Scientists headed by team at the Karolinska Institutet in Sweden have identified a new approach to cancer therapy that involves blocking a single enzyme that plays a key role in how tumors respond to oxidative stress. Elias Arnér, Ph.D., and colleagues identified highly specific inhibitors of the selenium-containing TXN reductase 1 (TXNRD1) that were effective against multiple tumor types in mice, without showing any obvious toxicity to mitochondria or other cellular systems. Based on their early preclinical in vivo studies, the researchers project that targeted TXNRD1 inhibitors could represent a promising new approach to cancer therapy.
“My hope is that we will be able to develop new treatments, effective against multiple forms of cancer but with few side effects,” comments Dr. Arnér, who is based at the Karolinska Institutet’s department of medical biochemistry and biophysics. “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.”
The Karolinska Intitutet team worked with colleagues in Sweden, Norway, and at the National Institutes of Health in Bethesda, MD. They report on the studies in Science Translational Medicine, in a paper entitled “Irreversible Inhibition of Cytosolic Thioredoxin Reductase 1 as a Mechanistic Basis for Anticancer Therapy.”
Cancer cells activate the glutathione (GSH) and thioredoxin (TXN) systems to compensate for and protect against damage caused by oxidative stress. Targeting both of these systems can effectively kill cancer cells, but normal cells do need either one of the systems for their own survival, so broad inhibition of both the GSH and TXN antioxidant systems is toxic, the authors write.
As an alternative approach, the Karolinska Institutet–led team developed an approach that would target just the TXN system and, more specifically, inhibit just the cytosolic enzyme TXNRD1, a selenoprotein that contributes to a wide range of antioxidant and redox regulatory functions and that has also been associated with worse outcomes in cancer patients. “The enzyme is overexpressed in multiple types of cancer and is suggested to serve as a key driver to cell growth and viability,” the authors write. “In addition, high expression of TXNRD1 is directly correlated with poor prognosis in head and neck, lung, and breast cancers.”
Interestingly, a number of current anticancer drugs, including cisplatin, carmustine, melphalan, and chlorambucil, inhibit TXNRD1 as an additional effect to their primary mechanisms of action, which suggests that blocking the enzyme may contribute to their efficacy. Some pan-TXNRD inhibitors are also in clinical use, such as the FDA-approved auranofin, which is used to treat rheumatoid arthritis, and arsenic trioxide, which is approved for acute promyelocytic leukemia. These drugs also inhibit mitochondria because they target the mitochondrial isoenzyme TXNRD2.
Although researchers have previously attempted to develop specific TXNRD1 inhibitors for cancer therapy, Arnér’s team says it isn’t aware of any studies that have described specific cytosolic TXNRD1 inhibitors that don’t target the TXNRD2 mitochondrial system. “Analyzing the in vivo effects of specific inhibitors of cytosolic TXNRD1, not inhibiting mitochondrial TXNRD2, would reveal whether it may be sufficient to target the cytosolic TXN system to yield anticancer efficacy.” Inhibiting TXNRD1 specifically should also cause less toxicity to normal cells, they note.
The team screened nearly 400,000 compounds to identify TXNRD1 inhibitors that did not affect other TXNRD isoenzymes. The top two candidates, which they named TRi-1 and TRi-2, were first tested against cultured human cancer cells and normal cells. They were found to be as effective as existing cancer drugs, and capable of treating 60 different types of cancer cells, but with far less toxicity. Further in vitro tests with TRi-1 strengthened the notion that the compound exerted its cytotoxic mechanism of action through cytosolic TXNRD1 inhibition, to which cancer cells were particularly sensitive.
The new compounds were subsequently found to be effective in different mouse models of head and neck and breast cancers, again, without causing any obvious toxicity. “The anticancer efficacy of TRi-1 in mouse tumor models is consistent with the idea that TXNRD1 is important for cancer cell growth in vivo, and the lack of overt systemic toxicity suggests that the enzyme can be dispensable for overall viability and function of normal adult noncancerous tissues,” the authors state. “The efficacy of TRi-1 suggests that such mitochondrial targeting is not necessarily required for anticancer efficacy and is not a necessary consequence of inhibiting cytosolic TXNRD1.…Considering the results of our studies and the fact that a range of clinically used anticancer compounds have TXNRD1 inhibitory activity as a part of their mechanisms of action, we suggest that specific targeting of cytosolic TXNRD1 is a pertinent anticancer therapeutic principle that should be further evaluated.”
Elias Arnér and the National Institutes of Health are listed as applicants for three patents based on the discoveries. Several of the coauthors are named as coinventors. Coauthor Owe Orwar, Ph.D., is CEO of Swedish start-up Oblique Therapeutics, which worked with the Karolinska Institutet on the reported TXNRD1 inhibitors. Coauthor William C. Stafford is also a shareholder in the company. In August 2016, Oblique in-licensed three chemical series of “novel, undisclosed anticancer agents” from the NIH and the Karolinska Institutet.