Anisimov, V. N. et al. Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp. Gerontol. 40, 685-693

University of Bologna, Bolonia, Emilia-Romagna, Italy
Experimental Gerontology (Impact Factor: 3.49). 08/2005; 40(8-9):685-93. DOI: 10.1016/j.exger.2005.07.007
Source: PubMed


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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Available from: Vladimir N Anisimov, Jan 11, 2014
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    • "These mice usually died before the age of 1 year developing from 1 to 10 mammary adenocarcinomas (Baturin et al. 2001; Anisimov et al. 2005). Transgenic HER-2/ neu mice were used in a number of our studies on effect of metformin, melatonin, rapamycin and some other drugs with potentially geroprotective and anticancer activity in mice (Anisimov et al. 2005, 2010a, b). However the comparison of parameters of aging in wild type and transgenic mice was never performed. "
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    ABSTRACT: FVB/N wild type and transgenic HER-2/neu FVB/N female mice breed at N.N. Petrov Research Institute of Oncology were under observation until natural death without any special treatment. Age-related dynamics of body weight, food consumption and parameters of carbohydrate and lipid metabolism, level of nitric oxide, malonic dialdehyde, catalase, Cu, Zn-superoxide dismutase, vascular endothelial growth factor were studied in both mice strains. The parameters of life span and tumor pathology were studied as well. Cancer-prone transgenic HER-2/neu mice developed in 100 % multiple mammary adenocarcinomas and died before the age of 1 year. Forty tree percent of long-lived wild type mice survived the age of 2 years and 19 %-800 days. The total tumor incidence in wild type mice was 34 %. The age-associated changes in the level of serum IGF-1, glucose and insulin started much earlier in transgene HER-2/neu mice as compared with wild type FVB/N mice. It was suggested that transgenic HER-2/neu involves in initiation of malignization of mammary epithelial cells but also in acceleration of age-related hormonal and metabolic changes in turn promoting mammary carcinogenesis.
    Biogerontology 10/2015; DOI:10.1007/s10522-015-9611-y · 3.29 Impact Factor
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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 · 3.61 Impact Factor
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    • "Interestingly, two independent clinical studies have shown that metformin may reduce the risk of cancer in patients with type II diabetes1112. This is consistent with the effect of metformin on suppressing the spontaneous development of breast tumors in HER-2/neu-transgenic mice13 as well as the induction of pancreatic cancer in the hamster models14. However, it is not clear whether the observed effects were due to the drug's direct activity on the tumor cells or if the effects resulted from the drug's regulation on insulin metabolism. "
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    ABSTRACT: Cancer is a leading cause of death worldwide. Because the cytotoxic effects of conventional chemotherapies often harm normal tissue cells along with cancer cells, conventional chemotherapies cause many unwanted or intolerable side effects. Thus, there is an unmet medical need to establish a paradigm of chemotherapy-induced differentiation of cancer cells with tolerable side effects. Here we show that low-dose metformin or SN-38 inhibits cell growth or survival in ovarian and breast cancer cells and suppresses their tumor growth in vivo. Low-dose metformin or SN-38 increases FOXO3 nuclear localization as well as the amount of DNA damage markers and downregulates the expression of a cancer-stemness marker CD44 and other stemness markers, including Nanog, Oct-4, and c-Myc, in these cancer cells. This treatment also inhibits spheroid body-formation in 3-dimensional culture. In contrast, silencing FOXO3 diminishes all these cellular events when ovarian/breast cancer cells are treated with the mentioned drugs. These results suggest that low-dose metformin or SN-38 may reprogram these cancer cells into non-cancerous cells in a FOXO3-dependent manner, and may allow patients to overcome these cancers with minimal side effects.
    Scientific Reports 07/2014; 4. DOI:10.1038/srep05810 · 5.58 Impact Factor
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