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Redox Biol. 2019 Aug 28;28:101310. doi: 10.1016/j.redox.2019.101310. [Epub ahead of print]

Anticancer activity of a Gold(I) phosphine thioredoxin reductase inhibitor in multiple myeloma.

Author information

1
School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, 4111, Australia.
2
Signal Transduction Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
3
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
4
Institute for Glycomics, Griffith University, Southport, QLD, 4222, Australia.
5
School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia. Electronic address: g.ditrapani@griffith.edu.au.
6
School of Environment and Science, Griffith University, Nathan, QLD, 4111, Australia; Griffith Institute for Drug Discovery, Griffith University, Nathan, QLD, 4111, Australia. Electronic address: k.tonissen@griffith.edu.au.

Abstract

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)2]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)2]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)2]Cl completely abrogated the tumourigenic capacity of MM cells, whereas auranofin was less effective. We also show that [Au(d2pype)2]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)2]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.

KEYWORDS:

Apoptosis; Auranofin; Gold(I) compounds; Multiple myeloma; Thioredoxin; Thioredoxin reductase

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