The gold complex auranofin: new perspectives for cancer therapy

Abstract

Advanced stages of cancer are highly associated with short overall survival in patients due to the lack of long-term treatment options following the standard form of care. New options for cancer therapy are needed to improve the survival of cancer patients without disease recurrence. Auranofin is a clinically approved agent against rheumatoid arthritis that is currently enrolled in clinical trials for potential repurposing against cancer. Auranofin mainly targets the anti-oxidative system catalyzed by thioredoxin reductase (TrxR), which protects the cell from oxidative stress and death in the cytoplasm and the mitochondria. TrxR is over-expressed in many cancers as an adaptive mechanism for cancer cell proliferation, rendering it an attractive target for cancer therapy, and auranofin as a potential therapeutic agent for cancer. Inhibiting TrxR dysregulates the intracellular redox state causing increased intracellular reactive oxygen species levels, and stimulates cellular demise. An alternate mechanism of action of auranofin is to mimic proteasomal inhibition by blocking the ubiquitin-proteasome system (UPS), which is critically important in cancer cells to prevent cell death when compared to non-cancer cells, because of its role on cell cycle regulation, protein degradation, gene expression, and DNA repair. This article provides new perspectives on the potential mechanisms used by auranofin alone, in combination with diverse other compounds, or in combination with platinating agents and/or immune checkpoint inhibitors to combat cancer cells, while assessing the feasibility for its repurposing in the clinical setting.

Keywords: Auranofin; Cancer; Cisplatin; Immunogenic cell death; Thioredoxin reductase.

Fig. 1

Structural formula of auranofin. The molecule consists of a monomeric linear complex with triethylphosphine and thiolate moieties bounded to an Au (I) center [10]. The molecule was adapted from the structure published in the CheBI database [11] using ChemDraw software

Fig. 2

Auranofin (AUR) inhibits the anti-oxidant enzymes thioredoxin reductase 1 (TrxR1) and 2 (TrxR2) resulting in an increase in the level of intracellular reactive oxygen species (ROS), mitochondrial permeability, and DNA damage. A AUR inhibits glycolysis resulting in reduced ATP levels and inhibition of the function of drug transporter, ABCG2, preventing development of drug resistance. B AUR-mediated ROS production causes ER stress and PERK activation, leading to cell death. C AUR inhibits the function of deubiquitinases enzymes (DUBs) in protein homeostasis and induction of tumor growth. D Increased ROS induced by AUR causes decreased membrane potential in the mitochondrial membrane, resulting in a decrease in anti-apoptotic proteins, caspase-dependent cell death, and translocation of apoptosis-inducing factor (AIF) into the nucleus to trigger caspase-independent cell death. E AUR inhibits the IKK-β signaling pathway, which normally induces FOXO3 tumor suppressor degradation. The inhibition of IKK-β by AUR allows the nuclear translocation of FOXO3, activating proapoptotic proteins, resulting in cell death. F AUR inhibits the PI3K/AKT/mTOR pathway, resulting in the inhibition of pro-angiogenic factors like HIF-1α, preventing tumorigenesis. G AUR activates ASK1 leading to p38-mediated cell death. H AUR promotes the conversion of H₂O₂ to ˑOH via the Fenton reaction, resulting in the induction of cell death

Fig. 3

Targeting cancer cells with a combination of auranofin (AUR) and a platinum agent in the context of the tumor microenvironment. AUR and platinum agents inhibit the function of TrxR, inducing an overproduction of reactive oxygen species (ROS), mitochondrial permeability, and DNA damage, resulting in cancer cell death. Accumulation of intracellular ROS induces ER stress, activation of PERK and caspase-8, and the upregulation of pro-apoptotic proteins BAX and BAK, further potentiating cell death. This pathway triggers the release of danger or damage associated molecular patterns (DAMPs) such as calreticulin (ecto-CRT), high mobility group box 1 (HMGB1) protein and ATP into the tumor microenvironment where they collectively activate antigen presenting cells (APCs). Mature APCs migrate into the lymph nodes and present tumor antigens to immature T cells, which develop into CD8+T cells with anti-cancer cytotoxic activity. The inhibition of the interaction between PD-1 on T cells and PD-L1 on cancer cells prevents the neutralization of T cells by cancer cells, maintaining T cell cytotoxicity and favoring tumor cell death. This release of DAMPs into the tumor microenvironment via ER stress and the consequent activation of T cells is known as immunogenic cell death or ICD