Digitalis-based drugs like digoxin have been used for
centuries to treat patients with irregular
heart rhythms and heart failure and are still in use today.
In the Dec. 16 issue of the Proceedings of
the National Academy of Sciences, researchers at the
Johns Hopkins University School of Medicine
now report that this same class of drugs may hold new
promise as a treatment for cancer. This finding
emerged through a search for existing drugs that might slow
or stop cancer progression.
"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," said Gregg L.
Semenza, director of the vascular program at
Hopkins Institute for Cell Engineering and a member of
McKusick-Nathans Institute of Genetic Medicine.
Semenza and his team have long studied the
hypoxia-inducible factor, or HIF-1, protein, which
controls genes that help cells survive under low-oxygen
conditions. HIF-1 turns on genes that grow new
blood vessels to help oxygen-starved cells survive. Regions
of low oxygen are common within the
environment of fast-growing solid tumors.
"Oxygen-deprived cancer cells increase their HIF-1
levels to survive in these unfavorable
conditions," Semenza said, "so turning down or blocking
HIF-1 may be key to slowing or stopping these
cells from growing."
For this study, the researchers took advantage of the
Johns Hopkins Drug Library — a collection
of more than 3,000 drugs already FDA-approved or currently
being tested in phase II clinical trials —
that was assembled by Johns Hopkins
pharmacology professor Jun O. Liu. The research team
every drug in the library for its ability to turn down
HIF-1 in cancer cells. The top 20 candidates
identified were able to reduce HIF-1 by more than 88
percent, and more than half of the 20 belong to
a class of drugs already commonly used for treating heart
failure, including digoxin.
The researchers focused on digoxin because of its
already well-established clinical use. They
treated prostate cancer cells grown at normal and
low-oxygen levels with digoxin for three days and
counted the number of cells each day. They found that cells
treated with digoxin significantly slowed
their growth, with fewer total cells after three days and
increased numbers of cells that had stopped
growing when compared to untreated cells.
"Many drugs may appear promising when used to treat
cancer cells in a dish in the lab but may
have little or no effect on tumors in living animals," said
Huafeng Zhang, a research associate in the
Department of Oncology and the Institute for Cell
Engineering at Johns Hopkins.
To see if digoxin had the same effect on cancer cells
in the physiological context of a whole
animal, the team administered daily injections of digoxin
to mice with tumors. In untreated mice,
tumors were large enough to be felt within nine days, but
in treated mice, tumors could first be felt
only after as long as 15 to 28 days. The team then examined
tumors from the mice and found that
HIF-1 levels were lower than in tumors from untreated mice.
The team then went on to show that it is
digoxin specifically reducing HIF-1 that leads to the
anti-tumor results they saw.
While Zhang said she thinks it is possible that drugs
like digoxin could someday be used for
treating cancer, she cautions that a great deal of work
remains to be done to understand in detail how
these drugs inhibit HIF-1 and slow or stop tumor growth.
Also, since this class of drugs acts by both
strengthening and slowing down the rhythm of the heart, she
notes that patients can safely tolerate
them in only a limited dosage range — a range that is
lower than the concentrations of digoxin used in
this study. "We're trying to kill a tumor," she said. "We
don't want to stop a heart."
Authors of this paper are Zhang, David Z. Qian, Yee
Sun Tan, KangAe Lee, Ping Gao, Yunzhao R.
Ren, Sergio Rey, Hans Hammers, Daniel Chang, Roberto Pili,
Chi V. Dang, Liu and Semenza, all of Johns
This work was funded by the Flight Attendant Medical
Research Institute and the Johns
Hopkins Institute for Cell Engineering.