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New approach to killing cancer cells
Source: (cancerfacts.com)
Thursday, February 01, 2007
ROCHESTER, N.Y. – Feb. 1, 2007 – Researchers believe they have discovered by chance a new way to fight colorectal cancer, and potentially cancers of the esophagus, liver and skin.
Led by co-author Dr. Katherine L. Schaefer, of the University of Rochester Medical Center, the researchers were looking at the role a group of compounds called peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibitors play in inflammatory disease, when they discovered the compounds may have an unexpected cancer-fighting effect with some of the same mechanisms as the blockbuster chemotherapy drug Taxol®, but with key differences.
"This is the first observation of a small molecule dramatically reducing levels of the proteins called tubulins, the building blocks of cancer cell skeletons," Schaefer said in a prepared statement. "Because cells that line the colon are similar to those in the liver, esophagus and skin, we see potential for a new way to treat those cancers as well." The researchers published their findings today in the journal International Cancer Research.
Beyond providing structural support and shape to cells, microtubules expand and shrink to generate the force needed for cells to divide, a basic process in tumor growth.
In the study the researchers were looking for new ways to reduce inflammation seen in Crohn's disease and ulcerative colitis, bowel diseases that cause pain and diarrhea. Specifically, they were comparing the effect on inflammation of encouraging the action of the PPARgamma protein (with activator compounds) against discouraging it (with inhibitors).
The team conducted these experiments using colorectal cancer cells as study models because they arise from normal gut cells and share some of their qualities. Unlike normal gut cells, however, cancer cells do not die when removed from the gut wall. Able to continue living in the absence of normal survival signals makes cancer cells dangerous in the body, but useful as cell lines for study.
While studying whether compounds known to affect PPARgamma could play a role in quelling inflammatory bowel diseases, Schaefer found with frustration that her cancer cells were dying before she could complete her experiments. Retracing her steps, she found that medium-to-high doses of PPARgamma inhibitor killed colorectal cancer cell lines.
Lead investigator Dr. Lawrence J. Saubermann, associate professor of medicine, realized they had come across a potentially new therapeutic effect, and launched experiments to confirm it.
Despite the compound's class name, the anti-cancer effect has nothing to do with the ability of the compounds to inhibit PPARgamma function. Researchers believe that PPARgamma inhibitors instead attack the "skeletons" of cancer cells that enable them to reproduce, grow and spread. It appears that high-dose PPARgamma inhibitors reduced levels of alpha and beta tubulin by 60 to 70 percent, enough to block the cancer cells from dividing and growing.
Moving forward, the research team will seek to determine exactly which proteins are involved in the anti-cancer effect of PPARgamma inhibitors. Combination therapy is the current leading strategy in treating cancer, and finding the mechanisms by which PPARgamma inhibitors work could be a first step toward their safe combination with other treatments.
"The last work attempting to reduce tubulin levels was abandoned approximately 25 years ago under the assumption that such drugs would be toxic, destroying microtubules in healthy cells as well as cancer cells," Schaefer said. "Our early studies, however, suggest that general toxicity does not rule out this approach as once feared. With new drug delivery technologies that help drugs target only cancer cells, we are very excited about the potential of this line of work."
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