Anti-myeloma activity of gold(I) compounds

JH Sze1,2, PV Raninga1,2, G Di Trapani1, SJ Berners-Price3 and KF Tonissen1,2

  1. School of Natural Sciences, Griffith University, Nathan, QLD 4111, Australia
  2. Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD 4111, Australia
  3. Institute for Glycomics, Griffith University, Southport, QLD 4215, Australia

Multiple myeloma (MM) is a clonal plasma B-cell neoplasm formed within the bone marrow. Despite being the second most common haematological malignancy after non-Hodgkin's Lymphoma, MM remains an incurable disease. Auranofin, a linear gold(I) compound known for its anti-arthritic properties has been recently trialled to treat a number of cancers including leukemia and lymphomas. Auranofin binds to the redox-sensitive selenocysteine residue present in thioredoxin reductase 1 (TrxR1) protein and therefore inhibits its activity. Previous studies in our lab demonstrated that auranofin exerts a significant anti-myeloma activity by inhibiting TrxR1 and increasing intracellular reactive oxygen species (ROS) levels. Although auranofin exerts a significant anti-cancer activity in vitro, its in vivo activity may be limited since it reacts readily and non-discriminately to protein thiols. In order to overcome these issues, a bis-chelated tetrahedral Au(I) phosphine complex called [Au(d2pype)2]Cl has been designed, which selectively targets selenol- and thiol- containing redox regulating proteins. In this study, we show that [Au(d2pype)2]Cl significantly inhibited TrxR1 activity in bortezomib-sensitive and resistant myeloma (RPMI8226 and U266) cells. [Au(d2pype)2]Cl treatment significantly inhibited cell proliferation and increased caspase-3 activity, an indicator of apoptosis, in bortezomib-sensitive and resistant myeloma cells. Currently we are investigating the underlying molecular mechanism for the anti-myeloma activity of this gold compound. Our findings indicate that this improved Au(I) compound exerts significant anti-myeloma activity in bortezomib-sensitive and resistant myeloma cells, suggesting it warrants further investigation in vivo.