- Apoptosis: 1 | 2 | 3 | 4 | Related article: How to kill a cancer cell
Releasing the brake
Letai compares a normal and a cancer cell to a pair of cars perched on the brink of a cliff. The Ford Taurus — a normal cell — is idling, with the driver's foot on the brake. The Chevy Corvette — the cancer cell — by contrast has its huge engine racing (pro-death signals) and only a heavy foot on the brake (Bcl-2 survival signals) keeps the vehicle still.
Left to right: DFCI investigators Nika Danial, PhD, Anthony Letai, MD, PhD, and Loren Walensky, MD, PhD, are helping fuel progress in understanding the role of apoptosis in cancer.
Now release the brakes on both cars. The Taurus continues to idle normally, but the Corvette with its pent-up energy shoots ahead — and over the cliff to destruction. Hence the promise of drugs aimed at releasing the Bcl-2 brake in cancer cells by disabling it, sending the cancer into apoptosis, while normal cells would be much less affected.
Letai, Korsmeyer, and colleagues demonstrated the principle with experiments using mice genetically prone to leukemia. The rodents had been engineered so that the Bcl-2 proteins in their cells could be turned off when an antibiotic was added to their drinking water.s
When the mice developed leukemia at five to seven weeks of age, half were given the antibiotic to shut down Bcl-2 activity. Within days, the lack of Bcl-2 caused the death of leukemia cells in the treated animals, and their blood counts returned to normal within 10 days. These mice far outlived their untreated counterparts, who died in just over 100 days. Some of the treated mice survived more than 200 days, and one more than a year.
Drugs that block Bcl-2 haven't reached human clinical trials, though Letai is collaborating with a drug company moving in that direction.
"What better way to kill cancer cells than targeting the molecules that directly control their survival?" he says. "I am confident that compounds like this will be an important class of arrows in our quiver to battle cancer — at least types of cancer in which Bcl-2 is blocking apoptosis."
Another Korsmeyer colleague, Loren Walensky, MD, PhD, has taken a different approach to anti-Bcl-2 drug development. In his work, he borrows a key portion from proteins in the Bcl-2 family that carries out apoptotic cell death. The so-called "BH3-only" protein segment, a string of amino acids nicknamed the "death domain," is critical to activating the cell death pathway.
As a step toward commandeering the natural death domain for use as an anti-survival drug, Walensky and colleagues made a synthetic copy and administered it to mice with leukemia. It required a neat biochemical trick to maintain the domain's Slinky-like coiled structure, but it worked. The artificial molecule blocked Bcl-2 family targets in the mice, and apoptosis killed the leukemia cells.
- Next: Research in high gear
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