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Arsenic and leukaemia

Monday 14 April 2008

“Scientists solve riddle of arsenic cancer treatment” is the headline in_ The Guardian_ today. Although arsenic is poisonous and has been associated with an increased risk of cancer, paradoxically, “compounds of the metal have also been used to treat leukaemia” in the past, the newspaper adds, and it is still used to treat one form of the disease: acute promyelocytic leukaemia. The newspaper reports that scientists have now discovered how arsenic exerts its beneficial effects and that these findings “could lead to better uses for arsenic in therapies for leukaemia with fewer side effects”.

Although the findings of this experimental study will be of great interest in the scientific community, they do not immediately suggest improved ways of using arsenic to treat leukaemia, or ways of reducing the side effects of arsenic treatment.

Where did the story come from?

Dr Michael Tatham and colleagues from the University of Dundee and the University of Kuopio in Finland carried out this research. The study was funded by Cancer Research UK and the RUBICON EU Network of Excellence. It was published in the peer-reviewed scientific journal: Nature Cell Biology .

What kind of scientific study was this?

This was an experimental study looking at how arsenic affects the biochemical processes occurring in cells affected by leukaemia. Acute promyelocytic leukaemia (characterised by a deficiency of mature white blood cells and excess growth of immature cells) is usually caused by the ends of chromosomes 17 and 15 breaking off and incorrectly “swapping places”. This brings two genes together (RAR and PML) which then make an abnormal “fusion” protein. Arsenic binds to the promyelocytic leukaemia (PML) fusion protein, and this causes a chain of small molecules called SUMO to attach to the fusion protein. Once a SUMO chain has attached, this tells the cell that this protein should be broken down. The researchers were interested in how another protein called RNF4 might play a role in this process.

The researchers conducted experiment to look at the interaction of RNF4 with the PML fusion protein and SUMO in human cells grown in the laboratory. They also looked at the effects of arsenic on these cells, and whether these effects changed when the levels of the RNF4 protein were reduced.

What were the results of the study?

The researchers found that stopping the cells from producing RNF4 led to a build up of the SUMO-tagged PML fusion protein in the cells, because it was not being broken down properly. They also found that RNF4 only targeted the PML fusion protein for breakdown if it had SUMO molecules attached. They found that treating cells with arsenic led to the addition of SUMO molecules to the PML fusion protein, and to the breakdown of the PML fusion protein.

However, when the researchers stopped these cells from producing RNF4, adding arsenic did not lead to the breakdown of the PML fusion protein, instead the SUMO-tagged PML fusion protein built up within the nucleus of the cell. When they replaced the RNF4 in these arsenic-treated cells, the PML fusion protein was broken down as normal.

What interpretations did the researchers draw from these results?

The researchers concluded that the RNF4 protein is needed for arsenic-induced breakdown of the PML fusion protein to occur.

What does the NHS Knowledge Service make of this study?

This study has identified a role for the RNF4 protein in the biochemical changes that happen in cells when they are treated with arsenic. Although this finding will be of great interest in the scientific community, it does not immediately suggest improved ways of using arsenic to treat leukaemia, or ways of reducing the side effects of arsenic treatment.

Sir Muir Gray adds...

To kill leukaemia cells you need a killer chemical; almost all cancer treatment uses chemicals with a high level of risk, like arsenic nut. When you have leukaemia, or any other cancer, the risks are worth running if there is a chance of benefit.

Analysis by Bazian
Edited by NHS Website

Links to the headlines

Arsenic used to treat leukaemia.

BBC News, 14 April 2008

Scientists solve riddle of arsenic cancer treatment.

The Guardian, 14 April 2008

Links to the science

Tatham MH, Geoffroy M-C, Shen L, et al.

RNF4 is a poly-SUMO-specific E3 ubiquitin ligase required for arsenic-induced PML degradation.

Nat Cell Biol 2008; Apr 13 [Epub ahead of print]