Thioredoxin Inhibition

Thioredoxin is a ubiquitous intracellular protein with a central role in DNA synthesis and the control of transcription factors that affect cell proliferation and cell death.

The Multiple Intracellular Roles of Thioredoxin

There is significant experimental and clinical evidence linking thioredoxin to cancer:

A wide range of human cancers have significantly increased levels of thioredoxin
Thioredoxin stimulates the growth of a wide variety of human tumour cells
Thioredoxin activates directly or indirectly a number of transcription factors that are closely involved in tumour growth and metastasis
Thioredoxin, when it is over-produced, transforms normal cells into cancer cells.
Thioredoxin is a potent inhibitor of apoptosis and provides a survival as well as a growth advantage to tumours.
Thioredoxin causes a significant decrease in the sensitivity of tumour cells to many commonly used cancer drugs, including doxorubicin, vincristine and cisplatin. Over-expression of thioredoxin could therefore be a factor in the problem of multi-drug resistance.

We have substantial evidence that PMX 464 and PMX 290 are potent inhibitors of thioredoxin signalling.

PMX 464 has been shown to bind nucleophilic cysteine residues of reduced human thioredoxin. In cells treated with PMX 464, thioredoxin reductase transcription is upregulated, and thioredoxin mediated reduction of insulin is inhibited.

PMX 464 Mediated Inhibition of thioredoxin catalysed insulin reduction

PMX 464 also inhibits the activity of NF-kB by inhibition of thioredoxin mediated NF-kB reduction, and by inhibition of Ik kinase (IKK), the kinase responsible for IkB phosphorylation and NF-kB activation.

	Cytotoxic and antiangiogenic activity of AW464 (NSC 706704), a novel thioredoxin inhibitor: an in vitro study.

	Elucidation of thioredoxin as a molecular target for antitumour quinols.

	Induction and apoptosis without redox catastrophe by thioredoxin-inhibitory compounds.





	The Multiple Intracellular Roles of Thioredoxin (480kb)

	PMX 464 Mediated Inhibition of thioredoxin catalysed insulin reduction (480kb)