I’m always happy to see something show up in the research literature that can be immediately applied in clinical practice. Working in drug discovery, you get used to everything maybe having an impact years in the future, if everything works out (and it rarely does!) So when you see an actionable idea that applies to current therapy, it seems a bit magical.
Here’s something in that category: a multicenter team led out of Glasgow reports that mannose can have a real effect on chemotherapy. It’s well known that many tumor types have enhanced uptake of glucose (this is tied in to the Warburg effect, the use of aerobic glycolysis as an energy pathway). The authors of this new paper have been looking at the effects of various monosaccharides on this process, and it turns out that mannose is the most effective. It’s taken up by the same transport proteins as glucose, but once in the cell it piles up as mannose-6-phosphate, and this impairs glycolysis and several other glucose-based pathways.
The team demonstrated this first in the U2OS cell line, and extended it to mouse models. When the animals were dosed with mannose, tumor growth seemed to be significantly impaired. And (even more relevant to human therapy), mannose supplementation seemed to make chemotherapy (doxorubicin or cisplatin) more effective, presumably because the tumor cells were already under stress from having their metabolism interfered with. The mannose treatment increased cell death through apoptosis, with further knockdown experiments showing that this is almost certainly through the intrinsic pathway rather than the extrinsic one. That makes sense – the intrinsic pathway involves the mitochondria, which is what you’d expect if you’re going after glucose-based metabolic pathways.
The paper goes on to find a potential biomarker for which tumor types will be most sensitive to this treatment. Phosphomannose isomerase (PMI) is the key: cell lines with high levels of the enzyme are resistant to the effects of mannose, because the enzyme converts mannose-6-phosphate to fructose-6-phosphate, which can then enter the glycolysis pathways. Cells with low PMI levels, though, are stuck. You can, in fact, turn resistant cells into sensitive ones by knocking down PMI, and take sensitive ones (such as the U2OS line that kicked off the study) into resistant ones by overexpressing it, which seems pretty definitive. Looking over tissue samples, it appears that colon cancer lines are particularly deficient in PMI, whereas ovarian, renal, breast, and prostate samples showed much more variable expression and cell-to-cell heterogeneity. The paper shows that mice with an induced colon-cancer phenotype have significantly fewer tumors when their water supply is supplemented with mannose, and there seemed to be no ill effects from the treatment.
So that would be the place to start. Mannose is not known to be a problem for humans, either, so I would say that physicians treating patients with colorectal cancer would be well advised to give it a try. I look forward to controlled data on this idea, but for now the risk/reward looks very favorable.