Compound Inhibits One Critical Pathway In Breast Cancer Growth

Laboratory experiments in human breast cancer cells suggest that the compound inhibits the constant activation of a protein called Stat3 that is found in several different types of cancer, including cancer of the breast, lung, prostate, head and neck, skin, pancreas and ovaries as well as lymphoma and certain kinds of leukemia.

Stat3 is constantly activated in about 50 percent of breast tumors, said Jiayuh Lin, the study's lead author and an associate professor of pediatrics at Ohio State University.

All cells contain Stat3 protein, but in normal cells, Stat3 activities are only turned on temporarily. Researchers do know, however, that Stat3 is constantly turned on in certain tumor cells.

"The cancer cells we studied seem to depend on Stat3 for survival," said Lin. "When we blocked the chain of events that activate Stat3, the cancer cells died."

Lin is also a member of Ohio State's Comprehensive Cancer Center and an investigator in the Center for Childhood Cancer at Columbus Children's Research Institute. He co-authored the study with Shaomeng Wang, Hui Song and Renxiao Wang, all with the University of Michigan Comprehensive Cancer Center.

The researchers named the compound STA-21. They tested STA-21 after using a computer program to narrow down a list of potential compounds to a manageable number that they could physically test in the lab.

When the computer screening process ended, the researchers tested the 100 top compounds. They tested these compounds on human breast cancer cells in order to find which one best stopped the constant Stat3 activation. STA-21 appeared to be the best inhibitor of Stat3 activity.

"This compound showed a remarkable ability to inhibit Stat3 activity, more than any of the other 99 compounds that we tested," Lin said.

The researchers then used STA-21 to treat several types of cells, including human breast cancer cell lines with constantly activated Stat3 as well as those without, and also normal human skin fibroblasts, cells that make up connective tissue. Stat3 isn't constantly activated in fibroblasts, and these cells were used as a control.

After exposure to STA-21, breast cancer cells with constantly active Stat3 were dying. However, STA-21 had a minimal effect on breast tumor cells that didn't express constantly activated Stat3, nor did it have an adverse effect on the normal fibroblasts.

“Many types of cancer cells express constantly activated Stat3 and seem to depend on it for survival,” he continued. “When we blocked that constantly activated Stat3 pathway, the cells died."

STA-21 is derived from a family of antibiotics but is not currently used as an antibiotic. The STA-21 molecule is small enough to enter a cell, and can be delivered directly to cancer cells or to a solid tumor.

Also, shutting down one of the key survival mechanisms in a cancer cell may help increase the effectiveness of chemotherapy and also lessen the toxicity of treatment, Lin said.

"Using a compound that inhibits the constantly activated Stat3 pathway may make tumor cells more sensitive to chemotherapy," Lin said.

He and his colleagues will continue to study the effects of STA-21 and related compounds, or analogs, in different types of cancer cells.

"An analog of STA-21 could work even better," he said. "We may be able to create one that can be even more effective and less toxic to normal cells."

Support for this research came from the Department of Defense Breast Cancer Research Program and a National Cancer Institute grant to the University of Michigan Comprehensive Cancer Center.