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Causal metabolic pathway identified for the anti-cancer effects of aspirin
It has been known for some time that the active ingredient acetylsalicylic acid ("aspirin") can prevent cancer, but the causative cellular processes have so far remained unclear, reports the German Cancer Research Center (DKFZ). Now scientists from the DKFZ, the National Center for Tumor Diseases (NCT) Heidelberg and the U.S. Cancer Research Centers in Salt Lake City and Seattle have carried out a detailed analysis of the effects of aspirin on the metabolism and have found that aspirin is the blood concentration of a cancer-promoting metabolite lowers.
The anti-cancer effects of aspirin have been confirmed in several previous studies, but how the active ingredient acetylsalicylic acid lowers the risk of cancer has not yet been explained. In the current study, the researchers have now analyzed the cellular processes that prevent cancer from developing. In doing so, "they came across a biochemical process that was previously not known to be regulated by ASA," reports the German Cancer Research Center.
Mechanism of action of aspirin in cancer prevention so far unclear
According to the DKFZ, several large studies have shown that "acetylsalicylic acid (ASA) reduces the risk of colorectal cancer" and "possibly also reduces the risk of other cancers". However, the drug can also have side effects, "including severe bleeding in the gastrointestinal tract," the DKFZ continues. Before ASA can be widely recommended for cancer prevention, the researchers wanted to decipher how cancer risk is reduced. "If we know the mechanism of action, it may help us to prescribe ASA to those who use it the most and who have the least risk of developing serious side effects," explains study director Cornelia Ulrich from the Huntsman Cancer Institute in Salt Lake City.
Analyzed biochemical processes
With the help of the new technique of so-called “metabolite profiling”, the researchers were able to identify a biochemical process that was previously not known to be regulated by ASA, reports the DKFZ. This newly discovered ASA effect could be determined on the basis of the falling concentration of the metabolite 2-hydroxyglutarate in the blood of the test subjects. The effect was also confirmed in the studies on two colon cancer cell lines. According to the DKFZ, the metabolic product 2-hydroxyglutarate is "a cancer driver because increased concentrations of the substance have been found in certain leukemias and brain tumors." The DKFZ is currently researching how 2-hydroxyglutarate drives cancer development.
ASA intake affects the metabolic processes
As part of their current study, the researchers initially evaluated the metabolic profiles of 40 subjects who had taken ASA for 60 days, with the study covering 360 metabolic products and small molecules such as sugar, amino acids or vitamins. According to the study director, almost all known metabolic processes were taken into account. The scientists found that "the 2-hydroxyglutarate concentration decreased on average by 12 percent while taking ASA," the DKFZ said. In the subsequent investigations of colorectal cancer cell lines in the culture dish, ASS even lowered the 2-hydroxyglutarate concentration by 34 percent. Further investigations showed that "ASA inhibits the enzyme HOT (hydroxyacidic oxoacid transhydrogenase), which in turn stimulates the production of 2-hydroxyglutarate," reports the DKFZ.
Aspirin has great potential in cancer prevention
"The fact that we came across a cancer-relevant metabolic pathway directly confirms our expectation of the potential of ASA in cancer prevention," emphasizes the first author David Liesenfeld from the NCT. While previous studies of ASA's cancer-preventive effects mostly focused on the drug's anticoagulant and anti-inflammatory effects, the current “results are an indication that the cancer-preventive effect may include other mechanisms, particularly at low doses.” The study have shown that the reduction of 2-hydroxyglutarate could also be a reason for the preventive effect, says Liesenfeld. (fp)