Pitt study finds NSAIDs cause stem cells to self-destruct, preventing colon cancer

November 01, 2010

PITTSBURGH, Nov. 1 - Nonsteroidal anti-inflammatory drugs (NSAIDs) prevent colon cancer by triggering diseased stem cells to self-destruct, according to researchers at the University of Pittsburgh Cancer Institute (UPCI) and the University of Pittsburgh School of Medicine. Their findings, reported in the early online version of this week's 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, said senior investigator Lin Zhang, Ph.D., associate professor, Department of Pharmacology and Chemical Biology, Pitt School of Medicine, and UPCI.

"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," Dr. Zhang said.

The 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 typically present in non-hereditary colon cancer, too.

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, the researchers found. 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," Dr. Zhang said.

He and his team 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.
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Co-authors of the paper include Jian Yu, Ph.D., Wei Qiu, Ph.D., Xinwei Wang, Ph.D., Brian Leibowitz, Ph.D., Hongtao Liu, B.S., and Robert E. Schoen, M.D., from UPCI and the School of Medicine; and other 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.

The research was funded by grants from the National Institutes of Health, the American Cancer Society, and the Flight Attendant Medical Research Institute.



About UPCI

As the only NCI-designated comprehensive cancer center in western Pennsylvania, UPCI is a recognized leader in providing innovative cancer prevention, detection, diagnosis, and treatment; bio-medical research; compassionate patient care and support; and community-based outreach services. UPCI investigators are world-renowned for their work in clinical and basic cancer research.

About the University of Pittsburgh School of Medicine

As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997 and now ranks fifth in the nation, according to NIH data for 2008 (the most recent year for which the data are final).

Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.

University of Pittsburgh Schools of the Health Sciences

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