Thioredoxin signaling as a target for cancer therapy

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Thioredoxin (Trx) family members play critical roles in the regulation of cellular redox homeostasis. Cancer cells exist in a stressed environment and rely on the Trxs for protection against stress-disregulated redox signaling. The most extensively studied member of the family is Trx-1 whose levels are increased in many human cancers most likely in direct response to stress. Trx-1 contributes to many of the hallmarks of cancer including increased proliferation, resistance to cell death and increased angiogenesis. Trx-1 is a validated cancer drug target associated with aggressive tumor growth, resistance to standard therapy and decreased patient survival. A surrogate target for Trx-1 may be thioredoxin reductase (TR). Drugs that inhibit Trx-1 and TR are in clinical development with early promising results.

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The thioredoxin family of redox proteins

The thioredoxin redox system comprises thioredoxin reductase (TR), a homodimeric selenium containing flavoprotein, which transfers reducing equivalents from NADPH to the small (12 kDa) redox protein thioredoxin (Trx). Trx has a conserved Cys-Gly-Pro-Cys redox catalytic site that in turn, reduces client proteins or binds to proteins to modify their activity. For full details of the Trx system the reader is referred to excellent reviews [1, 2]. This overview will be concerned with only the most

Thioredoxin as a validated cancer drug target

Most attention has been focused on Trx-1 and TR1 as targets for cancer therapy, although the increasing evidence of the importance of the UPR to protein synthesis and survival of cancer cells [6] suggests that the ER Trx family members may be therapeutic targets for cancer in their own right. Trx-1 has multiple functions in the cell (Figure 1) that include providing reducing equivalents for DNA synthesis through ribonucleotide reductase (RR), and for reactive oxygen radical scavenging through

Thioredoxin reductase as a cancer drug target

There are three mammalian TRs, TR1, TR2 and a third form TR3 expressed primarily in the testis that can also reduce glutathione disulfide. All three TRs are selenoproteins with a glutathione reductase-like base structure and a C-terminal 16 amino acid elongation containing the Gly-Cys-Sec-Gly active site. Structural studies have shown that the TR1 C-terminal catalytic site is readily accessible [25] and because of this TR is a promiscuous enzyme with a number of different substrates and

Antitumor thioredoxin inhibitors

AW464, a benzathiole-substituted quinol with antitumor activity has been reported to inhibit Trx-1 and TR, and to inhibit the proliferation of tumor cell lines and endothelial cells [31]. Paradoxically, AW464 and a related compound decrease HIF-1α transcriptional activity, DNA binding and the expression of VEGF, but at the same time increase HIF-1α protein levels [32]. A Trx-1 antisense phosphorothiote oligodeoxynucleotide GTI-2601 has been reported to exhibit in vivo antitumor activity in

Inhibitors of thioredoxin reductase

A number of electrophilic compounds inhibit TR, including organogold compounds such as auranofin that is used to treat rheumatoid arthritis, arsenicals [41], antitumor agents including the nitrosoureas, platinum agents such as cis-diamminedichloroplatin [42], antitumor quinols [43] and the newer anticancer agents myricetin, quercetin [44] and curcumin [45]. However, the agents can also inhibit other oxidoreductases and NF-κB, and the contribution of TR inhibition to their biological activity is

Conclusion

Trx family members play critical roles in the regulation of cellular redox homeostasis. Cancer cells exist in a stressed environment and rely on the Trxs for protection against stress-disregulated redox signaling. The most extensively studied member of the family is Trx-1 whose levels are increased in many human tumors most likely in direct response to microenvironment stress. Trx-1 contributes to many of the hallmarks of cancer including increased proliferation, resistance to cell death and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Conflict disclosure

Dr Powis is a founder, stockholder and consultant to ProlX Pharmaceuticals. Dr Kirkpatrick is a founder, stockholder and employee of ProlX Pharmaceuticals. One of the thioredoxin inhibitors discussed, PX-12, is a ProlX drug.

Acknowledgement

The work is supported by NIH Grant CA77204.

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