For the past seventy years, hydralazine has been a staple drug used to treat high blood pressure, particularly in cases of life-threatening pre-eclampsia (a pregnancy-related condition characterized by high blood pressure and protein in the urine after the twentieth week of pregnancy). Despite its widespread use, its molecular mechanism of action has remained a mystery, limiting our understanding of how to improve its efficacy and safety, as well as its potential use in treating other diseases.
In a new study, researchers found that hydralazine not only treats high blood pressure but can also halt the growth of aggressive brain tumors. These findings open up new avenues for understanding how long-established treatments can have unexpected applications in medicine.
"Hydralacine is one of the first vasodilators developed and remains a key treatment for preeclampsia, a disorder that causes a significant percentage of maternal deaths worldwide," says Kyosuke Shishikura, a physician and researcher at the University of Pennsylvania. "Until now, no one knew exactly how this drug works at the molecular level. But we've managed to solve that mystery."
The effect of hydralazine is based on blocking an enzyme called 2-aminoethanethiol deoxygenase (ADO), which reacts to oxygen levels in tissues. This enzyme acts as a "sensor" in blood vessels, alerting them when to constrict.
“The ADO enzyme is like an alarm bell that alerts the body to a lack of oxygen,” explains Megan Matthews, a researcher at the University of Pennsylvania. “While most biological processes require a long time to react, ADO bypasses these processes very quickly.”
By blocking this enzyme, hydralazine silences the oxygen deficiency alarm. As a result, the proteins that the enzyme breaks down remain stable, leading to a decrease in calcium levels within cells, a key factor in blood vessel tone. This reduction in calcium causes the smooth muscles in the vessel walls to relax, resulting in vasodilation and a drop in blood pressure.
Prior to this discovery, cancer experts had suggested that the ADO enzyme might play a role in brain cancer, particularly in tumors like glioblastoma, which grow in low-oxygen environments. Studies had shown that elevated levels of ADO and its metabolites were associated with increased disease severity, leading researchers to suspect that inhibiting this enzyme could be an effective treatment.
To test this hypothesis, Shishikura collaborated with biochemists at the University of Texas, who used advanced techniques such as X-ray crystallography to image hydralazine as it binds to the ADO enzyme.
The team found that the ADO pathway not only regulates blood vessel constriction but also helps tumor cells survive in low-oxygen environments. Unlike chemotherapy, which aims to directly destroy cancer cells, hydralazine disrupts the oxygen-sensing loop, leading to the "senescence" of cancer cells, rendering them unable to divide and thus halting tumor growth without triggering inflammation or resistance.
Researchers are now working on developing new ADO inhibitors that have a greater ability to target specific tissues, while ensuring the drug's ability to cross the blood-brain barrier. (The goal is to effectively target tumor tissue without affecting healthy tissue.)
The study was published in the journal Science Advances.