Lora Dyakova

In this study, we present new data about the cytotoxic activity of metal complexes of salinomycin with Co(II), Cu(II) and Zn(II) against human cervical cancer (HeLa) and melanoma (A375, SH-4) cell lines. The effect of the compounds on cell viability and proliferation was evaluated in short-term experiments (up to 72 h) with monolayer cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test, neutral red uptake (NR), crystal violet staining (CV) and double staining with acridine orange (AO) and propidium iodide (PI). The cytotoxic effect of the metal complexes of salinomycin was found to be comparable and even superior to that of the commercial antitumor agents cisplatin and oxaliplatin. Long-term experiments revealed the ability of the compounds to completely suppress 3D cell growth when applied at concentrations ≥ 3.1 μM (for HeLa cells) and ≥6.2 µM (for A375 cells). Embryonic Lep-3 cells are highly sensitive to the influence of the complexes investigated, whereas non-tumor HaCaT human keratinocytes exhibit relatively higher resistance to their cytotoxic effect compared to tumor cell lines. The Zn(II) disalinomycinate exerted the highest selectivity index among the tested compounds against melanoma cells, whereas the non-coordinated antibiotic showed pronounced selectivity toward HeLa cells.

The challenges of glioblastoma multiforme treatment are related to limitations in tumor removal surgery, its high heterogeneity and aggressiveness, development of resistance to standard therapy, the blood–brain barrier, and the side and toxic effects of the conventional antitumor agents used in clinical practice. Although new treatment strategies continue to emerge, progress remains slow and has not resulted in substantial improvements in patient survival. The main goal of research in recent years has been aimed at developing ways to deal with all these challenges. One of the ways to improve the control of glioblastomas is the introduction of effective new antitumor agents. Metal complexes represent a particularly promising class of compounds in this context. This is why the aim of this study was to assess the effects of six homo- and heterometallic coordination compounds bearing Schiff base ligands—[Zn₂(Ampy)(µ-OH)(H₂O)₂](ClO₄)₂ (ZnAmpy), [Zn₂(Dmen)(µ-OH)(H₂O)₂](ClO₄)₂ (ZnDmen), ¹_∞[{Zn₂(Ampy)(μ₃-OH)}₂(H₂O){μ-[Au(CN)₂]}](ClO₄)₃·THF·H₂O (ZnAmpyAu), [{Zn₂(Dmen)(μ-OH)}₂{μ-[Au(CN)₂]}{[Au(CN)₂]₂}](ClO₄)·H₂O (ZnDmenAu), ¹_∞[Zn(Salampy){μ-Au(CN)₂}] (ZnSalampyAu), and ¹_∞[Zn(Saldmen)(μ-Au(CN)₂}] (ZnSaldmenAu)—on the viability and proliferation of 8MGBA and U251MG human glioblastoma multiforme cells (HDmen and HAmpy are bicompartmental Schiff base ligands resulting from the condensation of 2,6-diformyl-p-cresol with N,N-dimethylethylenediamine and 2-(aminomethyl)pyridine, respectively, while HSaldmen and HSalampy are tridentate Schiff base ligands obtained via condensation of salicylaldehyde with N,N-dimethylethylenediamine and 2-(aminomethyl)pyridine, respectively). Among these compounds, ZnSaldmenAu is a new compound and is reported here for the first time. Cytotoxicity of the compounds was evaluated through analysis of cell viability, 2D/3D growth, cytopathological alterations, and induction of cell death. The results obtained by methods with different targets in cells and the associated mechanisms of action revealed that the compounds investigated show promising cytotoxic/potential antitumor activity in treated cells.

In this study we demonstrated for the first time synthetic procedures for composites of salinomycin (SalH) and two-line ferrihydrite. The products were characterized by various methods such as elemental analysis, attenuated total reflectance–Fourier-transform spectroscopy (ATR-FTIR), electron paramagnetic resonance spectroscopy (EPR), powder X-ray diffraction analysis (XRD), electrospray-ionization mass spectrometry (ESI-MS), thermogravimetric analysis with differential thermal analysis (DTA) and mass spectrometry (TG-DTA/MS). The EPR spectra of the isolated compounds consisted of signals associated with both isolated Fe³⁺ ions and magnetically coupled Fe³⁺ ions. Powder XRD analyses of the isolated products showed two intense and broad peaks at 9° and 15° 2Θ, corresponding to salinomycinic acid. Broad peaks with very low intensity around 35°, assigned to two-line ferrihydrite, were also registered. Based on the experimental results, we concluded that salinomycin sodium reacted with Fe(III) chloride to form composites consisting of two-line ferrihydrite and salinomycinic acid. One of the composites exerted pronounced antitumor activity in the sub-micromolar concentration range against human cervical cancer (HeLa), non-small-cell lung cancer (A549), colon cancer (SW480), and ovarian teratocarcinoma (CH1/PA1) cells.

