The anti-metastatic agent imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway

doi:10.1016/S0003-9861(02)00218-7

Archives of Biochemistry and Biophysics

Volume 403, Issue 2, 15 July 2002, Pages 209-218

https://doi.org/10.1016/S0003-9861(02)00218-7 Get rights and content

Abstract

Imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate (NAMI-A) is a new ruthenium compound active against lung metastasis in vivo and tumor cell invasion in vitro. Since angiogenesis was recognized as a key event in the metastasizing process, the manipulation of neo-vessel formation has been developed as a new therapeutic approach. Within this context, a pivotal role for apoptosis in regulating cellular growth has been proposed. In the present study, we exposed to NAMI-A the spontaneously transformed human endothelial cell line ECV304 and assessed a number of apoptosis-related features, including the DNA degradation rate, the activation of caspase-3 protease, the expression of Hsp27, and the release of cytochrome c. Cell treatment with NAMI-A elicited a significant increment in the apoptotic response, as indicated by DNA fragmentation and caspase-3 activation, two classical hallmarks of cellular suicide. Furthermore, NAMI-A was able to down-regulate Hsp27 protein expression and provoke the release of mitochondrial cytochrome c in the cytosol. Here, we analyze the involvement of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signal transduction pathway in the induction of apoptosis elicited by NAMI-A. Such a response was associated with a marked inhibition of MAPK/ERK kinase (MEK) and ERK phosphorylation with a time course and dose dependency overlapping those observed throughout NAMI-A-induced apoptosis. In addition, we report that PD98059, a selective MEK inhibitor, is able to induce apoptosis by itself in the ECV304 cell line. These results suggest that inhibition of MEK/ERK signaling by NAMI-A may have an important role in modulating an apoptotic event in ECV304.

Section snippets

Materials and methods

Cell culture. ECV304 is a spontaneously transformed, immortalized endothelial cell line established from the vein of an apparently normal human umbilical cord. Recent investigations indicate that this cell line is a suitable model for providing novel insights into the mechanisms governing angiogenesis under both physiological and pathological conditions [10]. The ECV304 cell line was provided by European Collection of Animal Cell Cultures (Salisbury, United Kingdom). ECV304 cells were grown in

Results

NAMI-A induces apoptosis in ECV304 cells. Using a radioactive fragmentation assay we assessed the percentage of DNA fragmentation as a measure of apoptosis. In the presence of $100 μM$ NAMI-A, cells showed a significant increase in DNA fragmentation after 24 h of exposure, as compared to untreated cells (Fig. 2A). Such an effect time-dependently increased with a maximum at 72 h (Fig. 2A) and occurred in a dose-dependent fashion, peaking after a 72-h treatment with $100 μM$ NAMI-A (inset of Fig. 2A).

Discussion

Ruthenium complexes characterized by the presence of at least one sulfoxide ligand have been shown to interfere with the processes of metastasis formation of solid tumors [13]. Among these complexes, NAMI-A was found to selectively reduce metastasis formation, significantly prolonging the lifetime expectancy of tumor-bearing mice. The most peculiar aspect is that the antimetastatic effect of NAMI-A seems unrelated to the concomitant effect at the primary tumor site and independent of the direct

Acknowledgements

We thank Ms. Annalisa Cossu for her technical assistance.

References (18)

P.C. Brooks et al.
Cell
(1994)
T.S. Lewis
Adv. Cancer Res.
(1998)
Y. Ishikawa et al.
Biochem. Biophys. Res. Commun.
(1999)
S.E. Hughes
Exp. Cell Res.
(1996)
E.A. Harrington et al.
Curr. Opin. Genet. Dev.
(1994)
G. Sava et al.
Anticancer Drugs
(1999)
A. Bergamo et al.
J. Pharmacol. Exp. Ther.
(1999)
S. Zorzet et al.
J. Pharmacol. Exp. Ther.
(2000)
J. Folkman
Nat. Med.
(1995)

There are more references available in the full text version of this article.

