- Researchers identified how the medication hydralazine works at the molecular level in the body.
- Hydralazine is commonly used to treat high blood pressure and preeclampsia.
- Understanding its mechanism revealed the potential it has for stopping glioblastoma — an aggressive brain tumor — growth.
The blood pressure drug hydralazine has been around for more than 70 years, but scientists did not previously know how it worked.
This is not uncommon, and the researchers have pointed out that between 10 and 20% of drugs have an unknown mechanism of action.
Researchers at the University of Pennsylvania recently uncovered hydralazine’s mechanism and also discovered that the drug has the potential to stop the growth of glioblastoma, an aggressive brain tumor.
These findings not only clear up confusion surrounding how hydralazine works, but also open the door to new therapies for preeclampsia and brain cancer.
Hydralazine is an older medication used to lower high blood pressure. It is a vasodilator, so it works by widening blood vessels and improving blood flow.
It is widely used in managing preeclampsia, which is a high blood pressure condition related to pregnancy. If preeclampsia goes untreated, it can cause organ damage and endanger the lives of both the pregnant parent and their baby.
Although hydralazine has been used for decades, scientists were never quite sure precisely how it worked.
Understanding a drug’s mechanism of action can provide insight into why certain side effects occur, help identify which patients are most likely to benefit based on genetics, and reveal potential new uses for the medication.
To figure out how hydralazine works, researchers created a special version of the drug, called HYZyne. This probe acted like hydralazine and had a “tag” that let scientists see which proteins it attached to inside cells.
After the researchers treated cells with HYZyne, it only tagged a few proteins, and an enzyme called 2-aminoethanethiol dioxygenase (ADO) stood out.
ADO detects oxygen and helps control blood pressure by regulating proteins that relax blood vessels, so when ADO is blocked, blood vessels stay relaxed and blood pressure drops.
The researchers discovered that hydralazine works by shutting down ADO, which contributes to the relaxation of blood vessel walls and lowers blood pressure.
Thanks to the ADO discovery, the researchers took a look at how hydralazine affects glioblastoma since ADO and this cancer have been connected before.
Most people with glioblastoma only live for around 12 to 18 months after receiving their diagnosis, and this form of cancer has a 5-year survival rate of around 5%. Some treatment options include surgery, radiotherapy, and chemotherapy.
According to the researchers, glioblastoma often depends on high ADO activity to survive and grow. When the team treated these cancer cells with hydralazine, the cells entered a process called “senescence.”
While this does not cause the cancer cells to die, it does slow their growth dramatically. The scientists noted that one dose of hydralazine kept the cells in this paused state for days.
While further research is needed on hydralazine and glioblastoma, the findings raise the possibility that ADO-blocking drugs could one day be used as a treatment.
Walavan Sivakumar, MD, a board-certified neurosurgeon and director of neurosurgery at Providence Little Company of Mary, spoke with Medical News Today about the findings.
“This is a very elegant piece of science,” said Sivakumar, who was not involved in this study. “The authors have finally clarified how hydralazine works at the molecular level and, in doing so, uncovered a completely new vulnerability in aggressive brain tumors,” he added.
Sivakumar touched on how the scientists were able to push glioblastoma cells into a “sleep mode” instead of destroying it.
“That’s a fundamentally different way of thinking about brain cancer therapy,” he noted.
While Sivakumar emphasized that the findings are preclinical and will not impact glioblastoma treatment presently, he pointed out that many things about the findings make hydralazine “attractive.”
“It’s one of the oldest blood pressure drugs we have, with decades of safety data and global availability. In neuro-oncology, where many of our therapies are expensive, toxic, and difficult to access, the idea that a low-cost, generic medication might help slow a tumor like glioblastoma is extremely attractive.”
– Walavan Sivakumar, MD
Nicholas Klaiber, MD, a physician and Eastern Virginia Medical School graduate, also spoke with MNT about the findings. Klaiber, who likewise was not involved in the research, described the study as “scientifically rigorous.”
While Klaiber found the data “compelling,” he was still unsure about the future of using hydralazine in people with glioblastoma.
“The problem with simply inducing senescence (dormancy) is that continuous therapy would be necessary to suppress tumor growth,” he told us.
“In addition, glioblastoma cells have a very high mutation rate and would likely upregulate ADO production to gain resistance to hydralazine,” he cautioned.
