Aspirin reduces colon cancer through newly discovered pathway

By John Murphy, MDLinx
Published November 20, 2015

Key Takeaways

Researchers used a new technique, metabolite profiling, to discover that aspirin substantially decreases the level of an oncometabolite in the blood of healthy volunteers and in two colorectal cancer cell lines. This discovery points to a previously unidentified biochemical pathway regulated by aspirin, according to a new study published online November 19, 2015 in the journal Cancer Epidemiology, Biomarkers, and Prevention.

“It is really exciting that aspirin, which can work in colorectal cancer prevention, is now linked to a new pathway that has shown to be relevant for cancer formation,” said co-senior author of the study Cornelia Ulrich, PhD, Senior Director of Population Sciences at Huntsman Cancer Institute in Salt Lake City, UT.

Aspirin is known to be effective for the chemoprevention of colorectal cancer, even at low doses. But, due to its risk of side effects—such as gastrointestinal bleeding—cancer researchers need to better understand its biologic mechanisms before recommending it as a preventative treatment, Dr. Ulrich said.

In this investigation, the researchers performed a metabolite analysis to better understand the mechanisms associated with the protective effect of aspirin.

The first part of the study involved 40 men and women (average age 31) in a randomized, double-blind, crossover trial of 325 mg/day aspirin versus placebo for 60 days. Their blood samples were taken before and after intervention for analysis of more than 360 metabolites. “This study covered most of the known biochemical pathways in the body,” Dr. Ulrich said.

Results showed that aspirin metabolites were increased in the volunteers, as expected. But researchers also noted a 12% decrease in an oncometabolite, 2-hydroxyglutarate, which was found to drive cancer development.

In the second part of the study, the researchers tested this result in the laboratory by treating cultured cancer cells with aspirin and evaluating the levels of 2-hydroxyglutarate. Results showed that 2-hydroxyglutarate was consistently reduced up to 34% in colorectal cells lines.

In addition, they found that salicylate (the primary metabolite of aspirin) inhibits the enzyme hydroxyacidic-oxoacid transhydrogenase (HOT), which triggers the production of 2-hydroxyglutarate.

While previous research has suggested that aspirin’s anti-inflammatory and anti-clotting effects may also play a role in preventing cancer, this study provides evidence that other pathways are involved, especially at lower aspirin doses. “This new study suggests that aspirin is playing a key role in interrupting multiple pathways that are linked to cancer development,” Dr. Ulrich said. “Here we show, both in the clinic and laboratory, that a reduction in 2-hydroxyglutarate may identify a new mechanism for aspirin in cancer prevention.”

Further investigations will need to confirm whether aspirin’s effect on 2-hydroyglutarate levels in blood plasma and cultured cancer cells also occur in colon tissue, the researchers noted.

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