Possible New Mechanism for Aspirin’s Role in Cancer Prevention
Acetylsalicylic acid (ASA, “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 Cornelia Ulrich, PhD. Ulrich, former Director of Preventive Oncology at the National Center of Tumor Diseases (NCT) Heidelberg, now moved to the position of Senior Director of Population Sciences at Huntsman Cancer Institute in Salt Lake City.
“In the long run we want to personalize prevention with Aspirin because like everything it can have side effects. We want to be able to tailor it to people who are most likely to have benefit and to have the lowest risk of adverse outcomes.”
In a study published in the journal of Cancer Epidemiology, Biomarkers, and Prevention, Ulrich and her collaborators used a new technique, metabolite profiling, to identify a biochemical pathway previously unknown to be regulated by aspirin. Specifically, 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, 2-hydroxyglutarate, is considered a driver of cancer development (known as an oncometabolite) because elevated levels have been found in certain cancers of the blood and brain and several groups are currently studying it as a molecule that promotes tumor formation.
The study adds to the overall evidence that aspirin is important for cancer prevention and points to a new pathway that deserves further study in the context of aspirin. “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”, says David B. Liesenfeld from the NCT Heidelberg, first author of the publication.
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, or small molecule chemicals such as sugars, amino acids, and vitamins, were analyzed, says Ulrich. “This study covered most of the known biochemical pathways in the body.”
The researchers found aspirin metabolites were increased in the volunteers as expected (p<0.001), but they also noted statistically significant changes in a metabolite that has been found to drive cancer development, 2-hydroxyglutarate, which was reduced by 12% (p=0.005).
To follow-up this result in the laboratory, the researchers evaluated the levels of 2-hydroxyglutarate in cultured cancer cells after treatment with aspirin. The colorectal cells lines showed consistent reductions in 2-hydroxyglutarate, up to 34%. In addition, they found that the primary metabolite of aspirin, called salicylate, inhibits an enzyme called HOT (hydroxyacidic-oxoacid transhydrogenase) that triggers the production of 2-hydroxyglutarate, suggesting 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 says there is 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.” She adds, “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.”
Ulrich says additional studies will be required to determine whether the changes in 2-hydroyglutarate levels after aspirin treatment, observed in blood plasma and cultured cancer cells, are also present in colon tissue.
Ulrich from Huntsman Cancer Institute and Johanna Lampe from the Fred Hutchinson Cancer Research Center are co-senior authors on this study. Other co-authors include David B. Liesenfeld, Akke Botma, Reka Toth, Christoph Weigel, Karel D. Klika, and Odilia Popanda from the German Cancer Research Center (DKFZ), Heidelberg, Germany; Nina Habermann from DKFZ and European Molecular Biology Laboratory (EMBL); and John D. Potter from the Centre for Public Health Research, Massey University, Wellington, New Zealand and from the Fred Hutchinson Cancer Research Center.
This work was supported by the National Institute of Health, Huntsman Cancer Foundation, and funding from the German Cancer Research Center.
About Huntsman Cancer Institute at the University of Utah
Huntsman Cancer Institute (HCI) is one of the world’s top academic research and cancer treatment centers. HCI manages the Utah Population Database - the largest genetic database in the world, with more than 16 million records linked to genealogies, health records, and vital statistics. Using this data, HCI researchers have identified cancer-causing genes, including the genes responsible for melanoma, colon and breast cancer, and paraganglioma. HCI is a member of the National Comprehensive Cancer Network (a 26-member alliance of the world's leading cancer centers) and is a National Cancer Institute-Designated Comprehensive Cancer Center. HCI treats patients with all forms of cancer and operates several high-risk clinics that focus on melanoma and breast, colon, and pancreas cancers. The HCI Cancer Learning Center for patient and public education contains one of the nation's largest collections of cancer-related publications. The institute is named after Jon M. Huntsman, Sr., a Utah philanthropist, industrialist, and cancer survivor.
The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) with its more than 3,000 employees is the largest biomedical research institute in Germany. At DKFZ, more than 1,000 scientists investigate how cancer develops, identify cancer risk factors and endeavor to find new strategies to prevent people from getting cancer. They develop novel approaches to make tumor diagnosis more precise and treatment of cancer patients more successful. The staff of the Cancer Information Service (KID) offers information about the widespread disease of cancer for patients, their families, and the general public. Jointly with Heidelberg University Hospital, DKFZ has established the National Center for Tumor Diseases (NCT) Heidelberg, where promising approaches from cancer research are translated into the clinic. In the German Consortium for Translational Cancer Research (DKTK), one of six German Centers for Health Research, DKFZ maintains translational centers at seven university partnering sites. Combining excellent university hospitals with high-profile research at a Helmholtz Center is an important contribution to improving the chances of cancer patients. DKFZ is a member of the Helmholtz Association of National Research Centers, with ninety percent of its funding coming from the German Federal Ministry of Education and Research and the remaining ten percent from the State of Baden-Württemberg.