Researchers in Switzerland suggest that combining the type 2 diabetes drug metformin with the antihypertensive drug syrosingopine could represent a surprising new approach to fighting cancer. Metformin is a mild mitochondrial inhibitor that has previously been shown to exhibit some degree of anticancer activity, but not enough to have significant clinical utility at the usual therapeutic dose. The Swiss team, led by Dr. Don Benjamin, at the Biozentrum, University of Basel, has now found that syrosingopine potentiates the anticancer effects of metformin, and that combination therapy is highly effective against different types of cancer cell without harming normal cells. The team’s results are published in Science Advances, in a paper titled “Syrosingopine Sensitizes Cancer Cells to Killing by Metformin.”
The Basel researchers screened a drug library to identify compounds that were cytotoxic, but only in the presence of metformin. Syrosingopine was the only drug to match their selection criteria. The syrosingopine–metformin combination was found to be highly effective against a range of cancer cell types in vitro. “For example, in samples from leukemia patients, we demonstrated that almost all tumor cells were killed by this cocktail and at doses that are actually not toxic to normal cells,” Benjamin noted. “And the effect was exclusively confined to cancer cells, as the blood cells from healthy donors were insensitive to the treatment.” Subsequent studies in a mouse model of liver cancer showed that the combination therapy led to reduced liver size and fewer visible tumor nodules.
The Basel team’s studies indicated that the metformin–syrosingopine combination triggers apoptosis and interrupts the ability of cancer cells to derive energy and use glucose. Metformin acts by lowering blood glucose levels, “and hence glucose availability to glucose-hungry cancer cells,” while at the same time blocking mitochondrial respiration in cancer cells that “already experience a shortfall in glucose uptake.” Syrosingopine appears to have an inhibitory effect on the degradation of sugars.
Further investigation by the researchers threw some light on how syrosingopine was potentiating the anticancer effects of metformin. They found that the blood pressure drug was also synthetically lethal when combined with other mitochondrial electron transport chain (ETC) inhibitors, at concentrations that were far lower than the toxic thresholds for any of the compounds on their own. In addition, cells engineered to lack mitochondrial DNA were far more sensitive to syrosingopine alone than their parent cells. “These results allow us to generalize that syrosingopine is synthetic lethal with inhibition of mitochondrial electron transport.”
“Syrosingopine and metformin are approved drugs with well-established clinical records outside cancer therapy,” the team concludes. “The interaction between these drugs in in vitro and animal models holds out the promise that, when appropriately combined, they may find application in the treatment of cancer.”