• MeSH
• klinické laboratorní techniky MeSH
• krevní nemoci diagnóza   MeSH

We report on the preparation and thorough characterization of cytotoxic half-sandwich complexes [Ru(η⁶-pcym)(bphen)(dca)]PF₆ (Ru-dca) and [Os(η⁶-pcym)(bphen)(dca)]PF₆ (Os-dca) containing dichloroacetate(1-) (dca) as the releasable O-donor ligand bearing its own cytotoxicity; pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), bphen = 4,7-diphenyl-1,10-phenanthroline (bathophenanthroline). Complexes Ru-dca and Os-dca hydrolyzed in the water-containing media, which led to the dca ligand release (supported by ¹H NMR and electrospray ionization mass spectra). Mass spectrometry studies revealed that complexes Ru-dca and Os-dca do not interact covalently with the model proteins cytochrome c and lysozyme. Both complexes exhibited slightly higher in vitro cytotoxicity (IC50 = 3.5 μM for Ru-dca, and 2.6 μM for Os-dca) against the A2780 human ovarian carcinoma cells than cisplatin (IC50 = 5.9 μM), while their toxicity on the healthy human hepatocytes was found to be IC50 = 19.1 μM for Ru-dca and IC50 = 19.7 μM for Os-dca. Despite comparable cytotoxicity of complexes Ru-dca and Os-dca, both the complexes modified the cell cycle, mitochondrial membrane potential, and mitochondrial cytochrome c release by a different way, as revealed by flow cytometry experiments. The obtained results point out the different mechanisms of action between the complexes.

• MeSH
• fenantroliny chemie   farmakologie   MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• kyselina dichloroctová chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• nádory vaječníků farmakoterapie   MeSH
• osmium chemie   MeSH
• proliferace buněk účinky léků   MeSH
• ruthenium chemie   MeSH
• uvolňování léčiv MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Conventional chemotherapy is mostly effective in the treatment of rapidly-dividing differentiated tumor cells but has limited application toward eliminating cancer stem cell (CSC) population. The presence of a very small number of CSCs may contribute to the development of therapeutic resistance, metastases, and relapse. Thus, treatment failure by developing novel anticancer drugs capable of effective targeting of CSCs is at present a major challenge for research focused on chemotherapy of cancer. Here, we show that Os(II) complex 2 [Os(η6-pcym)(bphen)(dca)]PF6 (pcym = p-cymene, bphen = bathophenanthroline, and dca = dichloroacetate), is capable of efficient and selective killing CSCs in heterogeneous populations of human breast cancer cells MCF-7 and SKBR-3. Notably, its remarkable submicromolar potency to kill CSCs is considerably higher than that of its Ru analog, [Ru(η6-pcym)(bphen)(dca)]PF6 (complex 1) and salinomycin, one of the most selective CSC-targeting compounds hitherto identified. Furthermore, Os(II) complex 2 reduces the formation, size, and viability of three-dimensional mammospheres which more closely reflect the tumor microenvironment than cells in traditional two-dimensional cultures. The antiproliferation studies and propidium iodide staining using flow cytometry suggest that Os(II) complex 2 induces human breast cancer stem cell death predominantly by necroptosis, a programmed form of necrosis. The results of this study demonstrate the promise of Os(II) complex 2 in treating human breast tumors. They also represent the foundation for further preclinical and clinical studies and applications of Os(II) complex 2 to comply with the emergent need for human breast CSCs-specific chemotherapeutics capable to treat chemotherapy-resistant and relapsed human breast tumors.

• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza účinky léků   MeSH
• chloracetáty farmakologie   MeSH
• cymeny farmakologie   MeSH
• fenantroliny farmakologie   MeSH
• komplexní sloučeniny farmakologie   MeSH
• lidé MeSH
• lokální recidiva nádoru patologie   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   MeSH
• nádorové mikroprostředí účinky léků   MeSH
• nádory prsu farmakoterapie   patologie   MeSH
• nekroptóza účinky léků   MeSH
• nekróza metabolismus   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• osmium farmakologie   MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The effects of two anticancer active copper(II) mixed-ligand complexes of the type [Cu(qui)(mphen)]Y·H2O, where Hqui = 2-phenyl-3-hydroxy- 1H-quinolin-4-one, mphen = bathophenanthroline, and Y = NO3 (complex 1) or BF4 (complex 2) on the activities of different isoenzymes of cytochrome P450 (CYP) have been evaluated. The screening revealed significant inhibitory effects of the complexes on CYP3A4/5 (IC50 values were 2.46 and 4.88 μM), CYP2C9 (IC50 values were 16.34 and 37.25 μM), and CYP2C19 (IC50 values were 61.21 and 77.07 μM). Further, the analysis of mechanisms of action uncovered a non-competitive type of inhibition for both the studied compounds. Consequent studies of pharmacokinetic properties proved good stability of both the complexes in phosphate buffer saline (>96% stability) and human plasma (>91% stability) after 2 h of incubation. Both compounds are moderately metabolised by human liver microsomes (<30% after 1 h of incubation), and over 90% of the complexes bind to plasma proteins. The obtained results showed the potential of complexes 1 and 2 to interact with major metabolic pathways of drugs and, as a consequence of this finding, their apparent incompatibility in combination therapy with most chemotherapeutic agents.

• Publikační typ
• časopisecké články MeSH

Two copper(II) complexes containing diplacone (H4dipl), a naturally occurring C-geranylated flavanone derivative, in combination with bathophenanthroline (bphen) or 1,10-phenanthroline (phen) with the composition [Cu3(bphen)3(Hdipl)2]⋅2H2O (1) and {[Cu(phen)(H2dipl)2]⋅1.25H2O}n (2) were prepared and characterized. As compared to diplacone, the complexes enhanced in vitro cytotoxicity against A2780 and A2780R human ovarian cancer cells (IC50 ≈ 0.4-1.2 μM), human lung carcinoma (A549, with IC50 ≈ 2 μM) and osteosarcoma (HOS, with IC50 ≈ 3 μM). Cellular effects of the complexes in A2780 cells were studied using flow cytometry, covering studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production. These results uncovered a possible mechanism of action characterized by the G2/M cell cycle arrest. The studies on human endothelial cells revealed that complexes 1 and 2, as well as their parental compound diplacone, do possess anti-inflammatory activity in terms of NF-κB inhibition. As for the effects on PPARα and/or PPARγ, complex 2 reduced the expression of leukocyte adhesion molecules VCAM-1 and E-selectin suggesting its dual anti-inflammatory capacity. A wide variety of Cu-containing coordination species and free diplacone ligand were proved by mass spectrometry studies in water-containing media, which might be responsible for multimodal effect of the complexes.

• MeSH
• antiflogistika farmakologie   chemie   MeSH
• antitumorózní látky * farmakologie   chemie   chemická syntéza   MeSH
• autofagie účinky léků   MeSH
• flavanony * farmakologie   chemie   MeSH
• komplexní sloučeniny * farmakologie   chemická syntéza   chemie   MeSH
• lidé MeSH
• měď * chemie   farmakologie   MeSH
• nádorové buněčné linie MeSH
• proliferace buněk * účinky léků   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The effects of four copper(II) mixed-ligand complexes [Cu(qui1)(L)]NO3·H2O (1-3) and [Cu(qui2)(phen)]NO3 (4), where qui1=2-phenyl-3-hydroxy-4(1H)-quinolinone, Hqui2=2-(4-amino-3,5-dichlorophenyl)-N-propyl-3-hydroxy-4(1H)-quinolinone-7-carboxamide, L=1,10-phenanthroline (phen) (1), 5-methyl-1,10-phenanthroline (mphen) (2), bathophenanthroline (bphen) (3), on transcriptional activities of steroid receptors, nuclear receptors and xenoreceptors have been studied. The complexes (1-4) did not influence basal or ligand-inducible activities of glucocorticoid receptor, androgen receptor, thyroid receptor, pregnane X receptor and vitamin D receptor, as revealed by gene reporter assays. The complexes 1 and 2 dose-dependently induced luciferase activity in stable gene reporter AZ-AhR cell line, and this induction was reverted by resveratrol, indicating involvement of aryl hydrocarbon receptor (AhR) in the process. The complexes 1, 2 and 3 induced CYP1A1 mRNA in LS180 cells and CYP1A1/CYP1A2 in human hepatocytes through AhR. Electrophoretic mobility shift assay EMSA showed that the complexes 1 and 2 transformed AhR in its DNA-binding form. Collectively, we demonstrate that the complexes 1 and 2 activate AhR and induce AhR-dependent genes in human hepatocytes and cancer cell lines. In conclusion, the data presented here might be of toxicological importance, regarding the multiple roles of AhR in human physiology and pathophysiology.

