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Statin plus cancer drug deliver combo punch to brain cancer cells

January 19, 2007

Drugs play on output of genes linked to 'cell-signaling' proteins

Building on newly discovered genetic threads in the rich tapestry of biochemical signals that cause cancer, a Johns Hopkins Kimmel Cancer Center team has dramatically killed brain cancer cells by blocking those signals with a statin and an experimental antitumor drug.

The unlikely pairing of cholesterol-lowering lovastatin and cyclopamine killed 63 percent of medulloblastoma cells grown in the laboratory. By contrast, using either agent alone wiped out fewer than 20 percent of cells. The Hopkins researchers published their findings in the January issue of the American Journal of Pathology.

The researchers caution that the cyclopamine-lovastatin combination has yet to be tested in animals, much less people, but they conclude that the tumor cell-killing by the combo is tantalizing. Cyclopamine works by blocking the so-called "hedgehog" pathway, long known to promote and guide cell and organ growth. Excessive growth is the chief characteristic of cancer. The investigators believe that blocking hedgehog with cyclopamine makes cancer cells more susceptible to lovastatin.

Along with its cholesterol-clogging effects, lovastatin, sold under the trade name Mevacor, is known to curb destruction of proteins that put the brakes on cell growth, causing cancer cells to self-destruct through a process called apoptosis. The effects of the statin already is being studied in people at high risk for the deadly skin cancer, melanoma.

First extracted from corn lilies in the 1950s, cyclopamine is a powerful toxin known to stunt fetal development and cause birth defects in humans and animals. Its connection to anti-cancer efforts grew out of later insights into its blockage of hedgehog, which gets its name from spiky hairs that develop on fruit flies lacking the signal.

"We already knew from earlier research that hedgehog controls brain cell survival and growth, and that blocking signals in this pathway may stop uncontrolled growth of cancer cells," says Charles Eberhart, M.D., Ph.D., associate professor of pathology, ophthalmology and oncology. "But the new work shows the hedgehog blockade may halt another powerful cell-survival signal, and lovastatin could provide the added boost necessary to kill more cancer cells."

Specifically, Eberhart found links between the expression of key hedgehog-related genes in medulloblastoma cells and another cell signal already tied to cancer, Bcl-2. Eberhart and his team believed that combination of a hedgehog blockade and a pro-apoptosis drug like lovastatin would kill more cancer cells.

"Our experiments suggest that hedgehog's action is woven together with Bcl-2, best known for its role in causing B-cell lymphomas," he says. "Cancer cells thwart suicide by overproducing Bcl-2, assuring them a long life."

When the Hopkins researchers noticed that Bcl-2 and hedgehog expression increased in tandem in medulloblastoma cells, they tried adding hedgehog-blocking cyclopamine to the cells and found that Bcl-2 production dwindled and tumor cells died off.

Lead author and pathology fellow Eli E. Bar, Ph.D., said he was "surprised by the degree to which the drug combination was so effective."

According to Eberhart, only half of children with medulloblastoma survive. "And those that do survive can suffer debilitating side effects caused by current toxic therapies."

Johns Hopkins Medical Institutions