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Multiple myeloma (MM), the second most common haematological malignancy, is a clonal plasma B-cell neoplasm that forms within the bone marrow. Despite recent advancements in treatment, MM remains an incurable disease. Auranofin, a linear gold(I) phosphine compound, has previously been shown to exert a significant anti-myeloma activity by inhibiting thioredoxin reductase (TrxR) activity. A bis-chelated tetrahedral gold(I) phosphine complex [Au(d2pype)]Cl (where d2pype is 1,2-bis(di-2-pyridylphosphino)ethane) was previously designed to improve the gold(I) compound selectivity towards selenol- and thiol-containing proteins, such as TrxR. In this study, we show that [Au(d2pype)]Cl significantly inhibited TrxR activity in both bortezomib-sensitive and resistant myeloma cells, which led to a significant reduction in cell proliferation and induction of apoptosis, both of which were dependent on ROS. In clonogenic assays, treatment with [Au(d2pype)]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)]Cl exerted a significant anti-myeloma activity in vivo in human RPMI8226 xenograft model in immunocompromised NOD/SCID mice. The MYC oncogene, known to drive myeloma progression, was downregulated in both in vitro and in vivo models when treated with [Au(d2pype)]Cl. This study highlights the "proof of concept" that improved gold(I)-based compounds could potentially be used to not only treat MM but as an alternative tool to understand the role of the Trx system in the pathogenesis of this blood disease.
This article was published in the following journal.
Name: Redox biology
A family of bimetallic and of tetrametallic phosphine-gold(I)-dithiocarbamate complexes were synthesized starting from cyclam and dimethylcyclam polyazamacrocycles respectively, along with their monom...
Novel electrophilic amides amenable by the Ugi reaction perturb thioredoxin system via thioredoxin reductase 1 (TrxR1) inhibition: Identification of DVD-445 as a new lead compound for anticancer therapy.
A series of peptidomimetic compounds incorporating an electrophilic moiety was synthesized using the Ugi reaction. These compounds (termed the Ugi Michael acceptors or UMAs) were designed to target th...
Auranofin is a gold (I)-containing compound used for the treatment of rheumatic arthritis. Auranofin has anticancer activity in animal models and is approved for clinical trials for lung and ovarian c...
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A subtype of thioredoxin reductase found primarily in MITOCHONDRIA.
A subtype of thioredoxin reductase found primarily in the CYTOSOL.
A FLAVOPROTEIN enzyme that catalyzes the oxidation of THIOREDOXINS to thioredoxin disulfide in the presence of NADP+. It was formerly listed as EC 188.8.131.52
Hydrogen-donating proteins that participates in a variety of biochemical reactions including ribonucleotide reduction and reduction of PEROXIREDOXINS. Thioredoxin is oxidized from a dithiol to a disulfide when acting as a reducing cofactor. The disulfide form is then reduced by NADPH in a reaction catalyzed by THIOREDOXIN REDUCTASE.
Unstable isotopes of gold that decay or disintegrate emitting radiation. Au 185-196, 198-201, and 203 are radioactive gold isotopes.
Blood is a specialized bodily fluid that delivers necessary substances to the body's cells (in animals) – such as nutrients and oxygen – and transports waste products away from those same cells. In vertebrates, it is composed of blo...