Protective Effect of Metformin Against Walker 256 Tumor Growth is Not Dependent on Metabolism Improvement

Abstract

Background/Aims: The objective of the current work was to test the effect of metformin on the tumor growth in rats with metabolic syndrome. Methods: We obtained pre-diabetic hyperinsulinemic rats by neonatal treatment with monosodium L-glutamate (MSG), which were chronically treated every day, from weaning to 100 day old, with dose of metformin (250 mg/kg body weight). After the end of metformin treatment, the control and MSG rats, treated or untreated with metformin, were grafted with Walker 256 carcinoma cells. Tumor weight was evaluated 14 days after cancer cell inoculation. The blood insulin, glucose levels and glucose-induced insulin secretion were evaluated. Results: Chronic metformin treatment improved the glycemic homeostasis in pre-diabetic MSG-rats, glucose intolerance, tissue insulin resistance, hyperinsulinemia and decreased the fat tissue accretion. Meanwhile, the metformin treatment did not interfere with the glucose insulinotropic effect on isolated pancreatic islets. Chronic treatment with metformin was able to decrease the Walker 256 tumor weight by 37% in control and MSG rats. The data demonstrated that the anticancer effect of metformin is not related to its role in correcting metabolism imbalances, such as hyperinsulinemia. However, in morphological assay to apoptosis, metformin treatment increased programmed cell death. Conclusion: Metformin may have a direct effect on cancer growth, and it may programs the rat organism to attenuate the growth of Walker 256 carcinoma.

Chronic Glibenclamide Treatment Attenuates Walker-256 Tumour Growth in Prediabetic Obese Rats

“…In the present work, Walker-256 tumour growth decreased insulin levels 4-fold in control rats and 8-fold in prediabetic obese rats, which is in agreement with previous reports [26, 32, 33],. Tumour requires lot of energy consuming very rapidly blood glucose.…”

“…In addition, chronic Gli treatment improved the metabolism of prediabetic obese MSG-rats. For example, Gli treatment normalized the tissue insulin sensitivity and glucose tolerance, suppressed the fasting hyperinsulinaemia and reduced adipose tissue accretion, effects that were previously reported by other studies with antidiabetic drugs [25, 26]. Gli treatment did not change the biometric and metabolic parameters of control rats.…”

“…Our results suggest that Gli has an antiproliferative effect. Using another antidiabetic drug, metformin, our group recently demonstrated that Walker-256 tumour growth was inhibited [26]. In the present study, the rats did not receive Gli during tumour growth.…”

“…As can be observed our results show that rats bearing tumour exhibit very low insulin blood concentration, even glibenclamide treated ones. It is surprizing that glucose levels are unchanged in those conditions, it means peripheral tissues from rats grafted with Walker256 tumour present reduction of glucose uptake regarding, ungrafted ones [26, 32, 33]. Regarding those observation, including insulin tissues resistance of tumour-bearing rats, it was expected hyperglycaemia; however, glucose levels are maintained similar to rat that were not transplanted with tumoral cells.…”

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B

“…Metformin can inhibit mitochondrial shuttles and glucagon signaling, attenuate inflammasome activation and terminal endoplasmic reticulum stress, and alter intestinal microbiota [21]. It also reduces cancer risk in diabetic patients and possesses antineoplastic activity against several tumors [22,23]. These data suggest that metformin may play an important role in regulating cell cycle.…”