Projects / Molecular structures to targeting tumor cells

TrxR as a target for anticancer drugs

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European Institute of Oncology

The tioredoxine reductases (TrxR) are a very important set of proteins and widespread. They play a crucial role in intracellular redox metabolism. In fact, are the only known enzymes capable of reducing the thioredoxin that, together with glutathione, has a fundamental role in the control of the intracellular redox machanisms. In particular, the mammalian TrxR, presents a selenolic group, at the C-terminal end, that is of extreme of relevance. Very recent studies have shown that TrxR, overexpressed in cancer cells, may represent a target for a variety of anticancer agents of inorganic nature. In fact, through studies of mass spectrometry, we demonstrated that antitumor agents based on gold (I) and gold (III) (auranofin and AuOXO6) binds preferentially to the selenolic group of the selenocysteine residue, present at the C-terminus of the enzyme and, in the second instance to the thiol group of cysteine, resulting in its inhibition or disruption of cellular redox mechanisms and thus cell death. Further investigation started on a set of different peptides of variable length, modelled on the active sequence of the tryptic fragment of human TrxR. These peptides are being been tested with different metal-based cytotoxic molecules and studied by ESI-MS.

 

A. Pratesi, C. Gabbiani, M. Ginanneschi, L. Messori ‘Reactions of medicinally relevant gold compounds with the C-terminal motif of thioredoxin reductase elucidated by MS analysis’ Chem. Comm., 2010, 46, 7001-7003.