Labelled micelles for the delivery of cytotoxic Cu(II) and Ru(III) compounds in the treatment of aggressive orphan cancers: Design and biological in vitro data

Brustolin, Leonardo; Pettenuzzo, Nicolò; Nardon, Chiara; Quarta, Santina; Montagner, Isabella Monia; Pontisso, Patrizia; Rosato, Antonio; Conté, Pierfranco; Merigliano, Stefano; Fregona, Dolores

doi:10.1016/j.jinorgbio.2020.111259

Cited by 10 publications

(10 citation statements)

References 62 publications

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“…This was observed in the study on the antiproliferative activity of two copper complexes of dithiocarbamate glycoconjugates (glucose and galactose) on human cancer cell lines [267]. [Cu(S 2 CNEt 2 ) 2 ] is also an effective anticancer [236,248,[251][252][253][254][255][256] especially in vitro as are many derivatives [36,37,[257][258][259][260][261][262]. This was first established for pyrrolidine dithiocarbamate, which exhibits high potency to inhibit a cancer-specific proteasome, showing a cytotoxic effect on different human tumour cells after complexation with copper.…”

Section: Anticancer Agentsmentioning

confidence: 94%

“…Biological detection of [Cu(S2CNEt2)2] is usually made by EPR [62] but, recently, mass spectrometry has also been used to detect this complex in A549 cell [250]. [Cu(S2CNEt2)2] is also an effective anticancer [236,248,[251][252][253][254][255][256] especially in vitro as are many derivatives [36,37,[257][258][259][260][261][262]. This was first established for pyrrolidine dithiocarbamate, which exhibits high potency to inhibit a cancer-specific proteasome, showing a cytotoxic effect on different human tumour cells after complexation with copper.…”

Section: Anticancer Agentsmentioning

confidence: 99%

“…Their activity is improved by supporting them on a non-ionic block copolymer, with the encapsulated copper complex showing enhanced stability, bioavailability and water solubility. Some of these complexes have shown comparable activity to standard drugs, with few showing higher activity when compared to standard anticancer drugs [259]. Carbohydrate-functionalised complexes have also been prepared and studied by Fregona and co-workers, and an example (CuGlu) is shown (Figure 28) [37].…”

Section: Anticancer Agentsmentioning

confidence: 99%

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Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Hogarth

Onwudiwe

2021

Inorganics

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Copper dithiocarbamate complexes have been known for ca. 120 years and find relevance in biology and medicine, especially as anticancer agents and applications in materials science as a single-source precursor (SSPs) to nanoscale copper sulfides. Dithiocarbamates support Cu(I), Cu(II) and Cu(III) and show a rich and diverse coordination chemistry. Homoleptic [Cu(S2CNR2)2] are most common, being known for hundreds of substituents. All contain a Cu(II) centre, being either monomeric (distorted square planar) or dimeric (distorted trigonal bipyramidal) in the solid state, the latter being held together by intermolecular C···S interactions. Their d9 electronic configuration renders them paramagnetic and thus readily detected by electron paramagnetic resonance (EPR) spectroscopy. Reaction with a range of oxidants affords d8 Cu(III) complexes, [Cu(S2CNR2)2][X], in which copper remains in a square-planar geometry, but Cu–S bonds shorten by ca. 0.1 Å. These show a wide range of different structural motifs in the solid-state, varying with changes in anion and dithiocarbamate substituents. Cu(I) complexes, [Cu(S2CNR2)2]−, are (briefly) accessible in an electrochemical cell, and the only stable example is recently reported [Cu(S2CNH2)2][NH4]·H2O. Others readily lose a dithiocarbamate and the d10 centres can either be trapped with other coordinating ligands, especially phosphines, or form clusters with tetrahedral [Cu(μ3-S2CNR2)]4 being most common. Over the past decade, a wide range of Cu(I) dithiocarbamate clusters have been prepared and structurally characterised with nuclearities of 3–28, especially exciting being those with interstitial hydride and/or acetylide co-ligands. A range of mixed-valence Cu(I)–Cu(II) and Cu(II)–Cu(III) complexes are known, many of which show novel physical properties, and one Cu(I)–Cu(II)–Cu(III) species has been reported. Copper dithiocarbamates have been widely used as SSPs to nanoscale copper sulfides, allowing control over the phase, particle size and morphology of nanomaterials, and thus giving access to materials with tuneable physical properties. The identification of copper in a range of neurological diseases and the use of disulfiram as a drug for over 50 years makes understanding of the biological formation and action of [Cu(S2CNEt2)2] especially important. Furthermore, the finding that it and related Cu(II) dithiocarbamates are active anticancer agents has pushed them to the fore in studies of metal-based biomedicines.

