After 70 Years, This Hypertension Drug Uncovers Surprising Anti-Cancer Properties

Despite more than 70 years of clinical use, the mode of action of hydralazine, the reference drug for hypertension, remained unknown. Used in particular to treat preeclampsia, a serious pathology affecting millions of pregnant women around the world, this molecule was rediscovered using structural biology and molecular chemistry tools.

Researchers at the University of Pennsylvania, in collaboration with several laboratories in the United States, China and the United Kingdom, have identified its target: a cellular enzyme called ADO, involved in both the regulation of blood pressure and tumor growth. Published on Science Advances, their work reveals that this ancient drug blocks a biological pathway common to two serious diseases: preeclampsia and glioblastoma, an aggressive brain cancer. A discovery that reshuffles the cards for therapeutic repositioning.

Rediscovery of a forgotten molecule: the hidden target of hydralazine

Hydralazine was one of the very first vasodilators approved for medical use. Since the 1950s, this molecule has been used urgently to treat severe hypertension, particularly in pregnant women suffering from preeclampsia. But if its clinical effectiveness is recognized, its precise mechanism of action remained unknown for a long time. But the mystery has just been solved by a team of researchers led by Megan L. Matthews and Kyosuke Shishikura at the University of Pennsylvania.

Using structural chemistry and cell biology techniques, researchers discovered that hydralazine specifically targets an enzyme called 2-aminoethanethiol dioxygenase (ADO). This enzyme, sensitive to oxygen, acts as a regulator of blood vessel tension. It degrades certain regulatory proteins as soon as the oxygen level drops, causing the vessels to contract. By blocking ADO, hydralazine inhibits this mechanism and thus promotes vasodilation.

The study details how hydralazine binds to the metal center of the ADO enzyme and prevents its enzymatic function. This blockage prevents the degradation of RGS (Regulators of G-protein Signaling) proteins. These are natural inhibitors of G protein-coupled receptors, involved in the control of blood pressure. This phenomenon explains the rapid effect of hydralazine on pressure reduction.

This understanding not only opens the way to better use of the drug, but also to the design of new, more targeted and less toxic derivative compounds. Particularly for vulnerable patients suffering from hypertensive complications during pregnancy.

ADO and glioblastoma: a common enzyme between hypertension and cancer

The involvement of ADO in vascular regulation is now established. But researchers have also discovered that this enzyme plays a central role in the biology of glioblastomas. These brain tumors are among the most aggressive and resistant. This observation marks a paradigm shift in the understanding of the links between oxygen metabolism and cancer.

Glioblastoma grows in low-oxygen (hypoxic) environments, which causes tumor cells to adapt. The Penn team observed that ADO is particularly expressed there. Indeed, it helps cancer cells to survive and proliferate despite the lack of oxygen. By blocking ADO, hydralazine interrupts this adaptation system.

Remember that conventional chemotherapy seeks to destroy tumor cells. However, here, hydralazine plunges the glioblastoma cells into a state of senescence. These cells stop dividing without dying, which slows down their expansion. The team demonstrated that this phenomenon is observed three days after treatment with doses of 10 to 30 micromoles. Senescence markers like p21, IL6 and MMP3 are significantly overexpressed.

Crystallographic analyzes carried out with partners at the University of Texas showed the direct interaction of hydralazine with the active site of ADO. At the same time, tests on glioblastoma cells carried out with the University of Florida confirmed the cessation of tumor growth.

This cytostatic action could prove valuable in cases where current therapies fail. Above all, it opens a new field. That of selective ADO inhibitors as a therapeutic alternative in brain cancers resistant to standard treatments.

Hydralazine stabilizes RGS proteins and interrupts a contraction signal

The effect of hydralazine on blood pressure is based on a very specific action at the cellular level. It prevents the degradation of certain key proteins called RGS (for
Regulators of G-protein Signaling). These proteins act as natural regulators of the signals that cause blood vessels to contract.

Normally, the enzyme called ADO quickly identifies and marks RGS proteins for destruction. This rapid elimination allows vessel contraction signals (in particular those activated by receptors called GPCRs) to be maintained. Which causes blood pressure to rise. When hydralazine is administered, it blocks the action of ADO. Result: RGS proteins are no longer destroyed, they accumulate in the cell and slow down the signals responsible for vascular contraction.

This phenomenon has been observed in human cells in the laboratory. In particular the SH-SY5Y line, often used as a model of the nervous system. After just one hour of treatment with low doses of hydralazine (10 µM), the levels of RGS4 and RGS5 proteins increased markedly. At the same time, the stimulation of certain receptors which normally cause an increase in intracellular calcium – a key signal for contraction – is largely slowed down.

This mechanism remains very specific, because it does not disrupt other oxygen-sensitive cellular pathways. Hydralazine therefore acts in a targeted manner, by keeping proteins active which deactivate contraction signals. This causes blood vessels to relax and blood pressure to drop quickly.

Towards new targeted therapies based on hydralazine

Although promising, the direct use of hydralazine in the treatment of glioblastoma remains limited by its low ability to cross the blood-brain barrier (BBB). To overcome this constraint, the researchers designed a derivative called HYZyne. It is a modified version of hydralazine with a chemical group allowing better traceability and potentially better distribution into brain tissue.

Tests performed on mice via intracerebroventricular injection showed that HYZyne selectively targets ADO in the brain. Without notable interactions with other proteins. This confirms the feasibility of a targeted pharmacological approach for neurological diseases linked to hypoxia, such as tumors or certain forms of cerebral preeclampsia.

At the same time, researchers are considering the design of new, more powerful and selective ADO inhibitors. Analysis of the structure of the ADO-hydralazine complex shows direct binding to the metal site of the enzyme. It involves the covalent modification of a histidine residue essential for its activity. This interaction serves as a basis for the design of new generation molecules, capable of specifically targeting the brain while minimizing systemic effects.

The long-term objective will be to offer treatments combining this approach with other therapies. By no longer aiming to destroy tumor cells, but to put them to sleep in a lasting manner, while preserving healthy tissues.

This repositioning of an old drug toward a new target illustrates the power of modern chemoproteomics approaches. It opens a strategic path in the treatment of diseases for which few alternatives exist. Professor Matthews' team is now working to define patient profiles likely to benefit from these future therapies.

Source: Kyosuke Shishikura et al., “Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma”. Science Advances (2025).