A groundbreaking study led by researchers at the University of Pennsylvania has revealed that hydralazine, a long-established blood pressure medication, may effectively inhibit the growth of aggressive brain tumors. This discovery not only sheds light on the drug’s molecular mechanisms but also opens new avenues for treatment of both preeclampsia and brain cancer.
For over 70 years, hydralazine has been a critical treatment for high blood pressure, particularly in pregnant women. Despite its widespread use, the specific mechanisms through which it operates have remained largely unclear. “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,” explained Kyosuke Shishikura, a physician-scientist involved in the study.
Uncovering the Mechanism of Hydralazine
The research team, which includes Shishikura and postdoctoral adviser Megan Matthews, has made significant strides in understanding hydralazine’s action at the molecular level. Their findings, published in Science Advances, reveal that hydralazine blocks an oxygen-sensing enzyme known as 2-aminoethanethiol dioxygenase (ADO). This enzyme plays a crucial role in signaling blood vessels to constrict when oxygen levels drop, effectively acting as an alarm system for the body.
“ADO is like an alarm bell that rings the moment oxygen starts to fall,” said Matthews. By inhibiting ADO, hydralazine effectively “mutes” this alarm. The resulting stabilization of signaling proteins called regulators of G-protein signaling (RGS) prevents blood vessels from constricting, which lowers intracellular calcium levels, leading to vasodilation and reduced blood pressure.
Linking Hypertension and Brain Cancer
Prior to this study, there were indications that ADO might also play a role in glioblastoma, a highly aggressive form of brain cancer. Elevated levels of ADO and its byproducts have been associated with more severe cases of the disease. Shishikura notes that the findings suggest that silencing ADO could provide an effective strategy for treating glioblastoma.
To investigate the potential of hydralazine as an ADO inhibitor, the research team collaborated with structural biochemists from the University of Texas. Using X-ray crystallography, they visualized how hydralazine binds to ADO’s metal center. Further tests conducted by neuroscientists at the University of Florida demonstrated that hydralazine disrupts the oxygen-sensing mechanism in tumor cells, prompting them to enter a state of cellular senescence—essentially pausing their growth without causing inflammation or resistance, unlike traditional chemotherapy.
The study underscores the potential for repurposing established medications to address new medical challenges. “It’s rare that an old cardiovascular drug ends up teaching us something new about the brain,” Matthews remarked. The researchers aim to develop more specific ADO inhibitors that can effectively cross the blood-brain barrier, targeting tumor tissues while minimizing side effects.
As they move forward, the team hopes to leverage this understanding to create safer, more effective treatments for conditions like preeclampsia and aggressive brain tumors. The implications of their findings could significantly improve outcomes for patients facing these health challenges, particularly vulnerable populations disproportionately affected by conditions such as preeclampsia.
This research not only contributes to the understanding of hydralazine but also exemplifies how long-standing medications can lead to innovative solutions in modern medicine.
