Guarding against cancer

Researchers from the University of Dundee have shown that a drug previously used to treat Type II diabetes could potentially be used to protect against cancer.

A study carried out by Professors Grahame Hardie and Doreen Cantrell has shown that the drug phenformin protects mice against a type of cancer called T-cell lymphoma. It does this by switching on the protein AMPK, which was first defined by Professor Hardie in the 1980s. Subsequent research at Dundee showed a link between AMPK and cancer.

AMPK was known to be activated by another anti-diabetic drug, metformin, and scientists at the University found that the use of metformin in people with Type II diabetes was associated with a lower incidence of cancer compared with other treatments.

This led Professors Hardie and Cantrell to investigate further the potential of metformin to protect against cancer, only for their results to cause them to switch their attention to phenformin.

“Our idea was to test whether this apparent protective effect of metformin was due to activation of AMPK in the cancer cells themselves,” said Professor Hardie. “To do this, we used a mouse strain prone to developing T-cell lymphoma. When we removed AMPK from the mouse T cells, they developed lymphoma earlier and the disease was more aggressive, showing that AMPK protects against lymphoma development.

“We also tested whether treatment with metformin protected against the cancer by activating AMPK in the cells giving rise to the cancer. Surprisingly, it did not, because it could not enter those cells. However, a related drug called phenformin did work, as long as treatment was started before the disease became evident.

“We now think that the apparent protective effect of metformin in humans was due to activation of AMPK not in the cancer cells themselves, but elsewhere in the body, which protects against cancer indirectly by lowering insulin levels. On the other hand, the protective effect of phenformin is due to activation of AMPK within the cells that give rise to the cancer, a mechanism that is likely to be applicable to other forms of cancer.”

In 2003, Professor Hardie and his colleague Professor Dario Alessi had shown that another protein called LKB1 was required to switch on AMPK. Mutations in the LKB1 gene were known to cause an inherited predisposition to cancer in humans, called Peutz-Jeghers Syndrome, and it was these findings that established a link between AMPK and cancer for the first time.

Phenformin was often used to treat Type II diabetes until the late 1970s, but was dropped in favour of metformin because it very rarely caused a dangerous side-effect called lactic acidosis.

Professor Hardie continued, “If our findings can be applied to humans, individuals at high risk of developing cancer might be treated with phenformin. The small risk of lactic acidosis caused phenformin to be dropped for use in diabetes, but may be more acceptable if it was used as an anti-cancer agent.”

Professors Hardie and Cantrell have published their work in the latest edition of the journal Cell Reports.

The research was funded by Cancer Research UK and the Wellcome Trust.

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