Hepatitis E virus (HEV) is a single-stranded positive-sense RNA virus that belongs to Hepeviridae family. HEV is the most common cause of acute viral hepatitis worldwide. According to the World Health Organization (WHO), there are estimated 20 million HEV infections worldwide every year, leading to estimated 3.3 million symptomatic cases of HEV infection. The WHO estimates that HEV infection caused approximately 44,000 deaths in 2015, which represents 3.3% of mortality rates due to viral hepatitis. In low-income (LI) countries and lower-middle-income (LMI) countries, HEV is a waterborne infection induced by HEV genotype (gt) 1 and HEV gt 2 that cause large outbreaks and affect young individuals with a high mortality rate in pregnant women from South Asian countries and patients with liver diseases. HEV gt 3, HEV gt 4, and HEV gt 7 are responsible for sporadic infections with zoonotic transmission mainly through the consumption of raw or undercooked meat from different animals. Acute HEV infection is relatively asymptomatic or mild clinical form, in rare cases the disease can be moderate/severe clinical forms and result in fulminant hepatitis or acute liver failure (ALF). Furthermore, HEV infection is associated with extrahepatic manifestations, including renal and neurological clinical signs and symptoms. Pregnant women, infants, older people, immunocompromised individuals, patients with comorbidities, and workers who come into close contact with HEV-infected animals are recognized as major risk groups for severe clinical form of HEV infection and fatal outcome. Chronic HEV infection can occur in immunocompromised individuals with the possibility of progression to cirrhosis.

Two new families of Cu(II) and Co(II) mononuclear complexes with mixed ligands, [Cu(VanTrpt)(bipy)]·MeOH (CuVanTrpt), [Cu(VanSer)(bipy)]·4H₂O (CuVanSer), [Cu(VanTyr)(bipy)]·H₂O (CuVanTyr), [Cu(VanThr)(bipy)]·MeOH (CuVanThr), [Co(VanTrpt)(bipy)(OH₂)]·H₂O·MeOH (CoVanTrpt), [Co(VanSer)(bipy)(OH₂)]·MeOH (CoVanSer), [Co(VanTyr)(bipy)(OH₂)]·3H₂O·MeOH (CoVanTyr), and [Co(VanThr)(bipy)(OH₂)] (CoVanThr), (VanX are Schiff base proligands resulted from the condensation of o‐vanillin with D,L‐tryptophan (VanTrpt), L‐serine (VanSer), L‐tyrosine (VanTyr), and L‐threonine (VanThr), respectively, and bipy is 2,2′‐bipyridine), have been obtained and characterized on the basis of elemental analysis, magnetic measurements, and spectral data (FT‐IR and UV–Vis–Nir spectroscopy). Crystal structures of CuVanTrpt, CuVanSer, and CuVanTyr have been solved by single‐crystal X‐Ray diffraction. Biological evaluation revealed that they are cytotoxic in HeLa (human carcinoma of the uterine cervix) and LSR‐SF‐SR (rat sarcoma induced by Rous sarcoma virus strain Schmidt‐Ruppin) cells, showing an enhancement of cytotoxicity dependent of concentration and treatment time. The most pronounced cytotoxic effect is expressed by CuVanSer and CoVanSer. Various cytopathological changes of both types of cancer cells were observed after treatment with Cu(II) and Co(II) complexes for 72 h at concentrations of 100 and 200 μg ml⁻¹. LSR‐SF‐SR cells were found to be relatively more sensitive to the cytotoxic effect of the complexes investigated as compared to HeLa cells.

Objective: The aim of our study was to evaluate the influence of two complexes of Zn(II)/Au(I) and Zn(II)/Ag(I) with Schiff base ligand (H2Salen) obtained from the condensation reaction between salicylaldehyde and ethylenediamine (abbreviated ZnSalenAu, ZnSalenAg) on viability and proliferation of cultured human cancer cells.Methods: The following cell lines were used as model systems: Human cervical carcinoma (cervical carcinoma), A549 (non-small cell lung cancer [NSCLC]), glioblastoma multiforme (8MGBA), and A431 (squamous cell carcinoma) and its multidrug-resistant (MDR) clones A431-MDR, A431-MRP, and A431-ABCG2 that express mdr1, mrp1, or abcg2 gene, respectively. The investigations were performed by thiazolyl blue tetrazolium bromide test, neutral red uptake cytotoxicity assay, crystal violet staining, hematoxylin and eosin staining, double staining with acridine orange, and propidium iodide in short-term experiments (12–72 h, with monolayer cell cultures) as well as colony-forming method in long-term experiments (25 days, with three dimensional cancer cell colonies).Results: The results obtained revealed that ZnSalenAu and ZnSalenAg decreased significantly viability and proliferation of the treated cells in a time- and concentration-dependent manner being more active as compared to the free ligand H2Salen.Conclusion: The present study demonstrates for the 1st time the ability of two heterometallic complexes ZnSalenAu and ZnSalenAg to decrease significantly viability and proliferation of cultured cell lines established from some of the most common and aggressive human cancers (NSCLC, carcinoma of uterine cancer, 8MGBA, and squamous cell carcinoma) as well as MDR cancer cells.