplatin-induced AMPK activation in U251 cells and other pharmacological AMPK activators failed to block cisplatin-mediated apoptosis. On the other hand, metformin induced Akt activation in cisplatin-treated cells and Akt inhibitor 10-DEBC hydrochloride or phosphoinositide 3-kinase/Akt inhibitor LY294002 abolished metformin-mediated antioxidant and antiapoptotic effects. In conclusion, the antidiabetic drug metformin reduces cisplatin in vitro anticancer activity through AMPK-independent upregulation of Akt survival pathway. These data warrant caution when considering metformin for treatment of diabetic cancer patients receiving cisplatin or as a potential adjuvant in cisplatin-based chemotherapeutic regimens.
    European journal of pharmacology 01/2011; 651(1-3):41-50. DOI:10.1016/j.ejphar.2010.11.005 · 2.68 Impact Factor
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