Article

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
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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    • "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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    • "Metformin, (known as Glucophage clinically) is the most widely used type 2 diabetes drug in the world and is taken daily by approximately 120 million patients worldwide. Several retrospective studies revealed a strong correlation between reduced cancer risk and mortality in diabetic patients taking metformin (Evans et al, 2005; Bowker et al, 2006; Pollak, 2010; Currie et al, 2012), agreeing with early studies showing that biguanides suppressed naturally arising tumours in both transgenic and carcinogen-treated rodent cancer models (Schneider et al, 2001; Anisimov et al, 2005). In order to inhibit complex I of ETC, metformin but not phenformin requires the cell membrane-bound organic cation transporter 1 (OCT1) for intracellular transport (Gorboulev et al, 1997; Segal et al, 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: The LKB1 tumour suppressor is a serine/threonine kinase that functions as master regulator of cell growth, metabolism, survival and polarity. LKB1 is frequently mutated in human cancers and research spanning the last two decades have begun decoding the cellular pathways deregulated following LKB1 inactivation. This work has led to the identification of vulnerabilities present in LKB1-deficient tumour cells. Pre-clinical studies have now identified therapeutic strategies targeting this subset of tumours that promise to benefit this large patient population harbouring LKB1 mutations. Here, we review the current efforts that are underway to translate pre-clinical discovery of therapeutic strategies targeting LKB1 mutant cancers into clinical practice.British Journal of Cancer advance online publication, 21 July 2015; doi:10.1038/bjc.2015.261 www.bjcancer.com.
    Full-text · Article · Jul 2015 · British Journal of Cancer
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