Although auranofin is a gold-based complex, it has been used to treat rheumatism. However, it is being investigated as a potential treatment for specific types of cancer. Researchers from the Karolinska Institutet in Sweden have discovered that other molecules that inhibit the biological system have a more powerful effect than auranofin. This could make them more effective as cancer therapies. The results have been published in the journal Redox Biology.
WHO has classified the gold complex auranofin (AF) as an anti-rheumatic drug. It is also an active ingredient in the drug Ridaura. AF is also currently being studied in a series of clinical trials to test the possibility of cancer therapy. Researchers are intrigued by AF because it blocks the activity of thioredoxin (TrxR), an important protein to the thioredoxin-related systems that protect cells from the effects of oxidative stress across all mammal species. It also protects cancer cells, which reduces the effectiveness of cancer treatments. Moreover, TrxR, which affects the growth of cells and their survival, is upregulated in certain forms of cancer.
There’s a great deal of interest in the capability to block the thioredoxin pathway for the treatment of cancer, however, there’s a possibility that healthy cells will also be destroyed and damaged. Our goal is to get TrxR inhibitors to be as specific as is possible.”
Elias Arner, study’s co-last author, professor, Department of Medical Biochemistry and Biophysics, Karolinska Institutet
The researchers examined the effects of AF on the mouse cancer cells (lung adenocarcinoma, melanoma) and also with other TrxR inhibitors, TRi-1 (thioredoxin reducer inhibitors 1 and 2). Elias Arner’s research team recently developed TRi-1, TRi-2 and demonstrated anticancer effects in mouse models.
The study, which was based on new proteomic methods for analyzing the whole set of proteins found in cells, suggests that TRi compounds are more specific in their actions than the AF compounds. The results suggest that AF causes very high levels of oxidative stress and has additional effects that do not appear to be related to the inhibition of TrxR. They also show that TRi-1 appears to be the most specific TrxR inhibitor to date.
Roman Zubarev (a co-author of the study), is a professor at Karolinska Institutet’s Department of Medical Biochemistry and Biophysics. He says that “our findings could provide a crucial blueprint for further research on AF’s mechanism of effect and adverse effects.” “Having been able to compare AF with the more specific molecules TRi-1 as well as TRi-2 We hope that our findings contribute to the further development of TrxR inhibitors as anticancer drugs.”
The study was financed by grants from the Knut and Alice Wallenberg Foundation, Karolinska Institutet, the Swedish Cancer Society and the Swedish Research Council. Elias Arner is coinventor and patent holder of TRi-1, TRi-2 compounds. These compounds are currently being developed for use in clinical trials.
Sabatier, P., et al. (2021) Comprehensive analysis of chemical proteomics shows that the new TRi-1 and TRi-2 compounds are more specific thioredoxin reductase 1 inhibitors than auranofin. Redox Biology. doi.org/10.1016/j.redox.2021.102184.
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