RESUMEN
Hyperglycemia and hyperinsulinemia accelerate both aging and cancer. Antidiabetic biguanides such as metformin decrease glucose, insulin and IGF-1 level. Metformin increases lifespan and prevents cancer in mice, although its effects vary, depending on mice strain and gender. Here we showed that chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreased body temperature and postponed age-related switch-off of estrous function. Surprisingly, metformin did not affect levels of serum cholesterol, triglycerides, glucose and insulin. Treatment with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. The treatment started at the age of 9 months insignificantly increased mean life span by only 6%, whereas the treatment started at the age of 15 months failed to increase life span. The mean life span of tumor-free mice was increased by 21% in 'the youngest group', by 7% in 'middle-aged group' and in contrast was reduced by 13% in 'the oldest group'. When started at the age of 3 and 9 months, metformin delayed the first tumor detection by 22% and 25%, correspondingly. Thus, in female SHR mice, metformin increased life span and postponed tumors when started at the young and middle but not at the old age. In contrast, metformin improves reproductive function when started at any age.
Asunto(s)
Hipoglucemiantes/farmacología , Esperanza de Vida , Longevidad/efectos de los fármacos , Metformina/farmacología , Neoplasias/prevención & control , Factores de Edad , Animales , Temperatura Corporal , Peso Corporal , Ingestión de Líquidos , Ingestión de Alimentos , Ciclo Estral/efectos de los fármacos , Ciclo Estral/fisiología , Femenino , Humanos , Ratones , Neoplasias/patologíaRESUMEN
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. 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. Antidiabetic biguanides are most promising among them. The chronic treatment of inbred 129/Sv mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but failed to influence the dynamics of body weight, decreased by 13.4% the mean life span of male mice and slightly increased the mean life span of female mice (by 4.4%). The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice, decreased by 3.5 times the incidence of malignant neoplasms in female mice while somewhat stimulated formation of benign vascular tumors in the latter.
Asunto(s)
Envejecimiento/fisiología , Hipoglucemiantes/farmacología , Longevidad/efectos de los fármacos , Metformina/farmacología , Neoplasias/prevención & control , Factores de Edad , Animales , Glucemia/metabolismo , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Colesterol/sangre , Aberraciones Cromosómicas/inducido químicamente , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Estro/efectos de los fármacos , Femenino , Hipoglucemiantes/toxicidad , Insulina/sangre , Masculino , Metformina/toxicidad , Ratones , Ratones de la Cepa 129 , Neoplasias/etiología , Neoplasias/patología , Factores Sexuales , Triglicéridos/sangreRESUMEN
Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. 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 resemble effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice. On the other side, treatment with metformin failed influence blood estradiol concentration and spontaneous tumor incidence in female SHR mice. Thus, antidiabetic biguanide metformin dramatically extends life span, even without cancer prevention in this model.
Asunto(s)
Envejecimiento/efectos de los fármacos , Longevidad/efectos de los fármacos , Metformina/farmacología , Animales , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Ciclo Estral/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Hormonas/sangre , Ratones , Neoplasias/patología , Análisis de SupervivenciaRESUMEN
The abundance of fat tissue surrounding normal and malignant epithelial mammary cells raises the questions whether such "adipose milieu" is important in the local proinflammatory/genotoxic shift, which apparently promotes tumor development and worsens prognosis, and what conditions stimulate this shift, or "adipogenotoxicosis." We studied 95 mammary fat samples from 70 postmenopausal and 25 premenopausal breast cancer (BC) patients at a distance of 1.5-2.0 cm from tumors. The levels of leptin, adiponectin, TNFalpha and IL-6 release after 4-hr incubation of the samples were evaluated with ELISA, nitric oxide (NO) production by Griess reaction and lipid peroxidation by determination of thiobarbiturate-reactive products (TBRP). Infiltration of fat with macrophages (CD68-positive cells) and expression of cytochrome P450 1B1/estrogen 4-hydroxylase (CYP1B1) were detected by immunohistochemistry. Aromatase (CYP19) activity in mammary fat was measured by (3)H(2)O release from (3)H-1beta-androstenedione. In the postmenopausal BC patients, NO and TNFalpha production by adipose tissue explants increased independent of BMI and in parallel with decreasing leptin and, especially, adiponectin release. In the premenopausal patients, higher CYP1B1 expression and TBRP level were found in mammary fat, while higher aromatase activity was combined with higher CYP1B1 expression as well as NO and IL-6 production. In the postmenopausal group, impaired glucose tolerance was associated with higher IL-6 release production by fat and with higher IL-6/adiponectin ratio. Thus, signs of adipogenotoxicosis in mammary fat can be found in both pre- and postmenopausal BC patients. This condition is likely being maintained through estrogen- and glucose-related factors and mechanisms presumably associated with less favorable types of hormonal carcinogenesis.
Asunto(s)
Tejido Adiposo/fisiología , Neoplasias de la Mama/patología , Estrógenos/fisiología , Hiperglucemia/patología , Glándulas Mamarias Humanas/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Aromatasa/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Humanos , Inflamación/patología , Leptina/metabolismo , Macrófagos/patología , Persona de Mediana Edad , Posmenopausia , PremenopausiaRESUMEN
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.
Asunto(s)
Adenocarcinoma/prevención & control , Hipoglucemiantes/farmacología , Longevidad/efectos de los fármacos , Neoplasias Mamarias Animales/prevención & control , Metformina/farmacología , Receptor ErbB-2/genética , Adenocarcinoma/sangre , Adenocarcinoma/química , Envejecimiento/fisiología , Animales , Glucemia/análisis , Temperatura Corporal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Estro/efectos de los fármacos , Femenino , Granzimas , Insulina/sangre , Lipoproteínas LDL , Neoplasias Mamarias Animales/sangre , Neoplasias Mamarias Animales/química , Glicoproteínas de Membrana/genética , Ratones , Ratones Transgénicos , Perforina , Proteínas Citotóxicas Formadoras de Poros , ARN Mensajero/análisis , Receptor ErbB-2/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Serina Endopeptidasas/genética , Tiroxina/sangre , Triglicéridos/sangre , Triyodotironina/sangreRESUMEN
Initiation and/or promotion of endometrial cancer is known to be associated with estrogen and androgen (androstenedione) excess as well as with hyperinsulinemia/insulin resistance. It is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. We evaluated here the role of CYP17 biallelic (MspAI) polymorphism in 114 endometrial cancer patients compared with 182 healthy women. Our data demonstrated that A2/A2 CYP17 genotype, considered on the basis of initial breast cancer studies as 'unfavorable', was under-represented in endometrial cancer group (odds ratio 0.48, 95% confidence interval 0.25-0.89) that confirmed results of two other recent investigations. Carriers of this genotype were characterized by having lower blood insulin (by 120 min of oral glucose tolerance test 36.7+/-3.9 microU/ml vs. 90.4+/-16.7 microU/ml in postmenopausal women with A1/A1 genotype, P=0.04) and C-peptide levels (after night fasting 575.2+/-78.3 pg/ml vs. 978.9+/-115.7 pg/ml, respectively, P=0.04). No significant difference was found between the mean concentrations of testosterone, dehydroepiandrosterone sulfate and estradiol concentrations in patients-carriers of separate CYP17 genotypes. Thus, CYP17 polymorphism (namely, carrying the 'normal' A1/A1 genotype) might be one of the risk factors for endometrial cancer development. A1/A1 CYP17 variant may be associated with untraditional (non-steroidal) pathways that calls for corresponding preventive measures in high-risk groups.