Cited by (67)

A review on metal complexes and its anti-cancer activities: Recent updates from in vivo studies
2024, Biomedicine and Pharmacotherapy
Research into cancer therapeutics has uncovered various potential medications based on metal-containing scaffolds after the discovery and clinical applications of cisplatin as an anti-cancer agent. This has resulted in many metallodrugs that can be put into medical applications. These metallodrugs have a wider variety of functions and mechanisms of action than pure organic molecules. Although platinum-based medicines are very efficient anti-cancer agents, they are often accompanied by significant side effects and toxicity and are limited by resistance. Some of the most studied and developed alternatives to platinum-based anti-cancer medications include metallodrugs based on ruthenium, gold, copper, iridium, and osmium, which showed effectiveness against many cancer cell lines. These metal-based medicines represent an exciting new category of potential cancer treatments and sparked a renewed interest in the search for effective anti-cancer therapies. Despite the widespread development of metal complexes touted as powerful and promising in vitro anti-cancer therapeutics, only a small percentage of these compounds have shown their worth in vivo models. Metallodrugs, which are more effective and less toxic than platinum-based drugs and can treat drug-resistant cancer cells, are the focus of this review. Here, we highlighted some of the most recently developed Pt, Ru, Au, Cu, Ir, and Os complexes that have shown significant in vivo antitumor properties between 2017 and 2023.
Ruthenium(III) and (II) complexes containing pyridine moiety: Synthesis, crystal structure and in vitro biological evaluation
2022, Journal of Molecular Structure
In the present study, reaction of tridentate chelating hydrazone Schiff base N'-(phenyl(pyridine-2-yl)methylidene)benzhydrazide (HL) with [Ru^IIICl₃(PPh₃)₃] afforded ruthenium(III) and ruthenium(II) complexeswith the composition of [Ru^III(L)Cl₂(PPh₃)] (1), [Ru^II(L)Cl(CO)(PPh₃)] (2) and [Ru^II(Bp)Cl(CO)(PPh₃)] (3) (where Bp= benzoyl pyridine) in one pot reaction. The molecular structures of synthesized complexes were examined by single crystal X-ray diffraction technique which revealed that the complexes are neutral in charge with distorted octahedral geometry. Further, the stability of the complexes were calculated theoretically and interaction of them with biomolecules resulted in change in binding energies dramatically. Complexes1–3 were evaluated for their interaction with calf thymus DNA (CT DNA) and bovine serum albumin (BSA) using theoretical as well as spectral techniques. In addition, the in vitro cytotoxic potential of the synthesised compounds were investigated against human breast cancer cell models (MCF-7 and MDAMB-453).
Enhanced bacterial uptake of <sup>131</sup>I -labeled antimicrobial imidazolium bromide salts using fluorescent carbon nanodots
2021, Materials Today Communications
Citation Excerpt :
Imidazolium salts (IMS) have been used in a variety of areas due to their inherent merits such as ease of synthesis, biocompatibility, high chemical and thermal stability, high ionic conductivity, and a wide electrochemical window [1–6].
Imidazolium bromide salts have been shown as potent antibiotic molecules that show structure-based bioactivity related to their cation alkyl side chain length. To enhance the bioavailability of lipophilic alkyl side chains herein, a 1,8-naphthalimide group containing imidazolium bromide salts bearing different lengths of alkyl chains (NIM1, 2, and 3) are coupled with fluorescent carbon dots (C-NIMs) through electrostatic and pi-pi interactions. Further, obtained nanocarriers were radio-labeled with iodine-131 (¹³¹I) to track the bacterial uptake of them by Staphylococcus aureus and Escherichia coli. Antibacterial activities were also investigated by the microdilution method. Comparison studies showed that both radiolabeling efficiency and lipophilicity increased when NIMs were integrated onto the CDots. More importantly, CDots resulted in 4-fold enhanced uptake of NIM1 by S. aureus bacterium as compared to pristine imidazolium bromide salts while at a higher number of alkyl chain lengths enhancement was 2-fold.
Berberine and ginsenoside Rg3 act synergistically via the MAPK/ERK pathway in nasopharyngeal carcinoma cells
2020, Journal of Functional Foods
