How Antidiabetic Drugs Kill Tumors
A few years ago, researchers found that antidiabetic drugs of the biguanide class have antitumor properties. A number of retrospective studies have shown that metformin, a drug widely used for the treatment of diabetes related to biguanides, has a positive effect on the condition of some cancer patients. However, knowing about these intriguing correlations, experts until recently proposed only one possible mechanism by which antidiabetic drugs have an effect on tumors – preventing the synthesis of pro-inflammatory cytokines. More importantly, it was not known which of the patients they were able to help with drugs that lower blood glucose levels.
Scientists at the Whitehead Institute of Biomedical Research managed to lift the veil over this mystery a little. To study the ability of malignant cells to survive in conditions with a low glucose content, the authors developed a system that ensures continuous circulation of a nutrient-poor environment around the cells. Most of the 30 malignant cell lines tested in the system did not suffer from low glucose content in the medium. However, at the same time, there were several lines that felt great in the created conditions and began to divide rapidly or, conversely, were close to death.
Such pronounced variability in the response of cells to glucose deficiency has puzzled scientists. They suggested that the sensitivity of malignant cells to low glucose concentrations could be used to influence tumors. Subsequent DNA screening of the cells of the most sensitive lines for the presence of genes, the suppression of the activity of which stimulated or, conversely, worsened their survival, revealed genes involved in glucose transport and oxidative phosphorylation.
Oxidative phosphorylation is a metabolic process that occurs inside organelles known as mitochondria, which are the energy centers of the cell. Mitochondria have their own DNA containing a number of genes, including genes that control the process of oxidative phosphorylation.
The authors suggested that malignant cells with mutations in these genes, under normal conditions, overburden their mitochondria. With a lack of glucose, their mitochondria cannot cope with the load, which disrupts the vital activity of cells. Based on this hypothesis, it can be assumed that further disruption of mitochondrial functions under the action of biguanides, which are inhibitors of oxidative phosphorylation, can completely exhaust mitochondrial reserves and lead to cell death.
To begin with, the hypothesis was tested on 13 cell cultures with impaired glucose utilization or mitochondrial DNA mutations. Compared with control cultures, such cells were 20 times more sensitive to phenformin, a more active representative of the biguanide class, than metformin.
Further experiments on mice implanted with tumors grown from malignant cells sensitive to low glucose levels also confirmed the ability of phenformin to suppress tumor growth.
The authors believe that the results obtained indicate the possibility of using mitochondrial DNA mutations and defects in glucose transport mechanisms as biomarkers of tumor susceptibility to the action of biguanides. To further confirm the data obtained, they plan to analyze the results of earlier clinical studies and find out whether the presence of the proposed biomarkers is really associated with the positive effect of taking metformin on the condition of cancer patients.
Article by Kivanc Birsoy et al. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides is published in the journal Nature.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the Whitehead Institute for Biomedical Research:
How diabetes drugs may work against cancer.
19.03.2014