Auranofin, a gold complex that has historically been used to treat rheumatism, is now being investigated as a cancer treatment.
Other chemicals that inhibit the same biological mechanism have a more specific effect than auranofin, according to researchers at Karolinska Institutet in Sweden, and hence may have greater potential as cancer medicines. The findings were reported in the journal Redox Biology.
The gold complex auranofin (AF) is an active component of the medicine Ridaura and is classified as an anti-rheumatic agent by the WHO (World Health Organization). A number of clinical trials are presently being conducted to see if AF may be used as a cancer treatment.
The potential of AF to inhibit thioredoxin reductase (TrxR), a protein crucial to the thioredoxin system, which protects cells from oxidative stress in all mammals, is one reason for the researchers’ interest in it.
It does, however, shield cancer cells, lowering the efficacy of cancer treatments. TrxR, which regulates cellular development and survival, is also increased in several cancers.
“There’s a great deal of interest in the ability to inhibit the thioredoxin system in the treatment of cancer, but there’s a risk that healthy cells will also be damaged and killed,” says the study’s co-last author Elias Arnér, professor at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet. “Our aim is for TrxR inhibitors to be as specific as possible.”
The researchers tested the effects of AF with other TrxR-inhibiting compounds termed TRi-1 and TRi-2 in mice cancer cells (lung adenocarcinoma and melanoma) (thioredoxin reductase inhibitors 1 and 2).
There’s a great deal of interest in the ability to inhibit the thioredoxin system in the treatment of cancer, but there’s a risk that healthy cells will also be damaged and killed. Our aim is for TrxR inhibitors to be as specific as possible.
Elias Arnér
Elias Arnér’s research group has created TRi-1 and TRi-2, which have proven anticancer effects in mice models. The research implies that TRi drugs have a more precise effect than AF, based on new proteomic methods for analyzing the whole collection of proteins in cells.
The findings demonstrate that AF creates a lot of oxidative stress and has other effects that don’t appear to be related to TrxR inhibition. TRi-1 appears to be the most specific TrxR inhibitor identified to far, according to the researchers.
“Our results can serve as an important blueprint for further studies of AF’s mechanism of action and side effects,” says the study’s other co-last author Roman Zubarev, professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.
“Having now compared AF with the more specific molecules TRi-1 and TRi-2, we hope that our findings will contribute to the further development of TrxR inhibitors as anticancer drugs.”
Grants from the Knut and Alice Wallenberg Foundation, Karolinska Institutet, the Swedish Cancer Society, and the Swedish Research Council helped fund the research. TRi-1 and TRi-2 chemicals, which are now being explored for clinical application, are co-invented and patented by Elias Arnér.
