Researchers at the UR Medical Center have purportedly discovered a new way to fight cancers of the esophagus, liver, skin, colon and rectum. The researchers inadvertently discovered that a collection of compounds known as peroxisome-proliferator-activated-receptor-gamma (PPARy) inhibitors have cancer-fighting characteristics (particularly against colorectal cancer cell lines).

The team, headed by Katherine Schaefer, Ph.D., recently published its findings in the International Cancer Research Journal. Schaefer’s team was originally investigating a new treatment methodology for Crohn’s disease and ulcerative colitis. Colorectal cancer cells were used in the study to model the diseases the team was trying to alleviate. However, the colorectal cells obfuscated researchers’ efforts by displaying a propensity for premature cell death – prior to the completion of relevant experimentation.

Schaefer eventually concluded that high levels of PPARy inhibitor were to blame. Team leader Lawrence Saubermann, M.D., decided that the previously unanticipated therapeutic effect of PPARy inhibitors merited further investigation and the study’s efforts soon shifted.

Researchers used three PPARy inhibitors known as T0070907, GW9662 and BADGE to examine the survivability of colorectal tumor cells. High dosages of all three inhibitors hampered cancer growth, reduced proliferative tendencies and caused autolysis, or cell-suicide, within 24 hours.

In addition to these impressive performance benchmarks, PPARy inhibitors work differently from most existing chemotherapy treatments. They do not inhibit malignant cell function so much as they compromise the cell’s ability to reproduce. PPARy inhibition effectively destroys a cancer cell’s microtubules. Microtubules, common to all cells within the body, are special structures with a variety of functions. Chiefly, they provide structural support to the cell and generate the force needed for cell division-not unlike a human being’s skeleton. High dosages of PPARy inhibitors drop a and b tubulin levels by 60 to 70 percent. Tubulin is the microtubule building block. By eliminating its supply, further cell growth and propagation becomes effectively impossible.

“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. “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 inhibitors that have been tested so far have performed impressively, operating by use of a unique metabolic pathway which lessens the chance that cancer cells will develop resistance and also release minimal toxins. Although an official toxicity study is currently ongoing, preliminary experimentation with diseased lab rats found that PPARy inhibitors killed the cancer cells with minimal toxin release. Researchers hope this attribute will allow patients to avoid the debilitating side effects of most existing chemotherapies like Taxol, which freezes a cell’s microtubular superstructure.

“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.”

Furthermore, while Taxol and other drugs like it are initially effective against most types of cancer, cancerous cells quickly learn to expel the cytotoxic chemicals upon detection. High-dose PPARy inhibitors are structurally dissimilar to existing chemotherapeutic drugs and therefore less likely to be identified and driven out by tumor cells.

Looking toward the future, URMC researchers will attempt to isolate the specific proteins involved in the anti-cancer effect of PPARy inhibitors. Once PPARy inhibitor’s operative mechanisms are accurately mapped, they will be ready to proceed to the next stage of therapy development-combination treatment.

News of these developments could not come fast enough for patients suffering from colorectal cancer. Colorectal cancer represents an urgent health crisis in the United States as it is the third highest cause of death for women and the second highest for men.

Singh is a member of the class of 2008.



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