Cancer cells need to create new blood vessels to survive. But many of these cells are oxygen-deprived and need to switch on genes that produce a protein called hypoxia-inducible factor (HIF-1), which help cells survive in low-oxygen conditions.
Digoxin reduces HIF-1, causing cancer cells to die, the scientists from Johns Hopkins University found.
“Anytime you see alternative uses for existing drugs, that always generates a certain amount of excitement,” said William Phelps, director of preclinical and translational cancer research at the American Cancer Society. “In the cancer field, we are always looking for any new compounds, so this is an exciting potential.”
For the study, Dr. Gregg L. Semenza, director of the vascular program at the Johns Hopkins Institute for Cell Engineering, and his colleagues tested more than 3,000 U.S. Food and Drug Administration-approved drugs for their ability to reduce HIF-1 levels in cancer cells.
They identified 20 drugs that reduced HIF-1 by more than 88 percent; more than half are used to treat heart failure. The researchers then looked specifically at digoxin because it is commonly used and its side effects are well-documented.
The researchers found that prostate cancer cells treated in a laboratory with digoxin grew significantly slower. After three days of treatment, there were fewer cancer cells, and many cells had stopped growing altogether, compared with untreated cells.
“This is really exciting, to find that a drug already deemed safe by the FDA also can inhibit a protein crucial for cancer cell survival,” Semenza said in a statement.
To see if digoxin would work on cancer cells in animals, and not just on isolated cancer cells in a lab, the researchers then gave mice with tumors daily injections of digoxin.
They found that in mice not given digoxin, tumors grew to the point where they could be felt after nine days. But, in mice treated with digoxin, tumors couldn’t be felt until 15 to 28 days.
And levels of HIF-1 were lower in the tumors of treated mice, compared with untreated mice. The researchers also found that it was digoxin that reduced HIF-1 levels leading to slower tumor growth.
The report was published recently in the Proceedings of the National Academy of Sciences.
There have been previous studies showing that digoxin and other so-called digitalis-based drugs reduce the risk of dying from or developing some cancers, Semenza’s team noted.
In one long-term follow-up of 175 breast cancer patients, those taking digitalis drugs had a 6 percent death rate, compared with 34 percent among those not taking these drugs. Another study of more than 9,000 patients taking digoxin found an association between high levels of the drug and a lower risk of leukemia and lymphoma and kidney and urinary tract cancers, according to the study.
Phelps said future research needs to focus on how these drugs slow tumor growth to see if it’s different from how they work to control heart function. “If so, can you improve the class to more specifically hit this new target that has the anti-tumor effects?” he said.
To learn more about digoxin, visit the U.S. National Library of Medicine.
SOURCES: William Phelps, Ph.D., director, preclinical and translational cancer research, American Cancer Society, Atlanta; Dec. 16, 2008, Proceedings of the National Academy of Sciences
By Steven Reinberg
Last Updated: Jan. 07, 2009
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