How Hydralazine Inhibits Growth of Glioblastoma, Study Sheds Light
USA: Researchers at the University of Pennsylvania have uncovered how hydralazine works and found that it may also inhibit the growth of glioblastoma, a highly aggressive brain tumor. These discoveries clarify the drug’s mechanism and suggest potential new treatments for preeclampsia and brain cancer.
The study, published in Science Advances by Kyosuke Shishikura from the Department of Chemistry and colleagues, sheds new light on a medication that has been used for more than 70 years without a clearly defined mechanism. Hydralazine, widely prescribed to manage preeclampsia and hypertensive emergencies, is even included on the World Health Organization’s list of essential medicines. Despite its long-standing clinical role, the precise molecular pathways through which it exerts its effects have remained elusive—until now.
The researchers identified 2-aminoethanethiol dioxygenase (ADO) as a primary and selective target of hydralazine. ADO is an important enzyme involved in targeted protein degradation, a process that regulates the stability and turnover of many cellular proteins. According to the team, hydralazine binds to ADO’s metal-containing cofactor and is capable of modifying one of the enzyme’s ligands. This interaction effectively shuts down the enzyme’s activity.
As a result of this inhibition, proteins known as RGS4 and RGS5 become stabilized in the cell. Normally, ADO flags these regulators of G-protein signaling for destruction, but with ADO blocked, their levels increase. The findings help explain hydralazine’s vasodilatory properties, as previous studies have documented reduced RGS levels in both patients with preeclampsia and in animal models of the condition. By preventing the degradation of these proteins, hydralazine appears to correct underlying dysregulation linked to abnormal blood vessel function.
The implications, however, extend far beyond pregnancy-related hypertension. Because ADO activity is also involved in the biology of glioblastoma (GBM), the team hypothesized that hydralazine could exert anticancer effects. Their cell-based experiments confirmed this: even a single dose of the drug induced strong senescence in cultured glioblastoma cells. Cellular senescence halts tumor growth by pushing cancer cells into a non-dividing state, suggesting that hydralazine—or refined versions of it—may hold therapeutic potential in combating this notoriously treatment-resistant cancer.
By connecting hydralazine’s effects to ADO, the study positions this enzyme as a critical link between two seemingly unrelated conditions: preeclampsia and glioblastoma. This revelation also opens the door for designing improved versions of hydralazine that specifically target ADO, potentially offering more effective or safer treatments for both disorders.
"Overall, the research brings long-awaited clarity to a decades-old drug and highlights how revisiting established medications with modern scientific tools can lead to entirely new therapeutic opportunities," the authors concluded.
Reference:
Shishikura, K., Li, J., Chen, Y., McKnight, N. R., Keeley, T. P., Bustin, K. A., Barr, E. W., Chilkamari, S. R., Ayub, M., Kim, S. W., Lin, Z., Hu, M., Hicks, K., Wang, X., BollingerJr., J. M., Binder, Z. A., Parsons, W. H., Martemyanov, K. A., Liu, A., . . . Matthews, M. L. (2025). Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma. Science Advances. https://doi.org/adx7687
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