Herein, we investigated the effects of combining berberine (Ber; the major active constituent of Rhizoma coptidis) with ginsenoside Rg3 (Rg3; an active ingredient of Panax ginseng) on the proliferation and apoptosis of nasopharyngeal carcinoma (NPC) cells, and explored the underlying mechanism. Combining Ber with Rg3 synergistically inhibited the proliferation of NPC CNE2 cells in vitro and in vivo. Additionally, Ber combined with Rg3 induced apoptosis by promoting the expression of apoptosis-related protein Bax, and inhibiting the expression of Survivin, PCNA and anti-apoptotic protein Bcl-2. Ber combined with Rg3 plays a role in anti-NPC through MAPK/ERK pathway. Ber combined with Rg3 is a potent natural combination agent with potential for treating and preventing NPC.
Carbonyl–heterobimetallic Ru(II)/Fe(II)–complexes containing polypyridyl ligands: Synthesis, characterization, cellular viability assays and interactions with biomolecules
2018, Archives of Biochemistry and Biophysics
Citation Excerpt :
The advent of the first metal based therapeutic agents, cisplatin, launched a new era in the application of transition metal complexes for therapeutic design, but it is known that all the anticancer drugs utilized in clinic exhibit serious side effects and acquired resistance [3–7]. Thus, the development of new anticancer agents is needed and due to their unique and versatile biochemical properties, ruthenium–based compounds are promising alternatives for the available platinum(II)–chemotherapeutic agents utilized in clinics [8–15]. Ruthenium ions has the ability to mimic iron ions in binding to biomolecules such as albumin and transferrin and offer different mechanisms of action against cancer cells from that one established by platinum metallodrugs [16–18].
This paper describes on the interaction studies of carbonyl heterobimetallic compounds of Ru(II)/Fe(II) containing polypyridyl ligands, with general formula ct–[RuCl(CO)(N–N)(dppf)]PF₆, N–N = 1,10–phenanthroline (phen) 5; dipyrido[3,2–f:2′,3′–h]quinoxaline (dpq) 6; dipyrido[3,2–a:2′,3′–c]phenazine (dppz) 7; dipyrido[3,2–f:2′,3′–h]quinoxalino[2,3–b]quinoxaline (dpqQX) 8 and dppf = 1,1‘–bis(diphenylphosphino) ferrocene], with calf thymus DNA (ct–DNA) and bovine serum albumin (BSA). Also, it describes the cellular viability assays of these complexes in tumorigenic and non-tumorigenic cell lines. The carbonyl complexes 5–8 and their respective precursors with formula cis–[RuCl₂(N–N)(dppf)], N–N = phen (1), dpq (2), dppz (3) and dpqQX (4), were characterized by elemental analysis and spectroscopic techniques (FTIR, UV–vis, ¹H and ³¹P{¹H} NMR). Also, a cyclic voltammetry study was performed for all complexes. The crystal structure of the complex 3 is presented and discussed. Spectrofluorimetric titrations shows spontaneous and strong interaction of 5–8 with BSA, through a static quenching mechanism, resulting in binding constants in the order of 10⁴–10⁶ L mol⁻¹, at 310 K. Viscosity measurements and circular dichroism spectra prompts interactions of 5–8 with ct–DNA via non–classical intercalations or by an electrostatic pathway. MTT assays in breast tumor cells MDA–MB–231 and in non-tumorigenic cells MCF-10A and V79–4 cell lines revealed IC₅₀ values ranging from 0.19 to 1.11 μmol L⁻¹, 1.07–3.18 μmol L⁻¹ and 1.29–3.85 μmol L⁻¹ respectively, for complexes 5–8.
Ruthenium(II) complexes of 2,2′-bipyridine-5,5′-dicarboxylic acid: Synthesis, structure, DNA binding, cytotoxicity and antioxidant activity
2013, Inorganica Chimica Acta
Two new Ru(II) complexes [RuH(HL)(PPh₃)₂(CO)] (1) and [RuH(HL)(AsPh₃)₂(CO)] (2) (HL = 2,2′-bipyridine-5,5′-dicarboxylic acid) were synthesized and characterized by analytical and spectral methods. X-ray diffraction was additionally used to characterize 1 in solid state which disclosed a distorted octahedral geometry around ruthenium with HL as neutral bidentate donor. The interactions of these complexes with DNA were explored by different techniques which revealed that the complexes could bind to CT-DNA through non-intercalation. The complexes have also been tested against a panel of cancer cell lines and a normal cell line which showed that the complexes exhibited substantial cytotoxic specificity towards cancer cells. In addition, antioxidant activity tests showed that the new complexes possess significant radical scavenging activity against free radicals outperforming standard antioxidants.

View all citing articles on Scopus

^☆: This study represents work done within the frame of the COST D20/0005/01 and supported by grants from Ministero della Sanità, Ministero dell'Istruzione Università e Ricerca, University of Sassari “Young Researches Grant.”

View full text

The anti-metastatic agent imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate induces endothelial cell apoptosis by inhibiting the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway☆

Abstract

Section snippets

Materials and methods

Results

Discussion

Acknowledgements

Cell

Adv. Cancer Res.

Biochem. Biophys. Res. Commun.

Exp. Cell Res.

Curr. Opin. Genet. Dev.

Anticancer Drugs

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Nat. Med.