Possible new principle for cancer therapy

Humans need the chemical element selenium for good health. The selenium-containing enzyme thioredoxin reductase 1 (TrxR1) can be used to support the growth of various cells and to protect them from harmful forms of oxygen radicals, known as oxidative stress. Selenium intake has long been a topic of discussion in connection with cancer, although results have proved inconclusive and the correlation between selenium intake and cancer growth is extremely complex.

Raised levels of TrxR1 can be seen in several forms of cancer and are linked to worse prognoses in head and neck, lung and breast cancers. Researchers therefore analysed almost 400,000 different molecules in the search for new and more specific TrxR1 inhibitors than those previously available. They discovered three different molecules that met their search criteria. Sure enough, when tested, these same molecules also proved to be active as cancer medicines. It proved possible to effectively treat over 60 different types of cancer cell under laboratory conditions. Normal cells were however much less sensitive to these molecules.

Sensitive to oxidative stress

“This effectiveness against cancer may be a result of cancer cells’ seemingly greater sensitivity to oxidative stress when compared to normal cells, which in turn can be utilised in cancer therapy,” says Professor Elias Arnér, Department of Medical Biochemistry and Biophysics at Karolinska Institutet, who led the study.

Researchers also found rapid tumoricidal effects when treating head and neck or breast cancers in mice, without obvious side-effects. The new molecules have yet to be tested on humans, but it is already known that several different cancer medicines currently in use, including cisplatin and melfalan, inhibit TrxR1. Thus far, whether or not this inhibition of the enzyme is important to the effectiveness of these medicines has remained unknown, but this study suggests that this might well be the case. Researchers now intend to further develop the new TrxR1 inhibitors to offer a new form of cancer therapy.

Effective against multiple forms of cancer

“My hope is that we will be able to develop new treatments, effective against multiple forms of cancer but with few side-effects. This seems to work in mouse models and we are therefore hopeful that this principle for treatment can be developed for humans, even if this will require many years of further research,” says Elias Arnér.

The study has been carried out in collaboration with researchers at the National Institutes of Health (NIH) in the United States.

This research was funded by Karolinska Institutet, the Swedish Research Council, the Swedish Cancer Society, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, NIH, National Center for Advancing Translational Sciences, the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and Oblique Therapeutics AB.

Elias Arnér and NIH are listed as applicants for three patents based on the discoveries made in this study, with several co-authors named as co-inventors. Owe Orwar and William C Stafford are employees and shareholders in a company that develops TrxR1 inhibitors for clinical use.

Publication

”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 och Elias S.J. Arnér
Science Translational Medicine, online 14 February 2018, doi: 10.1126/scitranslmed.aaf7444