Pregnancy Drug Weakens Brain Cancer – New Research
70-Year Mystery Solved: How Blood Pressure Drug Hydralazine Really Works – and a surprising Link to Brain Cancer
PHILADELPHIA, PA – For seven decades, hydralazine has been a critical medication for managing high blood pressure, especially during pregnancy. But until now, the precise how of its effectiveness remained a mystery. Researchers at the University of Pennsylvania have finally cracked the code, revealing that hydralazine blocks an oxygen-sensing enzyme, offering potential new avenues for treating both preeclampsia and glioblastoma, a deadly form of brain cancer. The discovery, published in Science Advances, underscores the value of revisiting established treatments to unlock hidden therapeutic potential.
Over the last 70 years, hydralazine has been an indispensable tool in medicine — a front-line defense against life-threatening high blood pressure, especially during pregnancy. But despite its essential role, a fundamental mystery has persisted: no one knew its “mechanism of action” — essentially how it works at a molecular level, which allows for improved efficacy, safety, and what it can treat.
Over the last 70 years, hydralazine has been an indispensable tool in medicine — a front-line defense against life-threatening high blood pressure, especially during pregnancy. but despite its essential role, a fundamental mystery has persisted: no one knew its “mechanism of action” — essentially how it works at a molecular level, which allows for improved efficacy, safety, and what it can treat.
“Hydralazine is one of the earliest vasodilators ever developed, and it’s still a first-line treatment for preeclampsia — a hypertensive disorder that accounts for 5 to 15% of maternal deaths worldwide,” says Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania. “It came from a ‘pre-target’ era of drug discovery,when researchers relied on what they saw in patients first and onyl later tried to explain the biology behind it.”
Now Shishikura, his postdoctoral advisor at Penn Megan Matthews, and collaborators have solved this long-standing puzzle.
In a paper published in Science Advances, they uncovered the method of action of hydralazine, and in doing so, revealed an unexpected biological link between hypertensive disorders and brain cancer. The findings highlight how long-established treatments can reveal new therapeutic potential and could help in the design of safer, more effective drugs for both maternal health and brain cancer.
“Preeclampsia has affected generations of women in my own family and continues to disproportionately impact Black mothers in the United States,” Matthews says. “Understanding how hydralazine works at the molecular level offers a path toward safer, more selective treatments for pregnancy-related hypertension — potentially improving outcomes for patients who are at greatest risk.”
Hydralazine blocks an oxygen-sensing enzyme
the team found that hydralazine blocks an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO) – a molecular switch that tells blood vessels when to tighten.
“ADO is like an alarm bell that rings the moment oxygen starts to fall,” Matthews says. “Most systems in the body take time; they have to copy DNA,make RNA,and build new proteins. ADO skips all that. It flips a biochemical switch in seconds.”
Hydralazine acts by binding to and blocking ADO, which means it effectively “mutes” that oxygen alarm. Once the enzyme was silenced, the signaling proteins it normally degrades — called regulators of G-protein signaling (RGS) — remained stable.
The buildup of RGS proteins, says Shishikura, tells the blood vessels to stop constricting, effectively overriding the ”squeeze” signal. This reduces intracellular calcium levels, which he calls the “master regulator of vascular tension.” As calcium levels fall, the smooth muscles in blood vessel walls relax, causing vasodilation