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.


Available from: Vladimir N Anisimov, Jan 11, 2014
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    • "Year Phenomenon being shown in the first time 1971 Vladimir Dilman originally developed idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs [16] 1974 Phenformin inhibits mammary carcinogenesis induced by DMBA in rats [17] 1977 Phenformin alleviates metabolic immunodepression induced by DMH in rats [25] 1979 Phenformin inhibits spontaneous carcinogenesis and increases of the life span in female C3H/Sn mice [18] 1980 Buformin inhibits spontaneous carcinogenesis, postpones of estrus cycle swithching-off and increases the life span in female rats [20] 1980 Buformin inhibits transplacental carcinogenesis induced by NMU in rats [27] 1982 Phenformin inhibits spontaneous carcinogenesis and the increase of the life span in female rats [21] 1982 Phenformin inhibits carcinogenesis induced by X-rays irradiation in rats [30] 2001 Metformin inhibits pancreatic carcinogenesis induced by NBOPA in hamsters [35] 2005 Metformin inhibits spontaneous carcinogenesis and the increase of the life span in female HER-2/neu transgenic mice [37] Metformin decreases the risk of cancer in type 2 diabetes patients [38, 39] 2008 Metformin increases life span in outbred female SHR [49] 2008- 2014 Treatment with metformin prevent spontaneous and/or induced carcinogenesis in: 2008: small intestines [79]; lymphoid tissue [79] 2009: uterus [58] 2010: cervix [61]; skin [54]; soft tissues [57]; lung [62]; pancreatic islets [70]; colon [80] 2012: oral mucosa [66]; liver [71] 2013: pancreas [67] 2014: kidney [65] 2014 Diabetes type 2 patients treated with metformin monotherapy have 15% longer survival than matched controls without diabetes [5] 2015 Announcing the project TAME (Targeting Aging with Metformin) suggesting delay age-related diseases and increase survival in elderly people [3, 4] "
    [Show abstract] [Hide abstract] ABSTRACT: During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides.
    Full-text · Article · Nov 2015 · Oncotarget
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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. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Oct 2015 · Biogerontology
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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]. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Jan 2015 · Oral Oncology
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