The first thing the researchers noticed was the shape of the cells: after three days of hydralazine treatment, the glioblastoma cells were no longer compact and aggressive. They had expanded and flattened, as if something had flipped a switch.
They weren't dying: they were simply stopping dividing. It was senescence, a state of "permanent sleep" in which tumor cells lose the ability to grow and spread. The drug responsible for this effect has been on the market since 1950, prescribed to millions of people to lower blood pressure. But no one had ever understood how it really worked. Until today.
70-Year-Old Mystery Solved in Lab
THEhydralazine It belongs to that generation of drugs created before medicine understood exactly what molecules did inside the body. It worked, that much was certain: lowered blood pressure, saved pregnant women from preeclampsia, reduced the risk of cardiovascular complicationsBut the precise molecular mechanism remained obscure. Kasuga Shishikura, researcher ofUniversity of Pennsylvania, he decided to investigate using a technique called X-ray crystallography. What he found surprised everyone.
Hydralazine binds to an enzyme called ADO (2-aminoethanethiol dioxygenase), a sort of molecular alarm bell that goes off when oxygen levels drop. It's a rapid, almost instantaneous sensor: it doesn't need to copy DNA or build new proteins. As soon as oxygen drops, ADO activates a cascade of signals that tells blood vessels to tighten.Hydralazine blocks this signal, silencing it. When ADO stops functioning, RGS proteins (regulators of G protein signaling) are no longer degraded. Their accumulation tells the vessels: relax. The pressure drops.
Glioblastoma is the most common primary brain tumor in adults. It accounts for approximately 45% of all brain tumorsThe median survival is about 15 months, with a 5-year survival rate of less than 5%.
The treatment options we currently have are limited: surgery, radiotherapy, chemotherapy with temozolomide. And almost always the tumor comes back.
From the heart to the brain: the unexpected connection
Cancer researchers already suspected that ADO played a role in glioblastoma. These tumors grow in areas of the brain where oxygen is scarce, and elevated ADO levels had been associated with more aggressive, resistant diseases, with worse prognosesBut no one had an inhibitor to test. When Shishikura discovered that hydralazine blocked ADO, he collaborated with neuroscientists at the University of Florida to test its effects on brain tumor cells.
The results are clear: the same mechanism that relaxes blood vessels helps glioblastoma cells survive in oxygen-poor environments. When Shishikura and his team treated human glioblastoma cell lines with hydralazine, the cells entered senescence: they put the tumor on forced standby. It is not direct cell death, but a permanent blockage of proliferation. And a single dose maintained the effect for days.
Hydralazine for the treatment of glioblastoma: how far from clinical use?
We're still far from routine use in patients. The tests were conducted on cultured cells, not on humans with glioblastoma. Clinical trials will be needed to verify whether hydralazine can actually slow tumor progression in people, what dosages to use, and how to manage side effects (which do exist: lupus-like syndrome, liver and nerve toxicity). But the fact that the drug is already approved, already in use, and studied for decades accelerates the process.
Megan Matthews, co-author of the study, emphasizes that understand how hydralazine works It opens a path to designing more selective ADO inhibitors, capable of better crossing the blood-brain barrier and targeting brain tumors without harming the rest of the body. It could also improve treatments for preeclampsia, reducing adverse effects in pregnant women. Two completely different medical problems, a single underlying molecular mechanism.
Glioblastoma is extremely heterogeneousEvery tumor has different mutations and resists them differently. This makes it difficult to find universal therapies. But ADO appears to be a common weakness.
If we can hit it more precisely, we might have a new weapon against this disease.
When old drugs teach new things
There's something ironic about this discovery. For decades we've been searching for new molecules, advanced therapies, sophisticated immunotherapies (and some are giving results). But the key to understanding how to block one of the most lethal cancers was hidden in a drug we were already prescribing. Not because it was a miracle drug, but because no one had stopped to really ask what it did.
The research published on Science Advances It shows that sometimes it's worth going back. Re-examining old drugs, understanding their mechanisms, and seeing if they can be repurposed for new uses. It's faster, safer (we already know the safety profile), and potentially cheaper than developing molecules from scratch.
Matthews says it clearly:
"It's rare for an old cardiovascular drug to end up teaching us something new about the brain. But that's exactly what we hope to find again: unexpected connections that could lead to new solutions."
Hydralazine, what happens now?
Glioblastoma remains a terrible disease. But now we have a better starting point. We know ADO is involved. We know that blocking it works, at least in the lab. We know that hydralazine can do it. And we know that from here we can build something better. It's not a cure. Not yet. But it's a step forward that no one would have imagined 70 years ago.
It remains to be seen whether this approach will hold up in clinical trials. Whether patients will respond like cultured cells. Whether we can dose the drug effectively without unbearable side effects. But at least now we have a path forward. And a lesson: sometimes the answers we seek are already there, hidden in plain sight.
You just have to have the courage to look where no one has looked before.
