ASPIRIN has been shown to decrease the risk of colorectal cancer and possibly other cancers. However, the risk of side effects, including in some cases severe gastrointestinal bleeding, makes it necessary to better understand the mechanisms by which aspirin acts at low doses before recommending it more generally as a preventative, says an international team of cancer researchers from the United States, Germany and New Zealand, led by Cornelia Ulrich, of Huntsman Cancer Institute in Salt Lake City, U.S. The long-term aim of the researchers is to investigate if aspirin can be used as part of personalised medicine to prevent cancer—to be able to tailor it to people who are most likely to have benefit and to have the lowest risk of adverse outcomes.
The study has been published in the journal of Cancer Epidemiology, Biomarkers, and Prevention. Ulrich and her collaborators used a new technique, called metabolite profiling, to identify a biochemical pathway previously unknown to be regulated by aspirin.
The researchers found that aspirin substantially decreases the level of a chemical called 2-hydroxyglutarate in the blood of healthy volunteers and in two colorectal cancer cell lines. This chemical is an “oncometabolite”, a driver of cancer development because elevated levels have been found in certain cancers of the blood and brain. The overall evidence, said Ulrich, is that aspirin is important for cancer prevention in general and its role calls for further study.
The first part of the study involved looking comprehensively at the metabolic profiles from the blood of 40 individuals who had taken aspirin for 60 days.
The design was rigorous, with participants each having a phase with and without aspirin. More than 360 metabolites were analysed. “The study covered most of the known biochemical pathways in the body,” said Ulrich.
The researchers found aspirin metabolites were increased in the volunteers as expected but they also noted statistically significant changes in a metabolite that has been found to drive cancer development. 2-hydroxyglutarate was found to be reduced by 12 per cent. The researchers evaluated the levels of 2-hydroxyglutarate in cultured cancer cells after treatment with aspirin. The colorectal cell lines showed consistent reductions in the chemical up to 34 per cent.
In addition, they found that the primary metabolite of aspirin, salicylate, inhibits an enzyme called HOT (hydroxyacidic-oxoacid transhydrogenase) that triggers the production of 2-hydroxyglutarate, suggesting that aspirin is acting on a previously unknown pathway at a concentration comparable to that of individuals treated with aspirin.
Prior studies looked at the anti-inflammatory and anti-clotting roles of aspirin as the possible reasons for the cancer-preventive effects, but Ulrich said there is evidence that other pathways are involved, especially at lower aspirin doses. The reduction in 2-hydroxyglutarate may identify a new mechanism for aspirin in cancer prevention, Ulrich said.
R. Ramachandran
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