Differential genomic and proteomic profiling of glioblastoma cells exposed to terpyridineplatinum(II) complexes.

Terpyridineplatinum(II) complexes (TPCs) efficiently inhibit the proliferation of glioblastoma cells in vitro and have been tested successfully in a rodent glioblastoma model. Apart from intercalation with DNA, the major mechanism of action of TPCs is a very potent and specific interaction with the human selenoprotein thioredoxin reductase (TrxR). TrxR plays a crucial role in cellular redox homeostasis and protection against oxidative damage.

Glutathione- and thioredoxin-related enzymes are modulated by sulfur-containing chemopreventive agents.

We studied the effects of sulfur-containing chemopreventive agents, including allyl sulfides and isothiocyanates, on human redox networks. Isothiocyanates inhibited isolated redox-active enzymes in a time- and dose-dependent manner. As shown for the most active compound, benzyl isothiocyanate (BITC), on thioredoxin reductase, the inhibition has an initial competitive part (Ki=6.

The structure of human thioredoxin reductase 1 provides insights into C-terminal rearrangements during catalysis.

Human thioredoxin reductase (hTrxR) is a homodimeric flavoprotein crucially involved in the regulation of cellular redox reactions, growth and differentiation. The enzyme contains a selenocysteine residue at its C-terminal active site that is essential for catalysis. This redox center is located on a flexible arm, solvent-exposed and reactive towards electrophilic inhibitors, thus representing a target for antitumor drug development.

On the potential of thioredoxin reductase inhibitors for cancer therapy.

Thioredoxin reductase (TrxR)-as part of a major thiol regulating system-allows redox metabolism to adjust to cellular requirements. Therefore, changes at the redox level reflect as a pars pro toto changes concerning the entire cell. Three different TrxR isoenzymes, TrxR1 as cytosolic, TrxR2 as mitochondrial, and TrxR3 as testis-specific thiol regulator are known.

Truncated mutants of human thioredoxin reductase 1 do not exhibit glutathione reductase activity.

The substrate spectrum of human thioredoxin reductase (hTrxR) is attributed to its C-terminal extension of 16 amino acids carrying a selenocysteine residue. The concept of an evolutionary link between thioredoxin reductase and glutathione reductase (GR) is presently discussed and supported by the fact that almost all residues at catalytic and substrate recognition sites are identical. Here, we addressed the question if a deletion of the C-terminal part of TrxR leads to recognition of glutathione disulfide (GSSG), the substrate of GR.

Antiglioma activity of 2,2':6',2"-terpyridineplatinum(II) complexes in a rat model--effects on cellular redox metabolism.

The mammalian thioredoxin system, comprising the selenoenzyme thioredoxin reductase (TrxR) and the 12-kDa protein thioredoxin (Trx), is implicated in thiol-mediated antioxidant defense and redox regulatory processes including transcriptional control, DNA synthesis, and apoptosis. Cell proliferation supported by the thioredoxin system can be suppressed by TrxR inhibition. In this study, we assessed the effects of the potent hTrxR inhibitors 4-mercaptopyridine (4'-chloro-2,2':6',2"-terpyridine)platinum nitrate (I(23)2N) and 2-mercaptopyridine (4'-chloro-2,2':6',2"-terpyridine)platinum nitrate (I(25)2N) on glioblastoma in a rat model.

Synthesis of 5-nitro-2-furancarbohydrazides and their cis-diamminedichloroplatinum complexes as bitopic and irreversible human thioredoxin reductase inhibitors.

The human selenoprotein thioredoxin reductase is involved in antioxidant defense and DNA synthesis. As increased thioredoxin reductase levels are associated with drug sensitivity to cisplatin and drug resistance in tumor cells, this enzyme represents a promising target for the development of cytostatic agents. To optimize the potential of the widely used cisplatin to inhibit the human thioredoxin reductase and therefore to overcome cisplatin resistance, we developed and synthesized four cis-diamminedichloroplatinum complexes of the lead 5-nitro-2-furancarbohydrazide 8 selected from high-throughput screening.

Mechanistic studies on a novel, highly potent gold-phosphole inhibitor of human glutathione reductase.

The homodimeric flavoprotein glutathione reductase (GR) is a central player of cellular redox metabolism, connecting NADPH to the large pool of redox-active thiols. In this work, the inhibition of human GR by a novel gold-phosphole inhibitor (GoPI) has been studied in vitro. Two modes of inhibition are observed, reversible inhibition that is competitive with GSSG followed by irreversible inhibition.

The thioredoxin system--from science to clinic.

The thioredoxin system-formed by thioredoxin reductase and its characteristic substrate thioredoxin-is an important constituent of the intracellular redox milieu. Interactions with many different metabolic pathways such as DNA-synthesis, selenium metabolism, and the antioxidative network as well as significant species differences render this system an attractive target for chemotherapeutic approaches in many fields of medicine-ranging from infectious diseases to cancer therapy. In this review we will present and evaluate the preclinical and clinical results available today.

The Escherichia coli dam DNA methyltransferase modifies DNA in a highly processive reaction.

The Escherichia coli dam adenine-N6 methyltransferase modifies DNA at GATC sequences. It is involved in post-replicative mismatch repair, control of DNA replication and gene regulation. We show that E.