Effects of Metformin, Buformin, and Phenformin on the Post-Initiation Stage of Chemically Induced Mammary Carcinogenesis in the Rat

Abstract

Metformin is a widely prescribed drug for the treatment of type-2 diabetes. Although epidemiological data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in non-diabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared to rats fed control diet (AIN93-G) during the post initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison to the control group, buformin decreased cancer incidence, multiplicity, and burden; whereas, metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.

Metformin Accumulation Correlates with Organic Cation Transporter 2 Protein Expression and Predicts Mammary Tumor Regression In Vivo

“…In contrast to our findings, a limited number of rodent studies have suggested that metformin does not affect mammary carcinogenesis (10,11). However, there are key differences in study design between our study and these previous reports that include variations in rodent age at initiation with MNU, diet, and dosage of metformin.…”

“…A number of preclinical studies of mammary carcinogenesis and in vitro studies using breast cancer cell lines are consistent with this assertion of metformin's beneficial effects (4-9). Even so, other preclinical studies of mammary carcinogenic models failed to see any effect of metformin when the animals were fed a low fat diet and exhibited no metabolic dysfunction (10,11). These conflicting reports suggest that there may be specific factors and metabolic conditions that confer a tumor's sensitivity to metformin.…”

“…The fact that metformin had little to no effect in preclinical studies in non-diabetic animals on a low fat diet would suggest the systemic effects of metformin are relevant (10,11). Observations that the effects of metformin are evident or more pronounced in obese or HF fed models (12,13) would support this notion.…”

Mitochondrial targets of metformin—Are they physiologically relevant?

“…57 Inherent risk connected with complex I inhibition is development of lactic acidosis. 3 It was published that more lipophilic metformin analogues, phenformin and buformin, have more potent antitumor effect, 58,59 but they are also more likely to trigger lactic acidosis. 3 Even metformin, which is considered relatively safe in this regard, may present higher risk of lactic acidosis in patients with associated condition, such as renal impairment, which increases metformin levels in plasma.…”

Buformin suppresses proliferation and invasion via AMPK/S6 pathway in cervical cancer and synergizes with paclitaxel

“…20 Interestingly, in another mammary cancer rat model, Zhu et al found that buformin notably decreased cancer incidence, multiplicity, and burden; however, these effects were not seen in rats fed with phenformin or metformin. 21 Based on these results, we propose that buformin might be a potent anti-cancer drug for treatment of cervical cancer, and we performed a series of experiments to illustrate this possibility.…”