Iminophosphorane–organogold(III) complexes induce cell death through mitochondrial ROS production

Abstract

Gold compounds are being investigated as potential antitumor drugs. Some gold(III) derivatives have shown to induce cell death in solid tumors but their mechanism of action differs from that of cisplatin, since most of these compounds do not bind to DNA. We have explored cellular events triggered by three different iminophosphorane-organo gold(III) compounds in leukemia cells (a neutral compound with two chloride ligands [Au{κ2-C,N-C6H4(PPh2=N(C6H5)-2}Cl2] 1, and two cationic compounds with either a dithiocarbamate ligand [Au{κ2-C,N-C6H4(PPh2=N(C6H5)-2}(S2CN-Me2)]PF6 2, or a water-soluble phosphine and a chloride ligand [Au{κ2-C,N-C6H4(PPh2=N(C6H5)-2}(P{Cp(m-C6H4-SO3Na)2}3) Cl]PF6 3). All three compounds showed higher toxicity against leukemia cells when compared to normal T-lymphocytes. Compounds 1 and 2 induced both necrosis and apoptosis, while 3 was mainly apoptotic. Necrotic cell death induced by 1 and 2 was Bax/Bak- and caspase-independent, while apoptosis induced by 3 was Bax/Bak-dependent. Reactive oxygen species (ROS) production at the mitochondrial level was a critical step in the antitumor effect of these compounds.

Hypoxic-Ischemic Injury in the Developing Brain: The Role of Reactive Oxygen Species Originating in Mitochondria

“…However, this loss of cytochrome c was not mediated by mPTP opening, and was not associated with changes in mitochondrial Bax, Bad, Bak or Bid [87]. Although, mitochondrial ROS appeared to be critical for the execution of Bax/Bak dependent apoptosis induced by anti-cancer drugs [88, 89], we have not found data that ROS originating in mitochondria are involved in the Bax/Bak-induced apoptosis in HI brain injury. Interestingly, oxidative stress-induced cell apoptosis clearly required the presence of ROS originating from MRC to signal mPTP opening, but this apoptosis was independent of Bax translocation [90].…”

Synthesis and Assessment of Antibacterial Activities of Ruthenium(III) Mixed Ligand Complexes Containing 1,10-Phenanthroline and Guanide

“…Based on this, synthesis of different coordination compounds with desired properties by ligand tailoring has become a fascinating research field. Designing new coordination compounds with therapeutic abilities has been part of this activity [9–17]. From this perspective, there has been a growing interest in the chemistry community to examine the biological activities of ruthenium complexes [18, 19].…”

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

“…Two gold(III) methylsarcosinedithiocarbamate derivatives, combining cytostatic and apoptotic activity with reduced nephrotoxicity for the management of myeloid leukemia, can down-regulate Bcl-2 and upregulate Bax to induce cell death [40]. Iminophosphorane-organogold(III) complexes can induce tumor cell death through mitochondrial ROS production [41]. …”