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Drug causes stem cells to go suicidal

U. PITTSBURGH (US) — Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon cancer by triggering diseased stem cells to self-destruct, according to new research.

The findings, reported in the early online edition  Proceedings of the National Academy of Sciences, could lead to new strategies to protect people at high risk for the disease.

Doctors have long known that NSAIDs, such as aspirin, can lower the risk of colon cancer, but it’s not been clear how they do it, says Lin Zhang, associate professor of pharmacology and chemical biology at the University of Pittsburgh.

“Our study shows NSAIDs target stem cells that have accumulated mutations that could lead to cancer development, and initiate a biochemical pathway that makes those cells undergo programmed cell death, a process called apoptosis.”

Researchers studied mice that have a genetic defect similar to one that is present in patients with familial adenomatous polyposis, a condition that accounts for about 1 percent of all cases of colorectal cancer, and is also typically present in non-hereditary colon cancer.

Mice that ate the NSAID sulindac in their feed had within a week markedly elevated rates of apoptosis in their intestinal polyps, and specifically in stem cells that had accumulated some dangerous, precancerous changes causing abnormal cell signaling.

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A section of small intestine from a mouse that is predisposed to develop intestinal tumors after treatment with a non-steroidal anti-inflammatory drug. A cell death marker is stained in brown, and cell nuclei are stained in blue. (Credit: U. Pittsburgh)

If the mice also lacked a gene called SMAC, which makes a protein that is released during apoptosis, sulindac was less effective at killing the diseased stem cells.

“That leads us to think that SMAC is an important regulator of this process,” Zhang says.

The researchers then took a closer look at polyps removed from patients and found higher levels of apoptosis in cells with stem cell features among those who were taking NSAIDs.

The findings indicate that apoptosis measures could be a useful way of assessing the effectiveness of cancer-prevention drugs, as well as lead to the development of new agents to further sensitize abnormal stem cells to NSAIDs.

Researchers from the Hubrecht Institute for Developmental Biology and Stem Cell Research, Netherlands; the Ontario Cancer Institute, Toronto; and the Hiroshima University Graduate School of Public Health, Japan contributed to the study, that was funded by grants from the National Institutes of Health, the American Cancer Society, and the Flight Attendant Medical Research Institute.

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