Compounds trigger tumor-cell suicide.

Cancer cells are a picture of conflict. Seemingly aware of the danger they themselves pose, these abnormal cells often try to commit suicide by activating destructive enzymes called caspases. But as if simultaneously compelled by a self-preservation instinct, tumor cells usually thwart this impulse using proteins that foil the caspases.

Now, a team of researchers has found compounds that inhibit a specific caspase inhibitor, thereby triggering the death of various tumor cells growing in laboratory dishes or in mice.

"It looks like cancers are poised to die if you take this roadblock away" says John C. Reed, president of the Burnham Institute in La Jolla, Calif., an independent biomedical research center.

Reed and his colleagues, who describe their work in the January Cancer Cell, knew from previous studies that a protein called X chromosome-linked inhibitor of apoptosis (XIAP) binds to and blocks the action of several different caspases. Numerous studies have shown that many kinds of cancer cells overproduce this caspase inhibitor, apparently to stymie the cellular-suicide program called apoptosis. Other researchers have identified compounds that prevent XIAP from inhibiting some of the caspases.

These blocking compounds don't directly kill cancer cells. Instead, they make the cells more susceptible to traditional chemotherapy drugs.

Using an automated system, Reed and his colleagues screened more than a million compounds for substances that thwart XIAP's inhibition of a particular caspase called caspase 3. This enzyme acts late in a cell's suicide program, so the investigators hypothesized that inhibiting XIAP's interaction with caspase 3 would guarantee a cancer cell's suicide.

The mass screening identified eight compounds-all belonging to a class of synthetic molecules called polyphenylureas--that block XIAP's action against caspase 3. Unlike previously known XIAP inhibitors, these compounds directly kill a broad range of solid-tumor cells and leukemia cells, Reed and his colleagues report. In their laboratory tests, the potency of these compounds compared favorably with that of already approved cancer drugs.

In separate tests, the investigators implanted human prostate or colon cancer cells into mice, permitted the cells to grow into tumors, and then injected the newfound compounds into the rodents. In postmortem analyses, the investigators found evidence that the compounds had killed cancer cells and slowed tumor growth.

Just as important, Reed and his colleagues saw no obvious sign of damage to normal cells and tissue. "We had concern about whether [inhibiting XIAP] would be a safe approach," he acknowledges.

The scientists have already developed a second generation of XIAP inhibitors that last longer in the body and have other improved biochemical properties. Reed notes that more safety tests are required.

Still, Reed and other researchers are excited about the strategy of hindering XIAP so that cancer cells will commit suicide.

"It's one of the most exciting molecular targets in the cancer pathway," says Lily Yang of Emory University School of Medicine in Atlanta, who is also developing XIAP inhibitors.