Scientists solve mystery of why arsenic works in cancer drugs

Since the 18th century, several arsenic compounds have been used as medicines, including arsenic trioxide (ATO) which is commonly prescribed in the treatment of certain types of cancer. Although they prove to be effective, no one knows how these compounds work.

Now, a group of European scientists have found the answer. They identified the mechanism by which arsenic compounds can have therapeutic properties when used to treat cancer, particularly acute promyelocytic leukaemia (APL). Their work, which is partially EU-funded, was recently published in Nature Cell Biology.

APL, a subtype of acute myelogenous leukaemia, is a rare form of cancer of the blood and bone marrow. Signs and symptoms of APL include anaemia, petechiae, fever, fatigue or weight loss. It is estimated that APL affects about 30 000 people in the EU.

The ATO compound is typically used to treat patients who are resistant to other drugs, or who have relapsed. It was identified in 1992 as the active ingredient in a traditional Chinese medicine.

Previous studies have shown how ATO breaks down the fundamental genetic material (DNA) of the cancer cell, effectively bringing on cell death. According to Professor Ronald Hay from the University of Dundee in the UK, who was lead author of the 'Arsenic action on leukaemia' study: "Our discovery is key to understanding how we can enhance the anti-cancer properties of this poison."

The results of this latest study help raise awareness about how arsenic and arsenic-related compounds can be used in the treatment of cancers, as well as in the development of new and improved treatments. "Knowing the specific molecules involved allows us to now work on creating more targeted and effective cancer drugs with fewer side effects," explains Professor Hay.

The scientists observed the drug at work in animal cells. After modifying a number of cells to remove certain proteins, they realised that the drug had different effects.

The development of APL is characterised by the fusion of the proteins promyelocytic leukaemia (PML) and retinoic acid receptor alpha (RAR alpha), causing the cells to become cancerous or leukaemic.

The scientists found that arsenic helps molecules called SUMO to stick onto the fused protein involved in leukaemia. An enzyme called RNF4 then 'pursues' the SUMO molecules, successfully breaking down the fused PML-RAR alpha protein that causes the cancer.

However, when the researchers removed the RNF4 enzyme, adding arsenic did not lead to the breakdown of the PML fusion protein. Instead, the fused PML-RAR alpha protein built up within the nucleus of the cell. When the researchers replaced the RNF4 in the arsenic-treated cells, the fused protein was broken down as normal.

From their observations, the researchers concluded that the RNF4 protein is needed for arsenic-induced breakdown of the fused protein to occur.

"Discovering which molecules are involved in this process is an exciting step forward in understanding this complex paradox - how can a chemical that causes cancer also cure it?" comments Dr Lesley Walker, Director of Cancer Information, Cancer Research UK, which co-funded the study. "It's a great piece of science that will hopefully lead to the development of drugs that hone in on specific cancer-causing proteins to beat the disease."

EU support for the study came from the RUBICON (Role of Ubiquitin and Ubiquitin-like Modifiers in Cellular Regulation) Network of Excellence, which is financed through the 'Life sciences, genomics and biotechnology for health' Thematic Area of the Sixth Framework Programme (FP6).

For further information, please visit: http://www.nature.com/ncb/index.html

Copyright ©European Communities, 2008
Neither the Office for Official Publications of the European Communities, nor any person acting on its behalf, is responsible for the use, which might be made of the attached information. The attached information is drawn from the Community R&D Information Service (CORDIS). The CORDIS services are carried on the CORDIS Host in Luxembourg - http://cordis.europa.eu. Access to CORDIS is currently available free-of-charge.

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