• MeSH
• aktivace transkripce účinky léků   MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• cytochrom P-450 CYP1A2 biosyntéza   genetika   MeSH
• dospělí MeSH
• dusičnany toxicita   MeSH
• enzymová indukce MeSH
• fenantroliny toxicita   MeSH
• genetická transkripce účinky léků   MeSH
• hepatocyty účinky léků   enzymologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• ligandy MeSH
• měď toxicita   MeSH
• messenger RNA biosyntéza   genetika   MeSH
• MFC-7 buňky MeSH
• primární buněčná kultura MeSH
• receptory aromatických uhlovodíků agonisté   genetika   metabolismus   MeSH
• senioři MeSH
• transfekce MeSH
• transkripční faktory bHLH agonisté   genetika   metabolismus   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH

A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2'-hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(NN)(μ-L)Cu(NN)](NO3)2⋅nH2O (n = 0-2) (1-5), where NN stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2'-bipyridine, 2), mebpy (5,5'-dimethyl-2,2'-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 ≈ 0.35-7.8 μM. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential. SYNOPSIS: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.

• MeSH
• antitumorózní látky * farmakologie   chemie   MeSH
• apoptóza MeSH
• chalkon * farmakologie   MeSH
• chalkonoidy * farmakologie   MeSH
• komplexní sloučeniny * farmakologie   chemie   MeSH
• lidé MeSH
• ligandy MeSH
• měď chemie   MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků * MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Six mixed-ligand copper(II) complexes with the composition [Cu(qui)(L)]BF(4)·xH(2)O (1-6), where Hqui=2-phenyl-3-hydroxy-4(1H)-quinolinone, L=2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), bis(2-pyridyl)amine (ambpy) (3), 5-methyl-1,10-phenanthroline (mphen) (4), 5-nitro-1,10-phenanthroline (nphen) (5) and bathophenanthroline (bphen) (6), were prepared, fully characterized and studied for their in vitro cytotoxicity on human osteosarcoma (HOS) and human breast adenocarcinoma (MCF7) cancer cell lines. The overall promising results of the cytotoxicity were found for all the complexes, while the best results were achieved for complex 6, with IC(50)=2.6 ± 0.8 μM (HOS), and 1.3 ± 0.5 μM (MCF7). The interactions of the Cu(II) complexes 1-6 with calf thymus DNA were investigated by the UV-visible spectral titration. An agarose-gel electrophoretic method of oxidative damage determination to circular plasmid pUC19 was used to assess the ability of the complexes to act as chemical nucleases. A high effectiveness of DNA cleavage was observed for 2, 4 and 5. In vitro antioxidative activity of the complexes was studied by the superoxide dismutase-mimic (SOD-mimic) method. The best result was afforded by complex 1 with IC(50)=4.7 ± 1.0 μM, which corresponds to 10.2% of the native Cu,Zn-SOD enzyme activity. The ability of the tested complexes to interact with sulfur-containing biomolecules (cysteine and reduced glutathione) at physiological levels was proved by electrospray-ionization mass spectrometry (ESI-MS).

• MeSH
• chinoliny chemie   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
• ligandy MeSH
• molekulární mimikry MeSH
• Ramanova spektroskopie MeSH
• spektrofotometrie ultrafialová MeSH
• spektroskopie infračervená s Fourierovou transformací MeSH
• štěpení DNA účinky léků   MeSH
• superoxiddismutasa metabolismus   MeSH
• techniky in vitro MeSH
• termogravimetrie MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH