Bold statement: A drug in use for seven decades is revealing a hidden Achilles’ heel in brain cancer. This unexpected twist could reshape how safer, smarter therapies are developed for both mothers and patients with brain tumors. And this is the part most people miss: long-standing medications may harbor unrecognized mechanisms that unlock new medical possibilities.
A drug called hydralazine has long stood as a critical tool in medicine, primarily as a frontline treatment to combat severe high blood pressure, including during pregnancy. Yet for many years, scientists lacked a complete understanding of exactly how it works at the molecular level, which made it harder to fully explain its proven effectiveness, ensure safety, and predict all the conditions it could treat.
In a recent study published in Science Advances, researchers led by Kyosuke Shishikura and Megan Matthews at the University of Pennsylvania have finally uncovered hydralazine’s mechanism of action. Their findings reveal a surprising and previously unappreciated link between hypertensive disorders in pregnancy and brain cancer, suggesting that a well-established therapy may contain untapped potential for treating other serious conditions.
The team identifies hydralazine as an inhibitor of an oxygen-sensing enzyme named 2-aminoethanethiol dioxygenase (ADO). ADO acts as an oxygen alert that signals blood vessels to constrict when oxygen levels drop. Normally, this system involves a rapid cascade that can lead to increased vascular tension. Hydralazine binds to ADO, effectively silencing this oxygen alarm. When ADO is blocked, the downstream regulators of G-protein signaling (RGS proteins) accumulate, telling blood vessels to relax. The result is reduced intracellular calcium levels—the master driver of vascular constriction—leading to vasodilation and lower blood pressure.
But the implications extend beyond blood pressure. In glioblastoma, tumors often survive in hypoxic (low-oxygen) regions. Elevated ADO activity and its metabolites have been associated with more aggressive cancer behavior, making ADO a compelling therapeutic target. Importantly, there had been no strong, selective ADO inhibitors available to test this idea—until hydralazine’s action was revealed.
To test the connection, the Penn team collaborated with structural biologists at the University of Texas to visualize hydralazine bound to ADO’s metal center using X-ray crystallography, and with neuroscientists at the University of Florida to assess its effects in brain cancer cells. The results showed that the same ADO pathway that helps regulate vascular contraction also helps tumor cells endure hypoxic stress. By interrupting this oxygen-sensing loop, hydralazine induces cellular senescence in glioblastoma cells—a dormant, non-dividing state that pauses tumor growth without causing widespread cell death or triggering harmful inflammation.
These discoveries open exciting possibilities. They hint at a broader therapeutic strategy: designing ADO inhibitors that are more tissue-specific or capable of crossing the blood–brain barrier more efficiently. Such drugs could target tumor tissue while sparing normal tissues, offering a safer approach to treat both pregnancy-related hypertension and brain cancer.
Megan L. Matthews and Kyosuke Shishikura emphasize that it is uncommon for a cardiovascular medication to illuminate new biology in the brain, yet this study demonstrates that long-standing drugs can reveal surprising connections and therapeutic opportunities. The researchers are now focused on advancing the chemistry to create next-generation ADO inhibitors and on further exploring how other established treatments might yield novel benefits when examined through a fresh scientific lens.
This work was supported by multiple funding bodies, including the National Institutes of Health, the National Science Foundation, the American Cancer Society, and several private foundations and partner institutions.
Would this insight shift how clinicians view older cardiovascular drugs? Could hydralazine or new ADO inhibitors become standard parts of combination therapies for glioblastoma or other brain cancers? Share thoughts and questions in the comments to explore how this unexpected link between pregnancy health and brain cancer might reshape medical research and patient care.
