Alkynyl gold(I) complex triggers necroptosis via ROS generation in colorectal carcinoma cells

Abstract

Given the rise of apoptosis-resistant tumors, there exist a growing interest in developing new drugs capable of inducing different types of cell death to reduce colorectal cancer-related death rates. As apoptosis and necroptosis do not share cellular machinery, necroptosis induction may have a great therapeutic potential on those apoptosis-resistant cancers, despite the inflammatory effects associated with it. We have synthesized an alkynyl gold(I) complex [Au(CC-2-NCH)(PTA)] whose anticancer effect was tested on the colorectal adenocarcinoma Caco-2 cell line. With regard to its mechanism of action, this gold complex enters the mitochondria and disrupts its normal function, leading to an increase in ROS production, which triggers necroptosis. Necroptosis induction has been found dependent of TNF-α (Tumor necrosisfactor α) and TNFR1(Tumor necrosisfactor receptor 1) binding, RIP1(Receptor-Interacting Protein 1) activation and NF-κB (Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells) signaling. Moreover, the antitumor potential of [Au(CC-2-NCH)(PTA)] has also been confirmed on the 3D cancer model spheroid. Overall, the obtained data show firstly that gold complexes might have the ability of inducing necroptosis, and secondarily that our compound [Au(CC-2-NCH)(PTA)] is an interesting alternative to current chemotherapy drugs in cases of apoptosis resistance.

The Important Role of the Nuclearity, Rigidity, and Solubility of Phosphane Ligands in the Biological Activity of Gold(I) Complexes

“…All the synthesized complexes gave satisfactory elemental analysis and were characterized by 1 H and 31 P NMR and IR spectroscopy as well as by ESI‐MS(+) spectrometry. The 31 P{ 1 H} NMR spectra display in all cases a single resonance, which is around 50 ppm downfield from the resonance of the corresponding free phosphine . Only one peak was recorded for the diphosphine derivatives 7 – 10 , in agreement with the formation of symmetrical dinuclear complexes (see the Supporting Information).…”

A Combination of Rosa Canina Extracts and Gold Complex Favors Apoptosis of Caco-2 Cells by Increasing Oxidative Stress and Mitochondrial Dysfunction

“…Gold complex was diluted in dimethyl sulfoxide (DMSO) at 2 mM and then in cell culture medium to the required concentration (IC 50 value: 3.8 µM) [16].…”

“…Caco-2 cells were seeded in 25 cm 2 flasks and then exposed to the drug panel for 48 h, then collected and the determination of receptor-interaction protein kinase 1 (RIP-1) levels was performed as previously described [16].…”

“…The antiproliferative effect of the acidic polyphenols fraction (AP) of rosehips from R. canina on Caco-2 cell line after 72 h of incubation were previously evaluated by us [17], reading an IC 50 value of 125 µg/mL. On the other hand, the effect of the gold complex (Au(C≡C-2-NC 5 H 4 )(PTA)) towards the same cell model displayed a higher in vitro effect than plant extracts with an IC 50 value of 3.8 µM [16].…”

“…Given the promising antitumoral potential of combinations of metallodrugs and plant extracts [3,4,14] along with our previous work, we have developed a new chemotherapy combination focused on CRC treatment. This drug combination is composed of the alkynyl gold(I) complex (Au(C≡C-2-NC 5 H 4 )(PTA)) (PTA = 1,3,5-triaza-7-phosphadamantane) [15,16] and acidic polyphenols (AP) extracted from the rosehips of Rosa canina [17]. The objectives of the present work were the analysis of the combined effect of the acidic polyphenols and the gold complex in order to assess the AP fraction as a potential adjuvant agent for organometallic-based chemotherapy, the characterization of the effect of the resulting drug combination in terms of the type of cell death, and the putative mechanisms of action.…”