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Cure or cause? Mixed messages for NSAIDs, including aspirin

In three recent papers , the pharmaceutical role of nonsteroidal anti-inflammatory drugs is described as a proven benefit and a potential toxic risk factor, depending on tumour type and duration of use.

For colorectal polyps, a precursor to tumours, Mayo Clinic researchers and a team of collaborating scientists from across the country have determined the comparative effectiveness of nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin and several supplements in preventing the recurrence of advanced neoplasia.

In their study, published this month in The BMJ, the research team showed that, for most patients, nonaspirin NSAIDs (e.g., ibuprofen) work better than aspirin or a host of nutritional supplements to prevent the growth of advanced adenomas.

In the paper, they say that due to most colorectal cancers developing from this type of polyps, preventing them is a good proxy for colorectal cancer prevention

"Approximately 85 percent of all colorectal cancers are thought to result from untreated adenomatous polyps," says M. Hassan Murad, M.D., a clinical epidemiologist and preventive medicine physician at Mayo Clinic, and the study's senior author. "If we can find a way to stop their growth, we could prevent a majority of these cases."

Similarly, scientists from Oregon Health & Science University and Oregon State University have outlined a key mechanism by which low-dose aspirin may inhibit cancer cell proliferation and metastasis in AJP-Cell Physiology;  inhibiting the normal function of blood platelets and reduces their ability to upregulate an “oncoprotein” called c-MYC, which plays an important role in cancer cell proliferation and survival.

“The benefit of aspirin may be due to its effect on blood cells called platelets, rather than acting directly on tumour cells,” said senior author Owen McCarty, a professor in the Department of Biomedical Engineering at Oregon Health & Science University.

“Our work suggests that the anti-cancer action of aspirin might be in part as follows: during their transit in the blood, circulating tumour cells interact with platelets, which spur tumour cell survival by activating oncoproteins such as c-MYC. The inhibition of platelets with aspirin therapy reduces this signalling between platelets and tumor cells, thus indirectly reducing tumour cell growth.”

These two stories build on years of research into cancer repurposing, with the onco-suppressive actions of aspirin starting to be revealed.

On the other hand, an observational study, a multi-institutional team of cancer researchers led by the The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) found that regular use of over-the-counter non-steroidal inflammatory drugs (NSAIDs) such as aspirin and ibuprofen is associated with an increased risk of dying in patients diagnosed with Type 1 endometrial cancers.

Regular NSAID use was associated with a 66 percent increased risk of dying from endometrial cancer among women with Type 1 endometrial cancers, a typically less-aggressive form of the disease.

The association was statistically significant among patients who reported past or current NSAID use at the time of diagnosis, but it was strongest among patients who had used NSAIDs for more than 10 years in the past but had ceased use prior to diagnosis.

Use of NSAIDs was not associated with mortality from typically more aggressive, Type 2 cancers.

"There is a increasing evidence that chronic inflammation is involved in endometrial cancer and progression and recent data suggests that inhibition of inflammation through NSAID use plays a role," says Theodore Brasky, PhD, co-lead author of the study and a cancer epidemiologist with the OSUCCC - James. "This study identifies a clear association that merits additional research to help us fully understand the biologic mechanisms behind this phenomenon. Our finding was surprising because it goes against previous studies that suggest NSAIDs can be used to reduce inflammation and reduce the risk of developing or dying from certain cancers, like colorectal cancer."

They report their findings in the Dec. 16, 2016, issue of the Journal of the National Cancer Institute.

"These results are intriguing and worthy of further investigation," says David Cohn, MD, gynaecologic oncology division director at the OSUCCC - James and co-author of the study. "It is important to remember that endometrial cancer patients are far more likely to die of cardiovascular disease than their cancer so women who take NSAIDs to reduce their risk of heart attack -- under the guidance of their physicians -- should continue doing so. While these data are interesting, there is not yet enough data to make a public recommendation for or against taking NSAIDS to reduce the risk of cancer-related death."

What this means for drug repurposing going forwards remains to be seen, but could be taken as a novel biomarker for the success, or threat, of long-term aspirin treatment.

For more on drug repurporsing for NSAIDs, read Pan Pantziarka et al's article in ecancermedicalscience on diclofenac.

Source: BMJ , AJP Cell Physiology & JNCI

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