A groundbreaking discovery has revealed that an ancient blood pressure medication, hydralazine, could be a game-changer in the fight against aggressive brain tumors. This revelation comes from a team led by researchers at the University of Pennsylvania, who have unraveled the molecular workings of this drug, shedding light on its potential beyond hypertension treatment.
For over seven decades, hydralazine has been a frontline warrior against life-threatening high blood pressure, especially during pregnancy. However, its exact mechanism of action remained a mystery, leaving room for improvement in its efficacy and safety.
"Hydralazine is a true pioneer in the world of vasodilators, and its continued use in preeclampsia treatment highlights its importance. Yet, its development predates targeted drug discovery, leaving its biological impact somewhat of an enigma," explains Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania.
The team's recent publication in Science Advances has not only solved this puzzle but also uncovered an intriguing link between hypertensive disorders and brain cancer.
"Preeclampsia has been a silent threat to pregnant women for generations, and its impact on Black mothers in the US is disproportionately high. Understanding hydralazine's molecular action could lead to safer, more targeted treatments for pregnancy-related hypertension," says Megan Matthews, a postdoctoral adviser at Penn and a co-author of the study.
The researchers found that hydralazine blocks an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO), which acts as a molecular switch, signaling blood vessels to tighten. By binding to and blocking ADO, hydralazine effectively silences this oxygen alarm, preventing the degradation of signaling proteins called regulators of G-protein signaling (RGS).
"The buildup of RGS proteins tells blood vessels to relax, overriding the constriction signal. This, in turn, reduces intracellular calcium levels, the master regulator of vascular tension, leading to vasodilation and a drop in blood pressure," Shishikura explains.
But here's where it gets intriguing: the ADO pathway, which regulates vascular contraction, also plays a role in the survival of tumor cells in low-oxygen environments. By disrupting this oxygen-sensing loop, hydralazine triggers cellular senescence, a dormant state in glioblastoma cells, effectively halting tumor growth without causing further inflammation or resistance.
And this is the part most people miss: the potential for hydralazine to treat brain cancer.
The researchers are now focused on developing new ADO inhibitors that are more tissue-specific and can effectively cross the blood-brain barrier, targeting tumor tissue while sparing healthy cells.
"It's an exciting prospect that an old cardiovascular drug could teach us something new about brain health. We hope to uncover more of these unusual links, leading to innovative solutions for complex medical conditions," Matthews concludes.
The study, "Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma," highlights the potential for established treatments to reveal new therapeutic avenues, offering hope for safer and more effective drugs in maternal health and brain cancer.
