Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria

Abstract

Two new ‘hybrid’ metallodrugs of Au­(III) (AuTAML) and Cu­(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au­(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu­(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology.

Mitochondrial Disruption Nanosystem Simultaneously Depressed Programmed Death Ligand-1 and Transforming Growth Factor-β to Overcome Photodynamic Immunotherapy Resistance

“…TMX has gained widespread recognition as the most efficient adjuvant chemotherapy option for addressing breast cancer with estrogen receptor (ER) positivity. − Its incorporation into endocrine therapy has notably enhanced the longevity and disease-free period of countless women, particularly those who have reached menopause. ,, Curiously, it is worth noting that amounts of preclinical or clinical evidence have also suggested that TMX can regulate various cellular mechanisms such as glucose metabolism, lipid synthesis, autophagy regulation, and even mitochondrial function depression. ,, The findings from our proteomic studies in this research also indicate the impact of TMX on mitochondrial oxidative phosphorylation, activating the AMPK pathway by the OXPHOS depression through independent inhibition of mitochondria complex I, regardless of ER status (Figure ). These findings suggest that TMX’s impact extends beyond its direct anticancer effects.…”

“…TMX has become the widely used adjuvant drug for the treatment of estrogen-receptor-positive breast cancer, which has usefully saved numerous lives worldwide in the past 50 years. , But, the usage of this drug in clinical situations was still seriously limited, since some of its significant functions may be neglected, especially its potent PD-L1 and TGF-β depression capacity. ,, As reported just recently, amplified AMPK phosphorylation by OXPHOS inhibitors may induce the downregulation of PD-L1 and TGF-β in tumor cells, which then could result in the conversion of cold tumors to hot ones. , Given the proven fact that TMX could effectively inhibit OXPHOS via depressing the mitochondria complex I activity to induce AMPK phosphorylation, TMX may also possess immune-regulation capacity. , To confirm this prediction, we proved in this research that TMX could inhibit PD-L1 and TGF-β expression in tumors at a dosage of 30 μM in bladder tumor cells and breast cancer cells in vitro (Figure ). Interestingly enough, as reported previously, the combination of mitochondria-targeting agents with TMX could potentially reduce the required dosage of TMX for inducing mitochondria dysfunction, which may offer an ideal TMX derivate for highly effective PD-L1 and TGF-β depression. , Based on this, we designed the MHI-TMX chemical compound by combining a mitochondria-targeted heptamethine cyanine dye called MHI with TMX, an agent that inhibited mitochondrial complex I, which was further assembled with ALB to create MHI-TMX@ALB nanoparticles (Figure ).…”

Exploring the potential of tamoxifen-based copper(ii) dichloride in breast cancer therapy

“…14 The copper(II) complex 1 was synthesised by reacting ligand L with CuCl 2 •2H 2 O under a nitrogen atmosphere. In contrast to the procedure reported by Scalcon et al, who prepared the copper(II) complex in dry DCM, 25 here the reaction mixture was stirred for 12 hours in degassed ethanol. The green Scheme 1 Tamoxifen (I) and the tamoxifen metabolites 6 13,14 and the dimeric copper(II) dichloride complex [CuCl(μ-Cl)(L-κ 2 N,N′)] 2 (1) reported here.…”

“…18,19 In parallel with our studies, Scalcon et al recently reported on the copper( ii ) dichloride and gold( iii ) chloride complexes of ligand L . 25 The copper( ii ) complex was shown to induce oxidative damage of mitochondria in two breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) by increasing the level of the reactive oxygen species (ROS). 25–27…”

“…25 The copper( ii ) complex was shown to induce oxidative damage of mitochondria in two breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231) by increasing the level of the reactive oxygen species (ROS). 25–27…”