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Pain killer fights breast cancer by targeting key enzyme

30.03.2006
A pain–killing medication appears to halt the production of an enzyme that is key to a common form of breast cancer, a new study using tissue cultures suggests.

The drug is called nimesulide. In laboratory experiments on breast cancer cells, scientists found that derivatives of nimesulide stopped the production of aromatase, the enzyme implicated in estrogen-dependent breast cancer. This form of breast cancer is the most common kind of breast cancer in postmenopausal women.

Aromatase converts hormones called androgens into estrogens, such as the hormone estradiol. Estrogen is a powerful mitogen – an agent that causes cells to divide, and too much estrogen can cause cells to divide too quickly.

While many women with estrogen-dependent breast cancer take aromatase inhibitors to control their disease, the problem is that the current inhibitor drugs halt estrogen production throughout the body, said Robert Brueggemeier, a study co-author and a professor of medicinal chemistry and pharmacognosy and dean of the College of Pharmacy at Ohio State University.

“That means that other tissues, like bone and brain, which rely on normal aromatase production, may suffer,” he said. “For one, we think that aromatase helps to maintain bone tissue throughout the postmenopausal period. Current aromatase inhibitors may disturb normal bone production – there is some suggestion that these drugs may increase the risk of fractures.”

The study’s results suggest that nimesulide may block aromatase production only in breast tissue. Nimesulide is a non-steroidal anti-inflammatory drug (NSAID), a drug that controls pain and inflammation. Studies of other NSAIDs, such as ibuprofen, have suggested that NSAIDs may reduce breast cancer incidence by 40 percent.

However, these drugs tend to halt aromatase production throughout the body.

Brueggemeier presented the work with Bin Su and Serena Landini, both graduate students in Ohio State’s pharmacy program, on March 27 in Atlanta at the annual meeting of the American Chemical Society.

By altering the drug’s basic chemical structure, the researchers could create several variations, or analogs, of nimesulide. Nimesulide has been around since 1985, but was banned from clinical and over-the-counter use in the United States due to rare cases of liver damage and related deaths.

“We are working on analogs that will be selective for aromatase expression and also have diminished side effects,” Brueggemeier said. “We are obviously in the very early stages of drug discovery with nimesulide analogs, and a long path of preclinical research is needed before we can even begin to think about potential drugs.”

The researchers took several of these nimesulide analogs and, in laboratory cultures, tested their effects on estrogen-dependent breast cancer cells taken from human breast tissue. They also tested the analogs on human placental cells to see if the analogs would stop aromatase production in these cells.

The nimesulide analogs stopped aromatase production in the breast cells, but not in the placental cells.

“Aromatase is necessary for normal functions of many tissues in the body,” Brueggemeier said. “We still have to test these analogs in other kinds of tissues, however, before we are completely sure that the nimesulide analogs’ effects are specific to breast cancer cells.”

The analogs prevented a crucial step in the aromatase production process in the breast cancer cells – they stopped transcription, the first step in gene expression. Compared to other tissues, breast cancer cells use a slightly different signal to indicate when it is time to make more aromatase.

“The pathway leading the aromatase production in breast cancer cells seems to be unique to these diseased cells,” Brueggemeier said. “It suggests that aromatase production in other tissues that rely on the enzyme could be spared if a nimesulide analog was taken as a drug.”

He said that the next step is to study how the analogs affect other types of tissues to make sure that nimesulide’s aromatase-inhibiting effects are truly isolated to breast tissue.

“Then we need to conduct animal studies to learn how effective these compounds are when they are actually inside the body and what the potential side effects may be.”

Robert Brueggemeier | EurekAlert!
Further information:
http://www.osu.edu

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