Metformin has been discovered for nearly 90 years. The advantages of safety, efficacy, and low price make it the most widely used oral hypoglycemic agent in clinical practice. In 2014, approximately 14.4 million people in the United States prescribed drugs containing metformin. As evidence of the benefits of metformin in more indications continues to be revealed, such as lowering blood lipids, anti-tumor, anti-aging, and even extending life expectancy, metformin has been crowned the “magic drug.”
Metformin is able to show some degree of anti-cancer activity because it is a mild mitochondrial inhibitor, but at a conventional dose, the “weak” anticancer activity of metformin is not clinically significant. However, the researchers found that if combined with the antihypertensive drug syrosingopine, the strength of this anti-cancer effect of metformin will be amplified, the effect strength is sufficient to kill many types of tumor cells, and will not cause damage to normal cells.
The study was published online by the team led by Prof. Don Benjamin of the University of Basel, Switzerland, in the Science Advances entitled “Syrosingopine Sensitizes Cancer Cells to Killing by Metformin”. “ScienceAdvances” is a new magazine created by Science, the world’s top journal, following “Signaling” and “Transnational Medicine”. The first article was officially published in February 2015.
Prof. Benjamin screened the compound library, hoping to find drugs that can kill tumor cells. Eventually it was found that in the presence of metformin, synosingopine was the only drug that met their pre-set criteria. In vitro experiments showed that the combination of metformin + syrosingopine has a very high inhibitory activity against various types of tumor cells.
“For example, for tumor cell samples from leukemia patients, we found that cocktails of metformin and syrosingopine can almost kill all of their tumor cells without harming normal cells,” Professor Benjamin said. “This drug combination The anti-cancer activity is only manifested in the tumor cells, and donor blood cells in healthy subjects are not sensitive to them.
Later studies on liver cancer mouse models also showed that “metformin + syrosingopine” reduced the size of the liver and made fewer macroscopic tumor nodules.
Prof. Benjamin’s results suggest that the combination of metformin and syrosingopine can induce tumor cell apoptosis and deprive cancer cells of their ability to transmit energy and metabolize glucose.
From a mechanistic point of view, metformin will reduce the supply of glucose, and at the same time block the mitochondrial respiration of “glucose starved” tumor cells and inhibit the metabolism of glucose by tumor cells.
The researchers further investigated the antihypertensive drug syrosingopine and found that when synosingopine is combined with other mitochondrial electron transport chain inhibitors at dose levels below their respective toxic dose thresholds, they also produce synthetic lethality (inactivation of two non-lethal genes simultaneously leads to cells Death) effect. In addition, cells knocked out of mitochondrial DNA by cell engineering are more susceptible to syrosing opine than their parental cells.
Prof. Benjamin pointed out: “These findings suggest that syrosingopine has a synthetic lethal effect by blocking the mitochondrial electron transport. Both syrosingopine and dimethyl sulfon are old drugs that have been approved for marketing, and have been widely used outside the tumor field. Safety was confirmed, and our results in vitro and in animal models suggest that the combination of syrosingopine and metformin in appropriate doses may be useful in the clinical treatment of cancer.”