Brain tumours: A Penn-led research team has finally pinned down how hydralazine, one of the world’s oldest antihypertensives and a mainstay for preeclampsia, acts inside the body. In the process, they uncovered a surprising second act: the drug can push fast-growing brain tumour cells into a growth-arrested state.
Published in Science Advances, the study explains that hydralazine blocks an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO). ADO acts like a rapid “oxygen alarm,” triggering blood vessels to constrict. When hydralazine binds to and inhibits ADO, it prevents the breakdown of regulators of G-protein signalling (RGS) proteins.
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The resulting buildup of RGS lowers intracellular calcium, the key driver of vascular tension, allowing smooth muscle in vessel walls to relax and blood pressure to fall.
Hydralazine has been used for roughly 70 years, particularly in pregnancy-related hypertension, but its precise mechanism has been unclear. The new work, led by physician-scientist Kyosuke Shishikura with senior author Megan Matthews at the University of Pennsylvania, closes that gap and links vascular biology to oncology.
Cancer researchers have suspected that ADO also helps glioblastoma survive in low-oxygen niches. Collaborating with structural biochemists at the University of Texas, the team visualised hydralazine docking at ADO’s metal centre using X-ray crystallography, and with neuroscientists at the University of Florida, showed the drug disrupts ADO signalling in glioblastoma cells. Rather than killing cells outright, hydralazine induced senescence, a dormant, non-dividing state, effectively halting tumour growth without adding inflammatory stress.
The authors say the findings open two paths: refining pregnancy-safe antihypertensives by targeting ADO more selectively, and designing next-generation ADO inhibitors that better reach brain tissue to treat glioblastoma. Follow-on work will focus on tissue-specific chemistry and strategies to traverse or exploit weak points in the blood–brain barrier.
