A high-throughput assay developed by University of Illinois at Chicago chemists has led to discovery of a small organic compound that shows the unusual ability to inhibit cell migration. The new compound, identified as UIC-1005, may play a role in developing new kinds of cancer drugs.
The findings are published in the November issue of the journal ChemBioChem.
"We've been looking for chemical compounds that slow the process of cell migration," said Gabriel Fenteany, assistant professor of chemistry and the study's principal author. "The process is poorly understood and has a lot of therapeutic potential."
Fenteany is also part of the UIC Cancer Center.
Fenteany and his co-workers grow skin-like epithelial cell sheets on tissue culture plates with many small depressions, or wells, each of which contains a culture of cells and a different chemical compound, providing the basis for the assay.
"We grow these cells and make little scratches in the resulting sheet of cells," Fenteany said. "A little gap forms, and cells move in to close that gap, similar to part of the wound healing process when you cut yourself.
"The process is also related to how a cancer cell will start to move to form a metastasis, and to how a tumor will recruit new blood vessels, which helps it grow," Fenteany said. "The phenomenon of cell shape change and movement is universal, even though details differ on how these cells move in different situations."
The assay developed by the UIC chemists makes the process to find molecules that inhibit cell movement quick and easy.
"We can easily screen a thousand compounds a day, or more," Fenteany said, adding, "We're one of the few labs doing these sorts of screens. Therefore, there's not really a good sense of what sorts of compounds will inhibit the process. That's what we're looking at."
Fenteany and his colleagues began their search using the high-throughput assay in December 2000 and discovered UIC-1005 a few months later. The new compound is from a class of molecules called oxazolidinones, which in recent years have been used successfully to develop new antibiotics that kill bacteria now resistant to older drugs. UIC-1005, however, shows no anti-bacterial properties and acts differently.
Fenteany hopes other labs adopt this high-throughput assay to hasten the discovery of additional molecules that inhibit cell migration. That search continues at UIC, along with work to modify the compound UIC-1005.
"Once you find the active structure, you can modify that structure to improve its activity, find out what it binds in the cell, and how," Fenteany said. "We're working to find the protein it binds, and we have a candidate. Since the small molecule targets the protein and inhibits the process of cell movement, the protein becomes a potential target for drug development to block the pathway during disease."
Fenteany predicts drugs that inhibit cell migration may prove effective in combination therapies against cancer.
"A person who has had a tumor removed through surgery still faces the problem that some cancer cells escaped. By taking a cocktail of drugs, including anti-migratory compounds like UIC-1005 and other compounds we've yet to discover, the cancer could be more effectively contained. So even if not every cancer cell was removed by surgery or controlled in traditional chemotherapy, you've limited the ability of cells to move and spread and start new tumors."
Other authors are Arun Ghosh, professor of chemistry, and researchers Kevin McHenry and Sudha Ankala, all of UIC.
Funding for this research was by grants from UIC and the National Cancer Institute. Ongoing research is supported by a new grant from the American Cancer Society.
Paul Francuch, 312-996-3457, firstname.lastname@example.org