Scientists at the Johns Hopkins University School of Medicine say that digitalis-based drugs like digoxin, which have been used to treat patients with irregular heart rhythms and heart failure for centuries, may prove helpful in treating cancer too.
The researchers came to this conclusion while researching into 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," says Dr. Gregg L. Semenza, director of the vascular program at the Johns Hopkins Institute for Cell Engineering and a member of the McKusick-Nathans Institute of Genetic Medicine.
Semenza and his team have long studied the hypoxia-inducible factor (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 unfavourable conditions. So turning down or blocking HIF-1 may be key to slowing or stopping these cells from growing," says Semenza.
For their study, the researchers relied upon the Johns Hopkins Drug Library, a collection of over 3,000 drugs that are either FDA approved or currently being tested in phase II clinical trials, assembled by Hopkins pharmacology professor Jun O. Liu.
They tested every drug in the library, and identified top 20 candidates that were able to to reduce HIF-1 in cancer cells by more than 88 percent.
The researchers said that more than half of the 20 drugs belonged to a class of drugs already commonly used for treating heart failure, and included digoxin.
During the study, the researchers 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," says Dr. Huafeng Zhang, a research associate in the Department of Oncology and the Institute for Cell Engineering at Hopkins.
The researchers also administered daily injections of digoxin to mice with tumours for determining whether the drug had the same effect on cancer cells in the physiological context of a whole animal.
They observed that tumours were large enough to be felt within nine days in untreated mice, tumours could first be felt only after as long as 15 to 28 days in treated mice.
Upon examining tumours from the mice that had been treated, the researchers observed that their HIF-1 levels were lower than tumours from untreated mice.
They then went on to show that it is digoxin specifically reducing HIF-1 that leads to the anti-tumour results they saw.
Zhang, however, cautions that a great deal of work remains to be done to understand in detail how drugs like digoxin inhibit HIF-1 and slow or stop tumour growth.
Given that this class of drugs acts by both strengthening and slowing down the rhythm of the heart, she says 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 tumour. We don't want to stop a heart," she says.
The study has been reported in the Proceedings of the National Academy of Sciences.