A team of researchers led by the University of Pennsylvania has uncovered how one of the world’s oldest blood pressure medications, hydralazine, actually works. In the process, the scientists made another surprising discovery that the same drug could potentially be slowing the growth of one of the most aggressive forms of brain cancer, glioblastoma.
The drug hydralazine has been in use for close to 70 years, mainly as a primary medication in life-threatening hypertensive disorders in pregnant women. Despite this long history, the mode of action has always been unclear to scientists. The only thing the physicians knew was that the drug was effective, but the process was unclear. Meanwhile, the mystery has now been resolved.
According to Dr. Kyosuke Shishikura, a physician-scientist at Penn, hydralazine was derived from the early days of pharmaceutical research, when the use of drugs was based upon the observation made in the clinic, prior to the detection of the involved mechanisms. The molecular basis, as well as the surprising potential use of hydralazine, has been identified in the latest research of his team, published in the journal Science Advances.
The scientists found that hydralazine prevents the action of an oxygen-sensing enzyme called ADO. This enzyme can be thought of as an oxygen alarm in the body, sending signals to the blood vessels to constrict when it senses the lack of oxygen. By inhibiting the enzyme ADO, the “oxygen alarm” is turned off, giving way to the accumulation of the protein that has the opposite effect of dilating blood vessels. This reduces the amount of calcium inside the blood vessels, causing the muscles to relax, and subsequently reducing blood pressure.
The most surprising result, though, was in the role that ADO has in the brain. Glioblastoma cancer tissues tend to reside in hypoxic regions, and previous research indicated that ADO was important for cancer cells adapting to this severe microenvironment. Until this research, there was no way to specifically turn off this enzyme.
However, hydralazine upended this model of operation. Together, the Penn lab and a series of biochemists and neuroscientists at other universities demonstrated how the drug inhibits not just the ADO, but also the survival circuit of the tumor. Rather than eliminating the cancer, hydralazine steers the glioblastoma cells into dormancy, effectively “pausing” the tumor’s growth instead of triggering another inflammatory reaction in the process.
The results provide an avenue for the development of more targeted ADO-blocking agents that could work better in the brain, as well as having fewer side effects in the pregnant population.
In a statement made by Megan Matthews, senior author of the study, “It’s uncommon for a drug that has been around for so long to show us something entirely new related to brain function”. In essence, this finding indicates that revisiting known drugs could result in unexpected breakthroughs, perhaps giving hope to people suffering from aggressive brain cancer.
