Abstract
[CuI(2,9-dimethyl-1,10-phenanthroline)P(p-OCH3-Ph)2CH2SarcosineGlycine] (1-MPSG), highly stable in physiological media phosphino copper(I) complex—is proposed herein as a viable alternative to anticancer platinum-based drugs. It is noteworthy that, 1-MPSG significantly and selectively reduced cell viability in a 3D spheroidal model of human lung adenocarcinoma (A549), in comparison with non-cancerous HaCaT cells. Confocal microscopy and an ICP-MS analysis showed that 1-MPSG effectively accumulates inside A549 cells with colocalization in mitochondria and nuclei. A precise cytometric analysis revealed a predominance of apoptosis over the other types of cell death. In the case of HaCaT cells, the overall cytotoxicity was significantly lower, indicating the selective activity of 1-MPSG towards cancer cells. Apoptosis also manifested itself in a decrease in mitochondrial membrane potential along with the activation of caspases-3/9. Moreover, the caspase inhibitor (Z-VAD-FMK) pretreatment led to decreased level of apoptosis (more pronouncedly in A549 cells than in non-cancerous HaCaT cells) and further validated the caspases dependence in 1-MPSG-induced apoptosis. Furthermore, the 1-MPSG complex presumably induces the changes in the cell cycle leading to G2/M phase arrest in a dose-dependent manner. It was also observed that the 1-MPSG mediated intracellular ROS alterations in A549 and HaCaT cells. These results, proved by fluorescence spectroscopy, and flow cytometry, suggest that investigated Cu(I) compound may trigger apoptosis also through ROS generation.
Highlights
Cancer is a leading cause of death worldwide
This means that the copper(I) compound had been effectively internalized by the studied cancer cells (A549: 63%, MCF7: 75%, PANC-1: 69%, DU-145: 61%). 1-MPOH (the copper(I) complex without the peptide motif) is accumulated inside cancer cells significantly less efficiently at the same conditions
We indicated that the introduction of methoxy group onto the phenyl rings of the phosphine ligand coordinated to the copper(I) ion resulted in a relevant increase of cytotoxicity in selected cancer cell lines
Summary
Cancer is a leading cause of death worldwide. Due to lack of drug selectivity, the administration of most drugs in cancer therapies is associated with severe side effects. In the case of all the selected tumor cell lines (A549, MCF-7, PANC-1, DU-145) after incubation with 1-MPSG, a significant increase in copper accumulation was detected in comparison with the control normal cells (MRC5, HEK293T, HaCaT)). The introduction of the peptide motif into the structure of the investigated metal complex resulted in an increased concentration of the copper(I) compound inside the cancer cells and in augmented cytotoxic activity in vitro.
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