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Section: Anticancer Agentsmentioning

confidence: 94%

Section: Anticancer Agentsmentioning

confidence: 99%

Section: Anticancer Agentsmentioning

confidence: 99%

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Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Hogarth

Onwudiwe

2021

Inorganics

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“…Their cellular uptake occurred via passive diffusion, and their mechanisms involved high DNA intercalation, intense DNA cleaving activity, and stimulation ROS production ( Barrett et al, 2020 ). [Cu( l -proline methyl ester DTC)2] copper compounds into micelles with a cancer-targeting biomolecule are presented as a proper “Trojan Horse” strategy for the delivery of Cu-DTC chemotherapeutics ( Brustolin et al, 2020 ).…”

Section: Copper Role In Cancermentioning

confidence: 99%

Role of Copper on Mitochondrial Function and Metabolism

Ruíz

Libedinsky

Elorza

2021

Front. Mol. Biosci.

264

174

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Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.

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“…It has been elucidated, from previous studies, that ruthenium derivatives are located in various cellular compartments (i.e., ER, mitochondria, nucleus for Ru derivatives, and cytoplasmic area for Au(III) derivatives) [ 35 , 36 ]. In this work, we focused our attention on the possible pathways implicated in causing cell death.…”

Section: Resultsmentioning

confidence: 99%

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

et al. 2021

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Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity. Many efforts have been spent in the last decades on achieving an early stage diagnosis of cancer, and more effective cures, leading to a decline in age-standardized cancer mortality rates. In the last years, our research groups have developed new metal-based complexes, with the aim to obtain a better selectivity for cancer cells and less side effects than the clinically established reference drug cisplatin. This work is focused on four novel Au(III) and Ru(III) complexes that share the piperidine dithiocarbamato (pipe-DTC) as the ligand, in a different molar ratio. The compounds [AuCl2(pipeDTC)], [Au(pipeDTC)2]Cl, [Ru(pipeDTC)3] and β-[Ru2(pipeDTC)5] have been synthesized and fully characterized by several chemical analyses. We have then investigated their biological properties in two different cell lines, namely, AGS (gastric adenocarcinoma) and HCT116 (colon carcinomas), showing significant differences among the four compounds. First, the two gold-based compounds and β-[Ru2(pipeDTC)5] display IC50 in the µM range, significantly lower than cisplatin. Second, we showed that [AuCl2(pipeDTC)] and β-[Ru2(pipeDTC)5]Cl drive different molecular mechanisms. The first was able to induce the protein level of the DNA damage response factor p53 and the autophagy protein p62, in contrast to the second that induced the ATF4 protein level, but repressed p62 expression. This study highlights that the biological activity of different complexes bringing the same organic ligand depends on the electronic and structural properties of the metal, which are able to fine tune the biological properties, giving us precious information that can help to design more selective anticancer drugs.

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Labelled micelles for the delivery of cytotoxic Cu(II) and Ru(III) compounds in the treatment of aggressive orphan cancers: Design and biological in vitro data

Cited by 10 publications

References 62 publications

Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Copper Dithiocarbamates: Coordination Chemistry and Applications in Materials Science, Biosciences and Beyond

Role of Copper on Mitochondrial Function and Metabolism

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells

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