The natural substance is a cell toxin known as BE-43547, which is normally only produced by bacteria in the soil and the sea floor, where oxygen is scarce. And this scarcity of oxygen is crucial. The cell toxin only attacks cells which basically don’t need oxygen (hypoxic cells).

This means that some time in the future BE-43547 could potentially be an effective weapon against the hypoxic cancer cells that survive the lack of oxygen inside growing cancerous tumours and that contribute to metastasis. Hypoxic cancer cells are resistant to radiation therapy and several types of chemotherapy.

In 2016, researchers at Aarhus University succeeded in synthesizing an exact copy of the substance, and since then laboratory tests and pre-clinical trials (on mice) have demonstrated that BE-43547 can quickly and efficiently kill hypoxic cells but leave normoxic cells in peace. The substance is very toxic in high doses, but in small doses it seems harmless - until, that is, you rob the cells of oxygen and thereby make them hypoxic. Then they will be poisoned to death within just a few hours.

Regulated suicide

"The next step in the development of this substance class was to understand how to get the cancer cells to die. It should preferably work differently than the existing treatments, because otherwise there’s no point in continuing with it. Now we've found that BE-43547 does this by damaging the cells ' mitochondria, thereby causing them to commit suicide in a way that we haven't seen before," says Associate Professor Thomas Bjørnskov Poulsen, whose laboratory at the Department of Chemistry at Aarhus University specialises in locating and copying natural substances that work against cancer.

Science is familiar with several different forms of so-called regulated suicide at cellular level. The most well-known is called apoptosis. For normal cells, this is a part of the body's natural balance. Cells are programmed to die and be absorbed by neighbouring cells or the immune system when they are damaged or become superfluous. But this suicide programme is put out of function in some cancer cells, which continue to divide, even if they are damaged. That’s why it is important to find new substances that can make cancer cells succumb in ways that do not involve these well-known suicide mechanisms.   

Using various microscopy techniques, researchers can see BE-43547 inside the cells' mitochondria, where the substance is not toxic as long as the oxygen level is normal. But as the oxygen level falls, the toxicity rises. After a couple of hours, the structure and function of the mitochondria have been destroyed and the cells are dead.

Many disciplines and many attempts

The new discovery is the result of a collaboration between researchers from no fewer than 11 different departments and sections at Aarhus University and Aarhus University Hospital, and as recently published in the journal Cell Chemical Biology.

"There have been many attempts to find clinically useable methods to eliminate hypoxic tumour cells, and one of them involves targeting and killing them. This is the approach being investigated by Thomas Poulsen's research group and partners. The novelty in our approach is that the cell toxin is a natural product rather than a chemical product and its effect mechanism is different from the treatments we have already or that are under development. This means that it may avoid some of the negative factors that have blocked the development of these other treatments," says Prof. Michael R. Horsman from the Department of Clinical Medicine at Aarhus University Hospital and the Department of Experimental Clinical Oncology at Aarhus University Hospital.

Still a long way to go

Both Michael Horsman and Thomas Poulsen stress, however, that there is still a long way to go before the natural substance finds its way to clinical trials, let alone treatment of cancer patients.

They point out that, because this is a natural substance, there is nothing to take out patents on, and therefore it is difficult to make the pharmaceutical industry interested in financing development.

"Furthermore, we’ve yet to find the protein that the toxin attacks, although it is probably in the mitochondria. And then we have to link it with the cell-death mechanism. We know that the toxin breaks the mitochondria into pieces, but we don’t know why. Furthermore, we don’t know the down side of these substances. They are large and complex molecules, and this increases the risk of adverse effects, even though we haven’t seen any yet. Perhaps the secret lies in just this complexity. If, in the future, we can achieve a precise understanding of the protein it works on, we’ll be able to test 100,000 other molecules against the protein, and perhaps we’ll be able to find a much simpler molecule with the same effect," explains Thomas B. Poulsen.

Further information:

The article in Cell Chemical Biology: APD-containing cyclolipodepsipeptides target mitochondrial function in hypoxic cancer cells

Contact:

Associate Professor Thomas B. Poulsen

Department of Chemistry
Aarhus University
Email:  thpou@chem.au.dk
Mobile: +45 6114 1844