from Preeclampsia to Brain Cancer: How a Century-Old Drug is Revealing New Pathways to Treatment
For decades,hydralazine has been a cornerstone in managing high blood pressure,especially in pregnant women facing the perilous complication of preeclampsia. Now, groundbreaking research from the University of Pennsylvania, detailed in recent findings, is revealing a surprising new role for this well-established drug – and the enzyme it impacts – in the fight against aggressive brain cancer, specifically glioblastoma. This discovery not only unlocks potential repurposing opportunities for existing medications but also illuminates a fundamental biological pathway linking oxygen sensing, vascular health, and tumor survival.
Understanding the Oxygen-Sensing Mechanism: The Role of ADO
The research centers around an enzyme called ADO (aldehyde oxidase). Traditionally understood for its role in metabolizing aldehydes, scientists now recognize ADO as a critical regulator of how blood vessels respond to low oxygen levels – a condition known as hypoxia. This is particularly relevant in preeclampsia, where placental dysfunction leads to reduced oxygen delivery to the mother.
“We’ve discovered that ADO acts as an oxygen sensor in blood vessels,” explains Kyosuke Shishikura, a postdoctoral researcher involved in the study.”When oxygen levels drop, ADO becomes more active, triggering blood vessel constriction. This is a natural response to try and maintain blood flow, but in preeclampsia, it can contribute to dangerously high blood pressure.”
The teamS investigation revealed a fascinating mechanism. When ADO is silenced – or inhibited, as hydralazine does – a family of proteins called regulators of G-protein signaling (RGS) accumulate. These RGS proteins effectively counteract the constriction signal, promoting blood vessel relaxation (vasodilation) and lowering blood pressure. this process hinges on regulating intracellular calcium levels, the “master regulator of vascular tension,” as Shishikura describes. by reducing calcium,hydralazine allows smooth muscles in blood vessel walls to relax,easing the pressure.
A Surprising Link to Glioblastoma: Tumor Survival in Hypoxic Environments
the connection to glioblastoma, one of the most aggressive and arduous-to-treat forms of brain cancer, emerged from observations that these tumors often thrive in low-oxygen pockets within the brain. Researchers had previously noted elevated levels of ADO and its byproducts in aggressive glioblastomas, suggesting a potential link. However, a lack of effective ADO inhibitors hindered further investigation.
Hydralazine, with its known ability to inhibit ADO, became a prime candidate for testing. A collaborative effort involving structural biochemists at the University of Texas (using X-ray crystallography to visualize the drug’s interaction with ADO) and neuroscientists at the University of Florida (testing the drug’s effects on brain cancer cells) confirmed the connection.
The findings were striking. The same ADO pathway that regulates vascular contraction also plays a crucial role in helping glioblastoma cells survive in hypoxic conditions. However, unlike conventional chemotherapy, which aims to kill rapidly dividing cells, hydralazine doesn’t directly kill tumor cells. Rather, it disrupts the oxygen-sensing loop, inducing a state of cellular “senescence” – a dormant, non-dividing state. this effectively pauses tumor growth without the damaging inflammation and drug resistance frequently enough associated with conventional cancer treatments.
Repurposing for Impact: A New Era of drug Discovery
This research exemplifies the power of repurposing existing drugs - a strategy gaining increasing traction in the pharmaceutical world. “Its rare that an old cardiovascular drug ends up teaching us something new about the brain,” notes Megan L. Matthews,an assistant professor in the Department of Chemistry at the University of Pennsylvania and a lead investigator on the project. “But that’s exactly what we’re hoping to find more of – unusual links that could spell new solutions.”
The implications extend beyond hydralazine itself. The team is now focused on developing new,more targeted ADO inhibitors. these next-generation drugs will be designed to specifically target tumor tissue, maximizing efficacy while minimizing side effects. A key challenge is improving the drugs’ ability to cross the blood-brain barrier, a protective mechanism that often hinders drug delivery to the brain.
Looking Ahead: Building on a Foundation of Discovery
This research, supported by grants from the National Institutes of Health, the National Science Foundation, and several foundations, represents a significant step forward in understanding the complex interplay between oxygen sensing, vascular health, and cancer biology.It underscores the importance of investigating the mechanisms of action of established drugs, potentially unlocking hidden therapeutic benefits.
The team’s ongoing work promises to not only refine existing treatments for preeclampsia and gl
