An old blood-pressure-lowering therapy known as a diuretic killed multiple myeloma cells in a lab and in mice, including those resistant to current treatments, Spanish researchers reported.
A combination of the therapy, amiloride, and existing myeloma drugs could be a good way to treat patients whose cancer has returned, the team said. Clinical trials should be held to see if it would work, they added.
Their study, “Amiloride, An Old Diuretic Drug, Is a Potential Therapeutic Agent for Multiple Myeloma,” appeared in the journal Clinical Cancer Research.
The study’s senior authors were Irena Misiewicz-Krzeminska and Norma C. Gutierrez of the Cancer Research Center-IBMCC in Salamanca, Spain. Gutierrez is also affiliated with the Department of Hematology at Salamanca University Hospital.
New treatments have increased multiple myeloma patients’ survival, but the disease is still incurable.
Developing cancer therapies is costly and time-consuming, and many don’t work, so some researchers have been looking at using drugs approved for other diseases to fight cancer. Scientists call this approach drug repositioning. Many of the approved therapies, such as amiloride, have well-known safety profiles, and scientists know their mechanism of action.
Amiloride has been used to treat high blood pressure, or hypertension; congestive heart failure; edema, or swelling in the feet and other areas; and low levels of potassium in the blood.
The drug also kills cancer cells, studies have shown. It does this by disrupting alternative splicing, a process that allows a single gene to produce a number of different messenger RNA sequences and thus different proteins. Messenger RNA provide genes with the instructions they need to generate proteins.
Alternative splicing is a prominent feature of cancer cells, so amiloride’s ability to influence this process makes it a promising cancer therapy, the Spanish researchers said.
They discovered that amiloride killed human multiple myeloma cells cultured in a lab and implanted in mice. This included myeloma with missing or faulty p53 protein, forms that are typically associated with poor outcomes.
Another finding was that combinations of amiloride and other drugs increased the survival of mice with multiple myeloma. The other therapies included dexamethasone, Alkeran (melphalan), Revlimid (lenalidomide) and Pomalyst (pomalidomide).
In addition, amiloride prompted both normal and faulty versions of the TP53 gene to produce p53 protein. Although this suggested that amiloride uses the protein in its myeloma-fighting work, the therapy also killed myeloma cells without p53. The implication on the second finding was that mechanisms besides p53 are involved in amiloride’s ability to kill myeloma.
Another important finding was that amiloride did not cause systemic toxicity in the mice, the researchers said.
Overall, the results “demonstrate the anti-myeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option” for relapsed multiple myeloma patients, the researchers wrote.
That’s especially true for people with genetic abnormalities such as 17p chromosome deletions or TP53 mutations whose multiple myeloma is “resistant to current therapies,” they wrote.