Auranofin and its analogs as prospective agents for the treatment of colorectal cancer

Abstract

Today colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought. Platinum drugs, oxaliplatin in particular, were reported to produce some significant benefit in CRC treatment, triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs. Within this frame, gold compounds and, specifically, the established antiarthritic drug auranofin with its analogs, form a novel group of promising anticancer agents. Owing to its innovative mechanism of action and its favorable pharmacological profile, auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment, capable of overcoming resistance to platinum drugs. Some encouraging results in this direction have already been obtained. A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations. The perspectives of the research in this field are outlined.

Keywords: Auranofin; CRC; anticancer agents; colorectal cancer; gold; gold-based drugs; metallodrugs.

Figure 1

Chemical structure of auranofin.

Figure 2

(A) Cartoon representation of the secondary structures of human thioredoxin-1-thioredoxin reductase 1 (Trx1-TrxR1) complex PDB: 3qfa. (B) The contact patches with direct molecular contacts are highlighted in yellow. (C) The isosurfaces of the electrostatic potential are depicted in blue (positive) and red (negative). The active site cysteinyl residues and interaction surfaces in the immediate contact area in both proteins are encircled in white lines. Reproduced and adapted from Hossain et al.^[47] under the Creative Commons Attribution License 4.0 International (CC BY 4.0).

Figure 3

Chemical structures of auranofin analogs bearing different ligands in place of thiosugar moiety.

Figure 4

Schematic representation of the Et₃PAuCl-loaded NPs tested against colorectal cancer models. Reproduced and adapted from Menconi et al.^[43] under the Creative Commons Attribution License 4.0 International (CC BY 4.0).

Figure 5

The effect of the combination of auranofin with celecoxib in mice. Athymic nude mice bearing DLD-1 xenografts were treated with the following drugs via oral injection (P.O.): olive oil (vehicle), AF 10 mg/kg, CE 20 mg/kg, CE 60 mg/kg, AF 10 mg/kg + CE 20 mg/kg (A + C20), and AF 10 mg/kg + CE 60 mg/kg (A + C60). Eight days after inoculation, the tumor size and body weight of mice from each group (six mice per group) were measured two times per week. The three panels show the body weight, tumor volume, and tumor weight during the treatment. Reproduced and adapted from Han et al.^[56] under the Creative Commons Attribution License 4.0 International (CC BY 4.0). AF: Auranofin; CE: celecoxib.

Figure 6

Synergy between auranofin and celecoxib against colon cancer in vitro and in vivo through a novel redox-mediated mechanism. CE induces ROS increase, which in turn causes oxidation of proteins (Trxs, HK, and MTCO2). AF inhibits TrxR, and thus keeps Trxs in oxidized form, which cannot reduce/repair the oxidized proteins (HK and MTCO2), leading to inhibition of both glycolysis and mitorespiration, ATP depletion, and cell death. Reproduced and adapted from Han et al.^[56] under the Creative Commons Attribution License 4.0 International (CC BY 4.0). CE: Celecoxib; ROS: reactive oxygen species; HK: hexokinase.