Mix one common diabetes medication with an antihypertensive drug and you’ve got yourself a deadly cocktail. Researchers from the University of Basel’s Biozentrum found that the combination would not only inhibit tumor growth but also induce cancer cell death by turning off their energy supply.
Besides reducing blood sugar, Metformin was shown to possess some anti-cancer properties, though its effect was very slight. The Swiss team found that it synergizes well with another drug designed to treat high blood pressure, Syrosingopine, and together they drive cancer cells to “suicide”.
The disease requires high amounts of energy in order to sustain its increased metabolic needs and rapid growth, being dependent on one particular molecule. “In order to keep the energy-generating machinery running, NAD+ must be continuously generated from NADH”, explains Don Benjamin, first author of the study. “Interestingly, both metformin and syrosingopine prevent the regeneration of NAD+, but in two different ways”.
Tumors generally shift their metabolism towards glycolysis, meaning they break down glucose into lactate. Accumulation of lactate leads to a blockade of the glycolytic pathway, so cancer cells export it from within via specific transporters. “We have now discovered that syrosingopine efficiently blocks the two most important lactate transporters and thus, inhibits lactate export,” says Benjamin. “High intracellular lactate concentrations, in turn, prevent NADH from being recycled into NAD+”.
The treatment results in complete loss of the cell’s NAD+ recycling capacity. Unable to produce sufficient energy, the abnormal cells die.
Identifying that Syrosingopine acts as a dual inhibitor of the two main lactate transporters is an important discovery, as currently there is no pharmacological inhibitor available for one of these two transporters (MCT4).