University of Pennsylvania researchers have uncovered how hydralazine, a blood pressure medication used for over 70 years, can halt the growth of aggressive brain tumors by targeting a critical molecular pathway. The discovery, published in Science Advances, reveals the drug's previously unknown mechanism of action and opens new possibilities for cancer treatment using existing cardiovascular medications.
Molecular Mechanism Revealed
The research team, led by physician-scientist Kyosuke Shishikura and assistant chemistry professor Megan Matthews, found that hydralazine directly targets a tiny but critical enzyme called 2-aminoethanethiol dioxygenase (ADO). This enzyme functions as an oxygen-sensing molecular switch that tells blood vessels when to constrict.
"ADO is like an alarm bell that rings the moment oxygen starts to fall," Matthews explained. "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."
The researchers discovered that hydralazine binds to ADO and shuts it down, effectively silencing the alarm system that helps cancer cells survive in low-oxygen environments. This same pathway that signals blood vessel constriction also supports tumor cell survival under hypoxic conditions.
Cancer Cell Growth Inhibition
In laboratory studies, the researchers treated glioblastoma cells with hydralazine for three consecutive days and observed that the cells entered a stage where tumor growth stopped. Glioblastoma represents one of the most aggressive forms of brain cancer, making this finding particularly significant for oncology research.
The oxygen-sensing enzyme pathway that hydralazine disrupts is crucial for cancer cell adaptation to low-oxygen environments commonly found in solid tumors. By suppressing this pathway, the drug prevents glioblastoma cells from maintaining their growth advantage.
Clinical Context and Significance
Hydralazine, sold under the brand name Apresoline, has been a mainstay treatment for high blood pressure and hypertensive emergencies, particularly during pregnancy. "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 5-15% of maternal deaths worldwide," Shishikura noted.
The drug emerged from what researchers call a "pre-target" era of drug discovery, when medications were developed based on observed patient outcomes before understanding the underlying biological mechanisms. This research finally explains how hydralazine works at the molecular level.
Implications for Treatment Development
The discovery has particular relevance for addressing health disparities, as Matthews noted that preeclampsia "continues to disproportionately impact Black mothers in the United States." Understanding hydralazine's molecular mechanism "offers a path toward safer, more selective treatments for pregnancy-related hypertension—potentially improving outcomes for patients who are at greatest risk."
The research team collaborated with structural biochemists at the University of Texas and neuroscientists at the University of Florida, using X-ray crystallography to determine the drug's potential applications in both brain cancer treatment and maternal health.
Drug Repurposing Potential
This breakthrough exemplifies the potential for repurposing existing medications that have established safety profiles for new therapeutic applications. The finding demonstrates how cardiovascular drugs can provide unexpected insights into neurological conditions and cancer biology.
"It's rare that an old cardiovascular drug ends up teaching us something new about the brain," Matthews observed, "but that's exactly what we're hoping to find more of—unusual links that could spell new solutions."
The research opens possibilities for developing more effective and selective cancer treatments based on the ADO enzyme target, potentially leading to improved therapeutic options for patients with aggressive brain tumors while maintaining the safety profile of a medication that has been used successfully for decades.
