BOSTON -- Scientists at Dana-Farber Cancer Institute have corrected a flaw in cancer cells that lets them evade the normal cell-death process, and as a result they eliminated leukemia cells from mice. With this achievement, the researchers confirm that a key anti-cell-death molecule called BCL-2 is required by many types of cancer cells to survive, and that silencing it with designer drugs may prove to be an effective new avenue for cancer therapy.
Using drugs to manipulate apoptosis, or "programmed cell death" in cancers "is a new paradigm that hasn't been well explored yet," said Anthony Letai, MD, PhD, in the laboratory of Stanley Korsmeyer at Dana-Farber. "What better way to kill cancer cells than targeting the molecules that directly control their survival?"
Letai is the lead author and Korsmeyer, a Howard Hughes Medical Institute investigator, is the senior author of a report published in the Sept. 21 issue of Cancer Cell. The other authors are Mia D. Sorcinelli and Caroline Beard. The report describes an experiment with laboratory mice genetically modified to be highly prone to developing leukemia. The mice were also modified so that the BCL-2 protein could be turned off by adding an antibiotic to the animals' water.
The scientists observed 28 mice, which, at 5 to 7 weeks of age, had developed leukemia. Fourteen were given the antibiotic in their water to turn off the BCL-2 genes. Within three days, the treated animals had a decline in leukemia cells and their white blood cell counts became normal within 10 days.
There was no such improvement in the untreated mice, whose cancers resisted death because of their active BCL-2 genes: they all died by just over 100 days of age. By contrast, five of the mice with silenced BCL-2 genes survived for over 200 days, and one of them lived more than a year. The findings confirmed a previously untested notion that cancer cells could not maintain their malignant behavior – growing out of control, invading normal tissues, spreading to other parts of the body – in the absence of BCL-2, and, further, that muzzling that "survival" molecule in cancer cells would allow them to self-destruct.
"This is the first specific evidence that removal of an apoptotic defect by itself can kill cancer in a living organism," said Letai. Apoptosis is a normal quality-control process within cells. In response to signals from their environment or signals from their own internal damage-sensors, a series of molecular interactions cause cells to release a lethal chemical that destroys them. Through apoptosis, the body can rid itself of cells that are no longer needed or are superfluous in embryonic development, or have sustained damage to their DNA and therefore should not live to reproduce.
But in cancer, despite the cells' damaged DNA and other abnormalities, the self-destruct signals are blocked by proteins belonging to the BCL-2 family: these molecules act as a check on apoptosis, and cancer cells take advantage of their inhibitory effect by making an excess of BCL-2 proteins. As a result, the death signals never reach their targets and the cell continues to live on and proliferate uncontrollably.
Overexpression of BCL-2 has been observed in many types of cancer, and was first discovered in lymphoma cells. Scientists speculated that overactive BCL-2 might be required by cancerous cells to survive in the face of the apoptosis process attempting to kill the cells, but the question hadn't been directly tested.
The experimental results provide strong support, the authors wrote, for the theory that blocking BCL-2 would be toxic to cancer cells. While mice lacking BCL-2 throughout their lives show abnormalities including altered regulation of their immune response, said Letai, their survival nonetheless suggests that treating humans with a BCL-2 inhibiting drug for a defined period of time should be tolerable. Drugs that block BCL-2 exist but have not been tested in humans, but Letai and his colleagues are working with a drug company on the preclinical development of such a drug.
### The study was funded by grants from the National Institutes of Health, the American Society for Hematology Scholar Award Program, and the Claudia Adams Barr Foundation.
Dana-Farber Cancer Institute (http://www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School and is among the leading cancer research and care centers in the United States. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), a designated comprehensive cancer center by the National Cancer Institute.
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