The anticancer effect related to disturbances in redox balance on Caco-2 cells caused by an alkynyl gold(I) complex

Abstract

The alkynyl gold(I) derivative [Au(C≡CPh)(PTA)] (PTA=1,3,5-triaza-7-phosphaadamantane) induces apoptosis in colorectal carcinoma tumour cells (Caco-2) without affecting to normal enterocytes. [Au(C≡CPh)(PTA)] is a slight lipophilic drug, stable in PBS (Phosphate Buffered Saline) and able to bind BSA (Bovin Serum Albumin) by hydrophobic interactions. Once inside the cell, [Au(C≡CPh)(PTA)] targets seleno proteins such as Thioredoxin Reductase 1, increasing ROS (Reactive Oxygen Species) levels, reducing cell viability and proliferation and inducing mitochondrial apoptotic pathway, pro-apoptotic and anti-apoptotic protein imbalance, loss of mitochondrial membrane potential, cytochrome c release and activation of caspases 9 and 3. Moreover, unlike other metal-based drugs such as cisplatin, [Au(C≡CPh)(PTA)] does not target nucleic acid, reducing the risk of side mutation in the DNA. In consequence, our results predict a promising future for [Au(C≡CPh)(PTA)] as a chemotherapeutic agent for colorectal carcinoma.

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).…”

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

“…Figure S10 displays that mobility of the plasmid is not affected after incubation with increasing amounts of our gold derivative, unlike the variation observed with the reference drug. This lack of DNA interaction is shared with auranofin and other gold(I) derivatives [20,50]. derivative is very soluble in water, shows the formation of gel structure in water solution, giving rise to long fibers, thanks to π-π interactions between the pyridyl units.…”

“…Treatment with metallic compounds usually induces apoptosis, one of the best characterized kinds of cell death [18,19]. As an example, we have recently described in detail the apoptotic insights of an alkynyl gold(I) complex [20]. But, given the rise of apoptosis-resistant tumors exist a growing interest in developing new drugs capable of inducing different types of cell death [21].…”

Gold and platinum alkynyl complexes for biomedical applications

“…An in-depth analysis to determine the mechanism of action of some of these alkynyl phosphane derivatives has revealed the significance of the alkyne structure. Thus, the PTA counterpart 34a to the previously reported 34b as a cytotoxic complex to ovarian cancer cell lines, has demonstrated to display strong antiproliferative activity against colon cancer cells 46 Caco-2/ TC7, which seemed to be selective to normal enterocytes (Caco-2/TC7 spontaneously differentiate in culture in enterocyte-like cells). 47 This cytotoxicity is due to the inhibition of the enzyme TrxR, which produces an increase in ROS levels leading to apoptosis induction by dissipation of mitochondrial membrane potential, release of cytochrome c and indirectly by altering the balance between pro-apoptotic and anti-apoptotic proteins.…”