New method to stop cells dividing 'could stop cancer spreading'

A drug that could stop cancer in its tracks is being developed by scientists.

It shuts down a specific protein that fuels the spread of tumours.

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Targeted therapy is a relatively new approach to curing the disease. It homes in on individual chemicals that cause cells to divide and multiply.

Stopping this process is the 'Holy Grail' for cancer researchers and although penetrating their outer shell, or membrane, is extremely difficult, the Swedish and British team have now found a way to do just that.

They say the method, described in the journal Cell Chemical Biology, can be used to combat the UK's third biggest killer. Only dementia and heart disease claim more lives.

Turning off enzymes that are important for the survival of growing cells is a promising strategy.

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But to be able to destroy one particular type out of the thousands in the body, a medication has to be tailored to an exact fit.

That is particularly hard for membrane proteins, since they only function when there is a further coating of fat, or 'lipid' - called an envelope - surrounding them. This means they often cannot be studied in isolation.

But using state of the art instruments the researchers discovered how anti-cancer drugs can bind to the membrane protein DHODH (dehydroorotate dehydrogenase). This helps cancer cells to survive and thrive.

Better binding

Professor Michael Landreh, of the Karolinska Institute in Sweden, said: "To our surprise, we saw that one drug seemed to bind better to the enzyme when lipid-like molecules were present."

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His team, which included colleagues at Oxford University, also found DHODH produces a lipid present in the cell's mitochondrial DNA that powers it.

Prof Landreh said: "This means the enzyme might use special lipids to find its correct place on the membrane."

The researchers combined computer simulations with a technique called native mass spectrometry where a protein is removed from its normal environment and accelerated into a vacuum chamber.

By measuring the time it takes for it to fly through, it is possible to determine its exact weight.

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They used this highly accurate 'molecular scale' to see how lipids, which are the building blocks of the cell membrane, and drugs bind to DHODH.

To understand why lipids can help a drug recognise its target, the computer simulations explored the structure and dynamics of DHODH.

These included both its free environment, as well as while being attached to a cell membrane.

Dr Erik Marklund, of Uppsala University, said: "Our simulations show the enzyme uses a few lipids as anchors in the membrane.

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"When binding to these lipids, a small part of the enzyme folds into an adapter that allows the enzyme to lift its natural substrate out of the membrane.

"It seems the drug, since it binds in the same place, takes advantage of the same mechanism."

Cancer kills 160,000 in the UK each year. But most tumours only become lethal once they spread, a process known as metastasis.

But it is hoped doctors will soon be able to prevent this simply by identifying, and 'switching off', particular molecules upon which they depend. Cancer scientists around the world are now focusing on this.

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Metastasis is thought to be the last stage of cancer as the tumour mutates making cells more mobile, able to enter the bloodstream and sticky enough to anchor down on bones, lungs, liver and other organs.

Co author Sir David Lane, of the Karolinska Institute, added: "The study helps to explain why some drugs bind differently to isolated proteins and proteins that are inside cells.

"By studying the native structures and mechanisms for cancer targets, it may become possible to exploit their most distinct features to design new, more selective therapeutics."

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