A team led by researchers from the University of Pennsylvania has discovered that hydralazine, a longstanding treatment for high blood pressure, has the potential to impede the growth of aggressive brain tumors. This finding sheds light on the drug’s previously unknown mechanism of action, revealing a significant link between hypertensive disorders and brain cancer.
Hydralazine has been an essential medication for over 70 years, primarily used to treat life-threatening high blood pressure, particularly during pregnancy. Kyosuke Shishikura, a physician-scientist at the University of Pennsylvania, noted its importance in managing preeclampsia, a pregnancy-related hypertensive condition responsible for 5% to 15% of maternal deaths globally. Despite its long history, the molecular workings of hydralazine remained unclear until now.
In a study published in Science Advances, Shishikura and his colleague Megan Matthews identified how hydralazine functions at the molecular level. They found that the drug blocks an oxygen-sensing enzyme called 2-aminoethanethiol dioxygenase (ADO), which typically signals blood vessels to constrict in low-oxygen environments. By inhibiting ADO, hydralazine effectively “mutes” this alarm, preventing blood vessels from tightening and consequently reducing blood pressure.
Shishikura explained, “ADO is like an alarm bell that rings the moment oxygen starts to fall. Hydralazine skips the usual biochemical processes and flips a switch in seconds.” This swift action causes a drop in intracellular calcium levels, the primary regulator of vascular tension, leading to vasodilation and lower blood pressure.
The implications of this research extend beyond hypertension. Prior to this study, scientists had suspected that elevated levels of ADO were linked to glioblastoma, a highly aggressive brain cancer. Shishikura pointed out that tumors often survive in low-oxygen pockets, making ADO a critical target for potential therapies. Researchers began to explore whether hydralazine could disrupt this pathway, ultimately leading to a new understanding of how existing medications might be repurposed.
To investigate further, Shishikura collaborated with structural biochemists at the University of Texas and neuroscientists at the University of Florida. They found that hydralazine not only inhibits ADO but also induces a state known as cellular “senescence” in glioblastoma cells. This state halts tumor cell growth without causing inflammation or resistance, a significant advantage over traditional chemotherapy.
As research continues, the team aims to develop new ADO inhibitors that can target tumor cells more effectively while minimizing impact on healthy tissue. Matthews emphasized the potential for this research to lead to safer treatments for both pregnancy-related hypertension and brain cancer. “It’s rare that an old cardiovascular drug ends up teaching us something new about the brain,” she stated, expressing hope for more discoveries that could provide innovative solutions to complex health issues.
In conclusion, the findings from this research not only elucidate the mechanism of hydralazine but also open doors for new therapeutic strategies. The ongoing work could significantly improve outcomes for patients affected by both preeclampsia and glioblastoma, illustrating the lasting impact of established medications in advancing modern medicine.
