Metformin in chemically-induced mammary carcinogenesis in rats

Abstract

In this paper the chemopreventive effect of peroral antidiabetic metformin in mammary carcinogenesis in female SpragueDawley rats was evaluated. Mammary carcinogenesis was induced by N-methyl-N-nitrosourea (NMU) administered in two intraperitoneal doses each per 50 mg/kg b.w. between 43.-55. postnatal days. Metformin was administered in drinking water (at a concentration of 50 µg/ml and 500 µg/ml) 13 days before the first NMU dose until the termination of the experiment. During the experiment the animals were weekly weighed and palpated for the presence of mammary tumors, the incidence, latency, tumor frequency, and tumor volume were recorded. The experiment was terminated 18 weeks after the first NMU dose, basic tumor growth parameters and metabolic and hormonal variables were evaluated. Metformin did not significantly alter the tumor growth although a delay in tumor onset was recorded after higher metformin dose. Metformin altered metabolic and hormonal variables. Insulinemia decreased after both metformin doses in comparison with intact rats without changes in glycemia, triacylglycerols concentration was decreased in liver and increased in serum when compared to intacts. Higher metformin dose attenuated lipoperoxidation in liver.

Rosiglitazone Shows Partial Oncostatic Effect in Rat Mammary Carcinogenesis

“…This was proved in our previous work with metformin [59] but not in this experiment, in NMU+ROS10 group, however, serum IGF-1 increased unexpectedly. Nunez et al [34] and Kocdor et al [35] found no changes in serum IGF-1 level after ROS administration and similarly, pioglitazone administration did not change serum IGF-1 level [52].…”

“…Serum cortisol increases in breast cancer patients, especially in those with weight loss [60], serum CTS increased in control animals (administered with NMU) in our previous reports too and chemoprevention (with metformin and pioglitazone, respectively) [59,52] decreased it. Surprisingly, in this work serum CTS was not changed after higher ROS dose and even rose after lower ROS dose, while metformin and particularly pioglitazone markedly decreased serum CTS [59,52]; this might contribute to lack of ROS antitumor efficacy as glucocorticoids can inhibit apoptosis in mammary epithelial cells [61,62].…”

Metformin extends life span of HER-2/neu transgenic mice and in combination with melatonin inhibits growth of transplantable tumors in vivo

“…Population studies have shown that treatment with the antidiabetic biguanide metformin significantly reduced cancer risk. [1][2][3][4] In animal studies it was revealed that metformin suppresses the mammary carcinoma development in transgenic HER-2/neu mice, 5 mammary carcinogenesis induced by N-nitrosomethylurea in rats, 6 but not that of spontaneous mammary tumors in female SHR mice. 7 It was shown that HER-2 oncoprotein represent a key cellular target in inhibitory effect of metformin on HER-2/neu-poisitve breast cancer cells.…”

The effects of metformin on the survival of colorectal cancer patients with diabetes mellitus

“…11 Interestingly, several recent preclinical studies in rodent models have shown that metformin induces AMPK activation and inhibits tumor development and growth, including colon carcinogenesis. [12][13][14][15] In addition, population studies have shown that patients with type 2 DM who are taking metformin have a lower risk of cancer and better outcomes compared with patients who do not take metformin. 6,7,16,17 Although there has been substantial evidence from in vivo and in vitro studies supporting the potential efficacy of metformin as an anti-cancer agent, there have been no clinical studies investigating the effect of metformin on CRC.…”