Thioredoxin reductase (TRX) is a
selenoprotein that reduces oxidized
protein substrates in an
NADPH-dependent process (cf. Fig. 1). The
thioredoxins (TX) are a family of small redox active
proteins that undergo reversible oxidation/reduction and help to maintain the redox state of cells. TX serves as a cofactor in many TRX-catalyzed reductions in a manner similar to
glutathione (GSH) in
thioltransferase reactions. For example, TX is a cofactor in
protein disulfide reduction and
DNA synthesis, but independently, it inhibits apoptosis, stimulates cell proliferation and angiogenesis, and increases
transcription factor activity. The role of the TRX/TX system is limited by its reducing capacity as well as the additional supply of electrons in the form of
NADPH provided by hexose monophosphate shunt (HMPS). TX is limited by the reduction capacity of its vicinal sulfhydryls and needs a source of electrons from the HMPS and TRX- coupled system to reduce
disulfides. Oxidized TX is reduced by TRX and
NADPH. Several lines of evidence suggest that the coupled HMPS/TRX/TX system represents an important target for
cancer therapy. TX overexpression has been reported in several
malignancies and may be associated with aggressive
tumor growth and poor survival. In some cells, TX is an important factor in conferring resistance to
chemotherapy and in stimulating production of
hypoxia-inducible factor (HIF-1). Several inhibitors of the TRX/TX system have been evaluated in experimental
cancer models: these include HMPS inhibitors,
carbohydrate analogues,
NADP synthesis blockers, vicinal
thiol reactants,
cisplatin, and TRX inhibitors. More recently, the targeted anti-
cancer agent
motexafin gadolinium has been identified.
Motexafin gadolinium is a redox mediator that selectively localizes to
cancer cells, and reacts with reducing metabolites and vicinal
thiols to generate
reactive oxygen species that ultimately block the TRX
enzyme as well as the analogous
glutaredoxin activity. In cell and animal models,
motexafin gadolinium is directly cytotoxic to various
tumor cells and enhances the activity of
radiation therapy and
chemotherapy. This
drug is now in a broad range of clinical trials investigating its therapeutic potential when used as a single agent or in combination with either
chemotherapy or
radiation therapy. Promising clinical activity has been reported in a clinical trial with
motexafin gadolinium and whole brain
radiation therapy for treatment of
brain metastases from solid
tumors. These findings suggest that the TRX/TX system may represent an attractive target for development of new
cancer therapeutics.