A research team at the University of Pennsylvania in the United States was able to uncover the molecular mechanism by which the drug hydralazine works, which is one of the oldest blood pressure-lowering drugs and the most widely used in the treatment of pre-eclampsia in pregnant women (a medical condition that may affect pregnant women after the twentieth week and is represented by high blood pressure and the appearance of signs of damage to one of the organs, often the kidneys or liver), seven decades after its adoption in medical practice.
The biggest surprise that scientists have discovered is that the same drug is also able to stop the growth of one of the most deadly types of brain cancer, which is glioblastoma.
Despite the widespread use of hydralazine since the 1950s as a first line of defense against dangerous high blood pressure during pregnancy, which is responsible for 5 to 15% of maternal deaths globally, its molecular mechanism of action has remained mysterious, according to the scitechdaily website.
Dr. Kyosuke Shishikura, a scientist and physician at the University of Pennsylvania, points out that the drug was developed in an “era before the discovery of molecular targets,” when drugs were approved based on their clinical effects before how they worked at the cellular level was understood.
The new study, published in the journal Science Advances, found that hydralazine inhibits an oxygen-sensitive enzyme known as 2-aminoethanethiol dioxygenase (ADO), which serves as a molecular switch that determines when blood vessels should constrict. When this enzyme is disrupted, proteins that regulate vasoconstriction signals accumulate, so the vessels receive the “stop constricting” signal, which leads to them relaxing and blood pressure falling.
But the most exciting aspect was the discovery that the same biological pathway that controls vasoconstriction also plays a pivotal role in the ability of brain tumor cells to survive in low-oxygen environments, a known feature of glioblastomas.
In collaboration with the universities of Texas and Florida, the researchers used X-ray crystallography techniques to demonstrate that hydralazine binds directly to the metal center within the ADO enzyme, and then tested its effect on brain cancer cells.
The results showed that hydralazine does not kill cancer cells directly, but rather pushes them into a state of cellular senescence, which is a “dormant” state in which cell division stops without provoking inflammation or enhancing resistance to conventional treatments, which practically stops tumor growth.
Co-researcher Megan Matthews explains that understanding this mechanism opens the door to developing safer and more effective treatments for both pregnancy disorders and brain tumors, noting that pre-eclampsia still disproportionately affects black women in the United States, which makes discovering more selective treatment mechanisms crucial.
The team is currently working on designing new ADO inhibitors that are more precise and targeted, with a better ability to cross the blood-brain barrier to reach tumor tissues directly.
The researchers confirm that this type of discovery reflects the potential in re-evaluating ancient medicines, which may open unexpected therapeutic horizons in complex health fields.
