27 February 2018

Small molecules that interfere with the cell's protection against harmful oxygen compounds can kill cancer cells. This has been shown by a multicentre team of researchers with members from Karolinska Institutet and LiU. The scientists hope that the molecules can eventually form the basis of anticancer treatments in humans.

3D illustration of dividing cancer cellsA high cell division rate is a common feature of cancer cells. Photo credit: selvanegra/iStockThe oxygen we breathe is, of course, vital to life, but it can also cause harm. During the natural metabolism that takes place in the cell, small amounts of variants of oxygen compounds, known as "reactive oxygen species", or "ROS", are formed. These can damage proteins and DNA. The phenomenon is known as "oxidative stress" and may be the Achilles heel of cancer cells. A new study, published in Science Translational Medicine, led by Professor Elias Arnér of Karolinska Institutet describes how researchers have used this weakness in tumour cells.Stig LinderStig Linder

"Tumour cells are exposed to high levels of oxidative stress. They divide more often than healthy cells, and their metabolism is higher, which means that large quantities of ROS are formed. It is an interesting idea to act against the protection against oxidative stress, which is a general process in cancer cells in various organs," says Stig Linder, professor at the Department of Medical and Health Sciences at LiU and the Department of Oncology-Pathology at Karolinska Institutet, one of the researchers behind the study.

Both healthy cells and cancer cells have two protective systems that counteract the damaging effects of oxidative stress. Previous work in the laboratory has shown that substances that inhibit both protective systems at the same time also kill the healthy cells and give serious adverse effects. This led the researchers behind the new study to seek substances that affect only one of the systems, the thioredoxin system. They examined a huge library of nearly 400,000 small molecules to find substances that specifically inhibit the enzyme thioredoxin reductase 1, TrxR1. They found two molecules with the properties they sought.

"We found that these molecules inhibit tumour growth. They are more specific against thioredoxin reductase 1 than other substances that also inhibit the thioredoxin system, and thus we hope that they will have fewer adverse effects", says Stig Linder.

Future anticancer drugs?

In the laboratory, the molecules have shown promising effects against 60 different forms of cancer cells in culture. Normal cells are less sensitive to the molecules than tumour cells. The researchers have also tested the treatment of tumours in mice with one of the molecules, and shown that it reduces tumour growth without obvious adverse effects. So far, the new substances have been tested only in mice, but the researchers are hoping in the long term to develop a new form of cancer treatment.

"I hope that it will be possible to develop a new anticancer treatment that is effective against several forms of cancer, with few adverse effects. It seems to work in mice, and this leads us to hope that the principle can be developed for use in humans. Many years of further research, however, will be needed," says Professor Elias Arnér of Karolinska Institutet.

The research has received financial support from, among other sources, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, Karolinska Institutet, the National Institutes of Health (NIH) and Oblique Therapeutics AB. The work has been carried out in collaboration with researchers at the NIH in the US. Several of the researchers are co-inventors for patent applications based on results from the study, and two of the researchers are employees and shareholders in a company that develops inhibitors of TrxR1.

The article: "Irreversible inhibition of cytosolic thioredoxin reductase 1 as a mechanistic basis for anticancer therapy", William C. Stafford, Xiaoxiao Peng, Maria Hägg Olofsson, Xiaonan Zhang, Diane K. Luci, Li Lu, Qing Cheng, Lionel Trésaugues, Thomas S. Dexheimer, Nathan P. Coussens, Martin Augsten, Hanna-Stina Martinsson Ahlzén, Owe Orwar, Arne Östman, Sharon Stone-Elander, David J. Maloney, Ajit Jadhav, Anton Simeonov, Stig Linder and Elias S. J. Arnér, 2018, Science Translational Medicine 10(428), published 14 February 2018, doi: 10.1126/scitranslmed.aaf7444


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