Published On December 1, 2016
SALICYLIC ACID, THE CORE INGREDIENT OF ASPIRIN, has been used medicinally for more than two thousand years. In today’s form, the humble white pill fights fever, rheumatoid arthritis and cardiovascular disease, and helps prevent heart attacks and stroke. In recent decades, researchers have shown that aspirin can also dramatically reduce the risk of some cancers. Clinical trials have shown that regular preventive doses lowered the incidence of colorectal cancer by 24% and significantly improved survival rates after 5 to 10 years of use.
The problem? Researchers don’t quite know why that happens. Beginning in 2011 the National Cancer Institute rounded up some of the field’s most pressing problems under its Provocative Questions Initiative, and the riddle of aspirin’s anticancer effects soon became high on the list. An unprecedented dissection of a single drug’s biological pathways in the body is now underway—an effort that may offer a model for looking at other miracle drugs.
Some researchers looked at how aspirin interacts with other ingested substances. Two investigators funded by the Provocative Questions Initiative—Dipak Panigraphy, pathologist at Beth Israel Deaconess Medical Center, and Charles N. Serhan, biochemist and molecular pharmacologist at Brigham and Women’s Hospital—probed the drug’s interaction with polyunsaturated fatty acids, like those found in fish oil. Together, these trigger the production of resolvins, the body’s anti-inflammatory molecules.
Inflammation is commonly associated with tumors, says Serhan, and aspirin’s ability to reduce inflammation may explain its usefulness in preventing cancer. Teams led by Panigraphy and Serhan blocked the production of resolvins in mice with cancer, and found that this reduces the aspirin’s anticancer benefit. And increasing the amount of resolvins, or administering synthetic ones, appears to boost aspirin’s benefits, thus reducing the tumors in the mice.
Researchers also know that aspirin interferes with the production of platelet-derived mediators, the cells responsible for making blood clots, a discovery that led to a Nobel Prize in 1982. Now researchers are looking into the critical role that platelets may play in the spread of tumors.
For a cancer to metastasize, a cell must dodge the immune system while running a complex gauntlet: It must detach from the primary tumor, cross the dense sheet of cells that line a blood vessel to enter the bloodstream, travel through the blood, cross the blood vessel barrier again at its destination and then set up shop. Cancer researchers have shown that tumor cells need platelets to pass through the barrier into the blood vessels. And once in circulation, tumor cells can use platelets as a kind of disguise, cloaking themselves with the blood cells to remain invisible to the immune system.
When tumor cells land at the metastatic site, they use platelets once again. Elisabeth Battinelli, a hematologist at Brigham and Women’s Hospital, has recently shown that platelets produce growth factors that promote the development of new blood vessels, which become essential avenues to carry nutrients and oxygen to the growing tumor. Battinelli’s team has demonstrated that blocking the platelets with aspirin short-circuited all of these steps, making it harder for cancer to move throughout the body.
New tools that look at gene expression may reveal another part of the story. At Duke University, cardiologist Deepak Voora and his team found that more than 60 blood cell genes switch on in the presence of aspirin, and chasing down what these do may lead to further discoveries. They also looked at the genetic activity of bone marrow cells that produce platelets, and saw that aspirin rewired them to produce platelets that are less likely to clump together. Those platelets also express a specific version of the gene RUNX1, which is associated with better outcomes and survival after patients are diagnosed with colon cancer.
Exploring the genetic pathways of aspirin may lead to more information about which patients are most likely to be helped by the drug and how much they need to take to achieve that benefit, said Voora. Knowing the specific pathways may also help researchers design a better drug for colon cancer prevention that doesn’t have the side effects—intestinal bleeding, mainly—associated with using aspirin to stave off cancer.
This scrutiny of aspirin, searching all of the avenues for its beneficial effects, may pave the way for other drugs that seem to help in a range of disparate conditions. For example, metformin is one of the more widely used drugs to treat type 2 diabetes, but recent research shows that it may also help cancer patients and possibly have anti-aging effects.
“All drugs have variability,” says Voora. “Not everyone gets the benefit—some people get more toxicity, some people get neither. But we really have no idea why. These tools and approaches have allowed us to characterize and quantify those unintended effects.” The research into aspirin—still a work in progress—may be a model for other drugs to come.
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