Anticancer effects against colorectal cancer models of chloro(triethylphosphine)gold(I) encapsulated in PLGA–PEG nanoparticles

Abstract

Chloro(triethylphosphine)gold(I), (Et3PAuCl hereafter), is an Auranofin (AF)-related compound showing very similar biological and pharmacological properties. Like AF, Et3PAuCl exhibits potent antiproliferative properties in vitro toward a variety of cancer cell lines and is a promising anticancer drug candidate. We wondered whether Et3PAuCl encapsulation might lead to an improved pharmacological profile also considering the likely reduction of unwanted side-reactions that are responsible for adverse effects and for drug inactivation. Et3PAuCl was encapsulated in biocompatible PLGA–PEG nanoparticles (NPs) and the new formulation evaluated in colorectal HCT-116 cancer cells in comparison to the free gold complex. Notably, encapsulated Et3PAuCl (nano-Et3PAuCl hereafter) mostly retains the cellular properties of the free gold complex and elicits even greater cytotoxic effects in colorectal cancer (CRC) cells, mediated by apoptosis and autophagy. Moreover, a remarkable inhibition of two crucial signaling pathways, i.e. ERK and AKT, by nano-Et3PAuCl, was clearly documented. The implications of these findings are discussed.

Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold(III) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

“…Recently, it was reported that auranofin alone or in combination with other drugs targeting TrxR can induce apoptosis through inhibition of the AKT pathway [ 29 , 52 , 53 , 54 , 55 ]. Similarly, the AKT pathway has been proven to take part in the apoptotic cell death induced by the auranofin-related compound chloro(triethylphosphine)gold(I) [ 56 ] and an N-heterocyclic carbene–gold(I) complex [ 57 ]. In accordance with this evidence, we demonstrated that Au 2 phen, Auoxo6, and AuL12 possess the ability to downregulate the phosphorylation of AKT, thereby suggesting an important role of the AKT pathway in regulating gold(III)-induced cell death.…”

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

“…Moreover, a few studies in the recent literature suggest new valuable strategies to improve the pharmacological profiles of AF and its analogs. We refer specifically to a couple of studies that delineate feasible strategies for therapeutic intervention [ 43 , 56 ] . In a first study, encapsulation of Et 3 PAuCl in PLGA nanoparticles proved to bring about some favorable pharmacological effects such as retention of the cytotoxic activity, attenuation of the general reactivity of the gold center, and expected reduction of the drug’s adverse effects.…”

“…Recently, various research groups have found that auranofin [ 35 , 36 ] , beyond its known anti-inflammatory actions, also exhibits prominent anticancer, antibacterial, and antiparasitic properties [ 37 - 43 ] . Accordingly, during the past few years, auranofin has attracted a lot of attention in the medicinal chemistry scientific community as a prospective anticancer and anti-infective agent on the ground of drug repurposing strategies.…”

“…To achieve this goal, Menconi et al . [ 43 ] exploited organic polyethylene glycol-poly lactic acid-co-glycolic acid (PLGA-PEG)-based nanoparticles of intermediate size, which could host a certain number of metallodrug’s copies into their hydrophobic core [ Figure 4 ]. Et 3 PAuCl was encapsulated in these biocompatible PLGA-PEG nanoparticles, and the new formulation was evaluated in colorectal HCT116 cancer cells in comparison to free Et 3 PAuCl.…”

“…Reproduced and adapted from Menconi et al . [ 43 ] under the Creative Commons Attribution License 4.0 International (CC BY 4.0).…”