Researchers have known for several decades that autophagy, which is the cell’s natural recycling system, is increased in cancer cells relative to healthy cells, suggesting that inhibiting autophagy might be a way to target cancer cells. However, results from almost 20 clinical trials testing autophagy inhibitors have been inconclusive.
"Within those clinical trials they found mixed results; there was some benefit, but for many patients there was no benefit, which really pushed researchers back to the drawing board,” says James Byrne, MD, PhD, UI assistant professor of radiation oncology and biomedical engineering and senior author on the new study.
Searching for insight into why autophagy inhibition only seems to work some of the time, the researchers made the surprising discovery that smokers in two of the previous trials of autophagy inhibitors seemed to do better than non-smokers.
Carbon monoxide boosts anti-cancer activity of autophagy inhibition
The team already had just such a “platform” to test their ideas. Byrne specializes in crafting gas-entrapping materials (GEMs)—foams, gels, and solids made from safe, edible substances that can be infused with different gas molecules. For this study, the researchers created a drinkable foam infused with carbon monoxide.
When mice with pancreatic and prostate cancers were fed the carbon monoxide foam and simultaneously treated with an autophagy inhibitor, tumor growth and progression was significantly reduced in the animals. The team also showed that combining carbon monoxide with autophagy inhibitors had a significant anti-cancer effect in human prostate, lung, and pancreatic cancer cells in petri dishes.
Ultimately, Byrne hopes to test this approach in human clinical trials.
“The results from this study support the idea that safe, therapeutic levels of CO, which we can deliver using GEMs, can increase the anti-cancer activity of autophagy inhibitors, opening a promising new approach that might improve therapies for many different cancers,” he says.
Reference: Bi J, Witt E, McGovern MK, et al. Oral carbon monoxide enhances autophagy modulation in prostate, pancreatic, and lung cancers. Adv Sci. 2023:2308346. doi: 10.1002/advs.202308346
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