Unlikely drug pair combine to cut off cancer's energy supply
Cancer cells are a hungry bunch, calling on relatively huge amounts of energy to feed their demanding metabolisms. There's a particular molecule that is pivotal to this process, converting nutrients into fuel to power the cells' rapid growth. New research out of the University of Basel describes a drug cocktail that has the effect of putting this out of action, leading the cancer cells to wither and die instead.
Molecular scientists at the University of Basel actually discovered two years ago that a commonly used diabetes drug could be combined with a 50-year-old hypertension medication to inhibit tumor growth. Named metformin and syrosingopine, respectively, the scientists knew beforehand that the former had some anti-cancer properties, but only by mixing it with the latter did it seem to have any meaningful effect.
They have now carried out follow-up experiments in mice to better understand how this process slows cancer growth, and it centers on a molecule called NAD+ that is central to converting nutrients into energy. NAD+ is produced through two cellular pathways, one of which metformin was known to block. The other, it has now been found, can be shut down by syrosingopine's ability to cause bottlenecks in some very key areas.
"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."
The metabolism of many cancer cells relies on a process called glycolysis, where they produce energy by breaking glucose down into lactate. But if enough lactate builds up it causes blockages in this pathway, something the cancer cells respond to by expelling them through special transporters. Syrosingopine's anti-cancer effects, as it turns out, are due to an ability to put these transporters out of action.
"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 scientists found that the backlogs of lactate caused by syrosingopine, when combined with metformin, completely shut off the cells ability to produce NAD+. And depleted stocks of NAD+ mean insufficient energy levels, which in turn means cellular death.
They describe this as an important discovery, because currently there are no drugs available that block those lactate-transporting pathways of the cancer cells. These newfound abilities could lead to new cancer therapies that swiftly kill off deadly cells, and as the scientists note, a second career for a drug that was developed in the 1950s for another purpose entirely.
The study has been published in the journal Cell Reports.
Source: University of Basel