Reactive oxygen is rather useful – it bleaches dirty laundry, and our bodies use it to kill invading bacteria – but too much may cause cancer. At the University of Groningen, chemists and medical scientists have joined forces to learn more about the power of oxygen.
‘You hear a lot these days about reactive oxygen, but this is often poorly defined. To a chemist, reactive oxygen species are a class of some twenty different compounds.’ Associate Professor of Biomolecular Chemistry Gerard Roelfes knows his oxygen: for his PhD he studied an oxidative organic iron complex, which was seen as a potential bleaching agent in washing powder. ‘But we also used this complex as a model system to study oxidative enzymes.’
Some twenty years later, Roelfes has formed a research group with about a dozen members, and is working on several different projects. One of these still relates to the iron complex from his PhD days. But this time, the focus is on cancer and ageing research.
‘There is an anti-cancer agent called bleomycin that acts by cutting the DNA of cancer cells. It does that by using iron-mediated oxidation. Our synthetic iron complex, iron-N4Py, can be used as a model to study the actions of bleomycin.’ And that is what one of Roelfes’ PhD students did. But she also proposed testing the ability of N4Py to kill cancer cells.
‘I was very sceptical about it’, he recalls. ‘When we studied it as a bleaching agent in washing powder, all sorts of toxicity studies were performed, and it wasn’t toxic at all.’ Nevertheless, he contacted Marianne Rots, a biomedical scientist at the University Medical Center, UMCG. ‘As it turned out, our compound was remarkably active in a cell assay.’ A paper detailing the effectiveness of ‘synthetic bleomycin mimics’ was published in ACS Chemical Biology in February.
The collaboration with Professor Rots led to a NWO research grant in chemical biology. ‘This grant programme is aimed at using tools from chemistry to study biological processes.’ The aim of the Roelfes/Rots collaboration is to learn more about reactive oxygen species in the cell.
‘The beauty of the system is that we can modify the N4Py molecule any way we want’, explains Roelfes. The molecule looks a bit like a basket, with an iron atom inside. The basket is made up of four ring structures. ‘We know exactly how to attach different chemical groups to these rings’, says Roelfes. For example, a side chain that binds to DNA may make the compound more active in DNA cleavage.
‘But our aim is not to design a DNA-cleaving anti-cancer agent. What we are doing is creating tools to study the action of reactive oxygen species.’ One modification of the N4Py molecule causes fluorescence in the presence of superoxide. ‘Superoxide is often generated as a first step to different reactive oxygen species, but it is difficult to visualize.’
Roelfes provides modifications to N4Py that will respond to different reactive oxygen species, and Rots uses these molecules to probe inside cells. ‘Furthermore, we can also attach an “address label” to the molecule, which will send it to a specific location inside the cell’, Roelfes continues. ‘We can then use our molecule to produce extra reactive oxygen species at specific locations and study their effect.’
Reactive oxygen isn’t bad in itself. The body produces a lot for physiological purposes, like killing invading microorganisms, but when there is too much of a good thing, the cell can get into trouble. ‘And that is how reactive oxygen can play a role in cancer, ageing or neurological diseases.’
The key is to understand how reactive oxygen acts in the cell. ‘We know a lot about oxidative reactions outside the cell. Now we want to find out how oxidative stress can cause a normal cell to become cancerous.’ The partnership between chemistry and biomedicine is a very promising way to make progress. ‘We are halfway through a four-year project, and the first paper is out.’
For Roelfes, this is just one of the themes he is working on. ‘We’re also developing new catalysts, inspired by biomolecules. And we’re using DNA to assemble complex molecular systems.’ The collaboration with Rots was an unplanned development, sparked by a question from a PhD student. ‘It shows that even if you are sceptical, like I was, it pays to just go ahead and see what happens.’ And the PhD student? ‘She’s now an assistant professor in Shanghai!’
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