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Scientists studying an existing blood pressure drug called hydralazine accidentally discovered that it could potentially fight cancer.
Hydralazine has been used to treat high blood pressure since the 1950s, but until now it’s been unclear exactly how it works.
“It came from a ‘pre-target’ era of drug discovery, when researchers relied on what they saw in patients first and only later tried to explain the biology behind it,” Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania who was involved in the study, said in a press release from the university.
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Shishikura and a wider research team uncovered that hydralazine directly targets a small but crucial enzyme called 2-aminoethanethiol dioxygenase (ADO).
This enzyme acts like a cellular oxygen sensor, helping cells survive when oxygen levels are low. This can help enable fast-growing tumors like glioblastoma, an aggressive form of brain cancer that resists treatment and almost always comes back.
Hydralazine has been around since the 1950s and is traditionally used to treat high blood pressure, but researchers didn’t understand exactly how it worked before now. (iStock)
In fast-growing cancers like glioblastoma, the tumor cells multiply so quickly that their blood supply can’t keep up. That means parts of the tumor don’t get enough oxygen.
Typical cells die in low-oxygen environments, but tumor cells switch on special survival systems that help them keep dividing even when oxygen is scarce. One of those systems involves the ADO enzyme, studies show.
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“ADO is like an alarm bell that rings the moment oxygen starts to fall,” Megan Matthews, an assistant professor in Penn’s Department of Chemistry and a researcher in the study, stated in the same press release.
The team used several advanced techniques — including X-ray crystallography, which analyzes the structure of molecules — to determine how hydralazine binds to ADO.
Hydralazine binds to the enzyme ADO and makes it stop working. This shuts down the cell’s oxygen response system, and in the case of cancer cells, forces them to stop dividing. (iStock)
They discovered that hydralazine silences that alarm by binding to ADO and making it stop working. This shuts down the cell’s oxygen response system — and, in the case of cancer cells, forces them to stop dividing.
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To test this discovery, the team treated human glioblastoma cells with hydralazine in the lab. After three days, they discovered that the cells had stopped multiplying and became larger and flatter. The cells had entered a kind of permanent “sleep mode” known as “senescence,” the researchers noted.
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While the drug didn’t kill the cells outright, it took away their ability to grow and spread.
That’s a huge step forward in controlling cancers like glioblastoma, which are extremely difficult to treat and often return even after surgery and chemotherapy, according to Memorial Sloan Kettering Cancer Center.
While other cells die when deprived of oxygen, cancer cells continue to adapt and grow due to the ADO enzyme. (iStock)
Because hydralazine is already FDA-approved, researchers hope it could be repurposed for cancer therapy much faster than a brand-new drug.
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The experiments so far have only been done with cell cultures, not yet in animals or humans, the researchers noted. The next step will be to test whether ADO can be blocked safely and effectively in living systems.
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The press release emphasizes that the discovery is only a starting point for drug repurposing, not yet a clinical treatment.
As Matthews said, “Understanding how hydralazine works at the molecular level offers a path toward safer, more selective treatments.”