Researchers Uncover How Blood Pressure Drug Fights Brain Tumors

A team from the University of Pennsylvania has discovered that hydralazine, a long-established blood pressure medication, may also inhibit the growth of aggressive brain tumors. This unexpected finding sheds light on the drug’s molecular mechanisms and opens new avenues for treating both hypertension and brain cancer.

For over 70 years, hydralazine has served as a critical treatment for high blood pressure, particularly in pregnant women facing preeclampsia, a condition that contributes to 5%–15% of maternal deaths worldwide. Despite its extensive use, the specific way hydralazine operates at a molecular level has remained largely unknown.

According to Kyosuke Shishikura, a physician-scientist involved in the research, “Hydralazine is one of the earliest vasodilators ever developed, and it’s still a first-line treatment for preeclampsia.” The research team aimed to elucidate the drug’s mechanism of action, which has implications for improving treatment efficacy and safety.

Unlocking the Mechanism of Action

The research, published in Science Advances, reveals that hydralazine blocks the activity of an oxygen-sensing enzyme known as 2-aminoethanethiol dioxygenase (ADO). This enzyme acts as a signal to constrict blood vessels when oxygen levels drop. By inhibiting ADO, hydralazine effectively “mutes” this signal, allowing blood vessels to dilate and blood pressure to decrease.

Shishikura explains, “ADO is like an alarm bell that rings the moment oxygen starts to fall.” This process is rapid, allowing the body to respond to changing oxygen levels without needing to produce new proteins. The study showed that blocking ADO stabilizes certain proteins called regulators of G-protein signaling (RGS), which leads to reduced intracellular calcium levels. This reduction allows blood vessel smooth muscles to relax, promoting vasodilation.

Implications for Brain Cancer Treatment

The team’s research also suggests a significant connection between hypertension and brain cancer. Previous studies indicated that elevated ADO levels correlated with more aggressive forms of glioblastoma, a highly lethal brain tumor. Shishikura notes that targeting ADO could provide a new approach to treating glioblastoma, as it thrives in low-oxygen environments.

To further investigate this potential, Shishikura collaborated with structural biochemists at the University of Texas and neuroscientists at the University of Florida. They utilized X-ray crystallography to visualize how hydralazine interacts with ADO, confirming it as a viable inhibitor. Instead of killing tumor cells outright, hydralazine induces a state of cellular “senescence” in glioblastoma cells, pausing their growth and reducing inflammation—a promising alternative to traditional chemotherapy.

The researchers aim to develop more targeted ADO inhibitors that can penetrate the blood-brain barrier effectively, maximizing therapeutic effects on tumor tissue while minimizing side effects on the rest of the body. Matthews emphasizes the importance of understanding the mechanisms behind established treatments, stating, “It’s rare that an old cardiovascular drug ends up teaching us something new about the brain.”

As research progresses, the team hopes their findings will lead to safer and more effective therapies for both pregnancy-related hypertension and aggressive brain tumors, potentially improving outcomes for patients at risk.

More information about this pioneering study can be found in the article by Kyosuke Shishikura et al., titled “Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma,” published in Science Advances in 2025. The DOI for the study is 10.1126/sciadv.adx7687.