Decades-Old Blood Pressure Drug Hydralazine Reveals unexpected link to Brain Cancer Treatment
A widely used medication for high blood pressure, hydralazine, has finally had its molecular mechanism of action revealed after 70 years, offering potential new avenues for treating both preeclampsia and aggressive brain cancers like glioblastoma. Researchers at the University of Pennsylvania, in collaboration with scientists across the globe, have discovered that hydralazine works by blocking an oxygen-sensing enzyme, a finding published recently in Science Advances.
For decades, hydralazine has been a critical first-line treatment, notably for preeclampsia – a hypertensive disorder affecting 5 to 15% of maternal deaths worldwide. Though, its precise method of operation remained a mystery, a relic of an earlier era of drug revelation where observation preceded detailed biological understanding.”It came from a ‘pre-target’ era of drug discovery,when researchers relied on what they saw in patients first and only later tried to explain the biology behind it,” explained a physician-scientist involved in the study.
The breakthrough centers on 2-aminoethanethiol dioxygenase (ADO), an enzyme the team identified as hydralazine’s target.ADO acts as a rapid-response “alarm bell” within blood vessels, triggering constriction when oxygen levels fall.”ADO is like an alarm bell that rings the moment oxygen starts to fall,” said a lead researcher. “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.”
Hydralazine effectively “mutes” this alarm by binding to and blocking ADO.This silencing allows for the stabilization of regulators of G-protein signaling (RGS) proteins,which then signal blood vessels to relax,reducing calcium levels – the “master regulator of vascular tension” – and ultimately lowering blood pressure.
But the implications extend far beyond maternal health. Prior research had hinted at a role for ADO in glioblastoma,an aggressive form of brain cancer where tumors frequently enough thrive in low-oxygen environments. Elevated ADO levels were correlated with more aggressive disease progression, suggesting that inhibiting the enzyme could be a therapeutic strategy. “To see if hydralazine was a contender, we worked closely with structural biochemists and neuroscientists,” a researcher stated.
The team’s findings revealed that the same ADO pathway involved in regulating blood vessel constriction also plays a role in tumor cell survival. Unlike traditional chemotherapy, which aims to kill cancer cells outright, hydralazine induced cellular senescence – a state of dormancy – in glioblastoma cells, effectively pausing their growth without triggering inflammation or resistance. .
This discovery highlights the potential of repurposing existing drugs for new applications. researchers are now focused on developing new ADO inhibitors that are more targeted and can effectively cross the blood-brain barrier, maximizing their impact on tumor tissue while minimizing side effects.
“Its rare that an old cardiovascular drug ends up teaching us something new about the brain,” noted a senior researcher, “but that’s exactly what we’re hoping to find more of — unusual links that could spell new solutions.” The work underscores the value of revisiting established treatments to unlock hidden therapeutic potential, paving the way for safer and more effective interventions
