Old Blood Pressure Drug Offers Hope Against Aggressive Brain Tumors

A team led by researchers at the University of Pennsylvania has discovered that hydralazine, a long-established blood pressure medication, can also inhibit the growth of aggressive brain tumors, specifically glioblastoma. This revelation comes after the team elucidated the drug’s molecular mechanism, a breakthrough that could open new avenues for treatment in both maternal health and oncology.

For over 70 years, hydralazine has been a crucial treatment for managing high blood pressure, particularly in pregnant women suffering from preeclampsia, a condition responsible for 5% to 15% of maternal deaths worldwide. Despite its widespread usage, the precise biological action of hydralazine remained a mystery until now. According to Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania, “Hydralazine is one of the earliest vasodilators ever developed, and it’s still a first-line treatment for preeclampsia.”

Revealing Mechanisms at the Molecular Level

In a paper published in Science Advances, Shishikura and his collaborator, Megan Matthews, alongside a team of researchers, have identified how hydralazine operates at the molecular level. They found that hydralazine inhibits an oxygen-sensing enzyme known as 2-aminoethanethiol dioxygenase (ADO). This enzyme acts as a critical switch for blood vessels, signaling when to constrict in response to low oxygen levels.

“ADO is like an alarm bell that rings the moment oxygen starts to fall,” Matthews explained. By blocking ADO, hydralazine effectively silences this alarm, preventing blood vessels from constricting. This action leads to decreased intracellular calcium levels, which is essential for relaxing the smooth muscles in blood vessel walls, resulting in vasodilation and a decrease in blood pressure.

Linking Preeclampsia and Glioblastoma

The research also uncovered a surprising connection between hypertensive disorders and brain cancer. Prior to this study, there was evidence suggesting that elevated levels of ADO might contribute to glioblastoma’s aggressive nature, particularly in low-oxygen conditions often present in tumors.

Investigators, including Shishikura, collaborated with structural biochemists from the University of Texas and neuroscientists from the University of Florida to further explore this link. Their findings indicated that the same pathway regulating vascular contraction also plays a role in tumor cell survival under hypoxic conditions. Instead of completely killing the cancer cells, hydralazine disrupts this oxygen-sensing loop, inducing a state of cellular “senescence” in glioblastoma cells. This effectively pauses tumor growth without triggering inflammation or resistance, which are common side effects of traditional chemotherapy.

The researchers believe that the next steps involve developing new ADO inhibitors that are more specific to tissue types and capable of more effectively crossing the blood-brain barrier. Matthews emphasized the importance of continuing to explore the mechanisms of established drugs, stating, “It’s rare that an old cardiovascular drug ends up teaching us something new about the brain, but that’s exactly what we’re hoping to find more of—unusual links that could spell new solutions.”

This research not only highlights the potential for repurposing existing medications for new therapeutic uses but also underscores the importance of understanding drug mechanisms to enhance patient care. With further development, hydralazine could pave the way for more effective treatments for both preeclampsia and aggressive brain tumors like glioblastoma.

The findings of this study present a promising avenue for future research and treatment strategies, potentially improving outcomes for patients facing these serious health challenges.