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New therapeutic approaches: nitric oxide for the treatment of brain tumours

Glioblastoma is the most common and most aggressive malignant brain tumour for which there is still no cure. Surgery, radiation and chemotherapy only have a temporary effect and relapses tend to occur a few months after surgery. Researchers led by neurosurgeon Dr. Astrid Weyerbrock from the Freiburg University Medical Centre are working on the improvement of therapies for the effective treatment of glioblastomas that involve deciphering the biological mechanisms that lead to these complex brain tumours. They are using a volatile molecule that is also found in the earth’s atmosphere. How can nitric oxide help? And how does it work?

Magnetic resonance image of a human glioblastoma © Dr. Astrid Weyerbrock

Glioblastomas affect just two to three people out of 100,000, predominantly in the fifty to seventy year-old age range. Once people develop these so-called astrocytes, they only have a few more months to live. Astrocytes usually arise in the connective tissue of the brain (astrocytes are glial cells, not nerve cells) and are well supplied with blood, divide rapidly, are very invasive and can become very large. They can also invade healthy brain tissue before a doctor detects them. Only the part that is visible in a nuclear resonance image can be surgically removed and relapses tend to occur six to twelve months after surgery. “During a research stay in the USA around ten years ago, I found that a standard chemotherapeutic drug had a greater effect in rats with glioblastomas when it was administered along with the gas NO (nitric oxide),” said Dr. Astrid Weyerbrock, a neurosurgeon who now works at the Neurocentre at the Freiburg University Medical Centre where she heads up a neurooncology research group. Weyerbrock’s scientific work concentrates on the gas nitric oxide.

Enabling drugs to cross the blood-brain barrier

It has been known since the early 1990s that NO is an important cell signalling molecule in humans and other mammals. The gas exerts its most prominent physiological effect on blood vessels by dilating them, thereby enhancing blood flow throughout the body. During her stay at the National Institutes of Health (NIH) in Bethesda/USA, Weyerbrock showed that nitric oxide is able to open the blood-brain barrier, i.e. the barrier that normally prevents the medical treatment of brain tumours because therapeutically active chemotherapeutics concentrations are effectively blocked from entering the brain. The problem is that NO is a gas and hence volatile. Donors are needed to transport NO to the desired location in the brain. The donors are molecules that only release nitric oxide under specific conditions (e.g., altered blood pH). The NO donor initially used by Dr. Weyerbrock released its cargo very early, namely at the blood-brain barrier. A new generation of NO donors are now available that react to certain molecules, for example the molecule glutathione S transferase, an enzyme that is present in large quantities in glioblastomas. Using glutathione S transferase-activated NO donors enables the researchers to specifically target the tumour tissue, whilst sparing the surrounding tissue.

During their work with the new NO donors, Weyerbrock and her team also found out that NO can have a toxic effect on brain tissue. “After we had carried out the initial investigations we asked ourselves why our experimental animals responded more effectively to chemotherapeutic treatment when they were also exposed to NO,” said Weyerbrock. “Does the gas only improve the transport of the drug into the brain or does it also attack the tumour cells?” The researchers from Freiburg have since been able to show with glioblastoma cell cultures that NO also attacks tumour cells. They tested different NO donor types: those that bound NO only temporarily exert their effect at the moment they reach the blood-brain barrier. However, the new generation of NO donors, which are able to reach brain tumour cells, can switch on several death cascades in the cells and stop cell division. Another hypothesis, which the researchers have been able to substantiate with experiments, holds that NO increases the sensitivity of tumour cells to chemotherapeutic drugs because it switches off the DNA repair mechanisms that tumour cells usually use to protect themselves against the effect of drugs. The researchers succeeded in boosting the effect of the drug temozolomide, which is standard glioblastoma therapy, by the simultaneous application of NO donors. Weyerbrock and her team will now focus on finding further evidence to support this hypothesis. 

The figure shows two columns with three photos each that show blue and green spheres against a black background. The number of green spheres gradually decreases from the top left to the bottom right.
Immunocytochemical images showing the inhibition of glioblastoma cell proliferation using BrDU (green fluorescent). The concentration of the NO donor JS-K added to the cells increases from the above left to the bottom right, and the proliferation of the cells decreases as the quantity of JS-K increases. © Dr. Astrid Weyerbrock

Looking at molecular mechanisms

Animal experiments have shown that combined therapy with NO and a chemotherapeutic drug is more effective in treating glioblastomas than the drug alone. However, the probability of survival does not increase. “The selectivity of the substances and their ability to cross the blood-brain barrier still needs to be improved,” said Weyerbrock. The clinical application of this type of glioblastoma therapy is still far off. The researchers from Freiburg will continue looking at the basic aspects associated with the treatment of glioblastomas. They have already been able to show that high NO concentrations are able to prevent glioblastoma cells from invading healthy brain tissue. This anti-infiltration property needs to be investigated further. There is also initial evidence that the combination of NO with radiation therapy is also quite effective and Weyerbrock and her team are also working on coming up with further evidence that this is the case.

Their ultimate goal is to investigate glioblastoma cells on the molecular level: what happens on the level of signalling molecules and genes when nitric oxide enters glioblastoma cells? Which intermediary products of the NO metabolism are formed? Which genes do the cancer cells switch on in response to NO exposure? In order to achieve greater control over the processes, Weyerbrock and her team are working with microsystems engineers from the University of Freiburg to develop a Petri dish equipped with chemical sensors that help monitor the molecular processes.

The application of nitric oxide is still far from clinical application. And if NO is used some time in the future for the treatment of glioblastomas it will nonetheless only be one of the many ways of attacking glioblastomas, these extremely complex tumours that rapidly adapt to therapies. But who knows, maybe the gas will at least be able to make life more difficult for these particular brain tumours.

Further information:

Dr. Astrid Weyerbrock
Head of Department
Freiburg University Medical Centre
Breisacher Straße 64, D-79106 Freiburg
Tel.: 0761/ 270 - 500 70
Fax: 0761/ 270 - 510 20
E-mail: astrid.weyerbrock(at)uniklinik-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/new-therapeutic-approaches-nitric-oxide-for-the-treatment-of-brain-tumours