Hybrid Molecule Induces Cancer Cells to Self-Destruct

The researchers, from Johns Hopkins University (Baltimore, MD, USA), cautioned that their double-punch molecule has not yet been evaluated on animals or humans. Nevertheless, they believe it may be a promising new approach for fighting the lethal disease. The study was published in the December 2006 issue of the journal Chemistry & Biology.

"For a long time, cancer researchers did not pay much attention to the use of sugars in fighting cancer,” said Dr. Gopalan Sampathkumar, a postdoctoral fellow in the university's department of biomedical engineering, and lead investigator of the study. "But we found that when the right sugar is matched with the right chemical partner, it can deliver a powerful double-whammy against cancer cells.”

Dr. Sampathkumar and his colleagues built upon 20-year-old findings that a short-chain fatty acid called butyrate has been shown to slow the metastasis of cancer cells. In the 1980s, researchers found that butyrate, which is formed naturally at high levels in the digestive system by symbiotic bacteria that feed on fiber, can restore healthy cell functioning.

Efforts to utilize butyrate as a general drug for tumors elsewhere in the body, however, have been hindered by the high doses of the compound needed to effectively eradicate cancer. To tackle this problem, scientists have tried to make butyrate more powerful by modifying it or binding it to other compounds. Typically, the results have been disappointing because the molecular partner added to butyrate to improve delivery to the cancer cells frequently produced debilitating side effects.

In some of the less successful experiments designed to avoid toxic side effects, investigators used innocuous sugar molecules such as glucose to carry butyrate into the cells. The Johns Hopkins team tried a different avenue. "We didn't think they chose the right partner molecule,” said Dr. Kevin J. Yarema, an assistant professor of biomedical engineering who supervised the project. "Our insight was to select the sugar partner to serve not just as a passive carrier but as additional ammunition in the fight against cancer.”

The researchers focused on a glucose molecule called N-acetyl-D-mannosamine (ManNAc). The team devised a hybrid molecule by linking ManNAc with butyrate. The hybrid easily penetrates a cell's surface, where it is split apart by enzymes inside the cell. Once inside the cell, ManNAc is processed into another sugar known as sialic acid, which plays a vital role in cancer biology, while butyrate controls the expression of genes responsible for halting the uncontrolled growth of cancer cells.

Although the study of the precise molecular process is still in its early stages, the researchers believe the separate chemical components work together to enhance the cancer-fighting power of butyrate. This double-punch triggers cellular suicide, known as apoptosis, in the cancer cells.

To determine whether this butyrate-ManNAc hybrid alone would produce the positive results, the researchers assessed three other sugar-butyrate combinations and a butyrate salt compound with no glucose molecule attached. The four other compounds and the butyrate-ManNAc hybrid were each added to lab dishes containing cancer cells. After three to five days, cancer growth had slowed in all of the dishes. After 15 days, however, cancer growth had resumed in dishes treated with four of the compounds. But in samples treated with the butyrate-ManNAc hybrid, all of the cancer cells had died.

The researchers also tried to determine whether administering the two parts of the hybrid independently would achieve the same result. But in these experiments, the cancer cells did not self-destruct. The researchers believe this is because the hybrid molecules more easily penetrate the surface of the cell than the individual compounds. Once the components are inside, the researchers believe the partners help enzymes to resume the normal assembly of sugar molecules and correct aberrant gene expression patterns, two processes that go out of control when cancer occurs.

Now that they have identified the butyrate-ManNAc molecule as a potential anti-cancer agent, the Johns Hopkins researchers are expanding their study, looking for new drug-delivery techniques and preparing for animal testing. The researchers believe the hybrid molecule will have minimal effect on healthy cells. Through the Johns Hopkins Technology Transfer Office, they have filed an application for a U.S. patent covering this class of compounds.



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