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Publications

Rahn, J.; Lennicke, C.; Kipp, A. P.; Müller, A. S.; Wessjohann, L. A.; Lichtenfels, R.; Seliger, B. Altered protein expression pattern in colon tissue of mice upon supplementation with distinct selenium compounds Proteomics 17, 1600486, (2017) DOI: 10.1002/pmic.201600486

The essential trace element selenium (Se) is controversially discussed concerning its role in health and disease. Its various physiological functions are largely mediated by Se incorporation in the catalytic center of selenoproteins. In order to gain insights into the impact of Se deficiency and of supplementation with different Se compounds (selenite, selenate, selenomethionine) at defined concentrations (recommended, 150 μg/kg diet; excessive, 750 μg/kg diet) in murine colon tissues, a 20‐week feeding experiment was performed followed by analysis of the protein expression pattern of colon tissue specimens by 2D‐DIGE and MALDI‐TOF MS. Using this approach, 24 protein spots were identified to be significantly regulated by the different Se compounds. These included the antioxidant enzyme peroxiredoxin‐5 (PRDX5), proteins with binding capabilities, such as cofilin‐1 (COF1), calmodulin, and annexin A2 (ANXA2), and proteins involved in catalytic processes, such as 6‐phosphogluconate dehydrogenase (6PGD). Furthermore, the Se compounds demonstrated a differential impact on the expression of the identified proteins. Selected target structures were validated by qPCR and Western blot which mainly confirmed the proteomic profiling data. Thus, novel Se‐regulated proteins in colon tissues have been identified, which expand our understanding of the physiologic role of Se in colon tissue.
Publications

Pantelić, N.; Stanojković, T. P.; Zmejkovski, B. B.; Kaluđerović, G. N.; Sabo, T. J. Antiproliferative Activity of Gold(III) Complexes with Esters of Cyclohexyl-Functionalized Ethylenediamine-N,N’-Diacetate Serb J Exp Clin Res 18, 289-294, (2017) DOI: 10.1515/sjecr-2017-0067

Six gold(III) complexes with esters of cyclohexyl-functionalized ethylenediamine-N,N’-diacetate, general formula [AuCl2{(S,S)-R2eddch}]PF6, [(S,S)-eddch = (S,S)-ethylenediamine-N,N’-di-2-(3-cyclohexyl)propanoate, R = Me, Et, n-Pr, n-Bu, i-Bu, i-Am, 1–6, respectively], were tested against cancer cell lines such as human melanoma Fem-x, human colon carcinoma LS174T and non-small cell lung carcinoma A549 as well as a non-cancerous human embryonic lung fibroblasts MRC-5 using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay with the aim of assessing in vitro antitumoral activity and selectivity. All investigated complexes showed lower cytotoxicity and better or similar selectivity in comparison to cisplatin, used as reference compound. Complex [AuCl2{(S,S)-(i-Am)2eddch}]PF6 (6) demonstrated the highest activity against Fem-x (IC50 = 14.98 ± 0.34 μM). Additionally, the same complex expressed 4.5 times higher selectivity than cisplatin.
Publications

Lennicke, C.; Rahn, J.; Kipp, A. P.; Dojčinović, B. P.; Müller, A. S.; Wessjohann, L. A.; Lichtenfels, R.; Seliger, B. Individual effects of different selenocompounds on the hepatic proteome and energy metabolism of mice BBA-Gen Subjects 1861, 3323-3334, (2017) DOI: 10.1016/j.bbagen.2016.08.015

BackgroundSelenium (Se) exerts its biological activity largely via selenoproteins, which are key enzymes for maintaining the cellular redox homeostasis. However, besides these beneficial effects there is also evidence that an oversupply of Se might increase the risk towards developing metabolic disorders. To address this in more detail, we directly compared effects of feeding distinct Se compounds and concentrations on hepatic metabolism and expression profiles of mice.MethodsMale C57BL6/J mice received either a selenium-deficient diet or diets enriched with adequate or high doses of selenite, selenate or selenomethionine for 20 weeks. Subsequently, metabolic parameters, enzymatic activities and expression levels of hepatic selenoproteins, Nrf2 targets, and additional redox-sensitive proteins were analyzed. Furthermore, 2D-DIGE-based proteomic profiling revealed Se compound-specific differentially expressed proteins.ResultsWhereas heterogeneous effects between high concentrations of the Se compounds were observed with regard to body weight and metabolic activities, selenoproteins were only marginally increased by high Se concentrations in comparison to the respective adequate feeding. In particular the high-SeMet group showed a unique response compromising higher hepatic Se levels in comparison to all other groups. Accordingly, hepatic glutathione (GSH) levels, glutathione S-transferase (GST) activity, and GSTpi1 expression were comparably high in the high-SeMet and Se-deficient group, indicating that compound-specific effects of high doses appear to be independent of selenoproteins.ConclusionsNot only the nature, but also the concentration of Se compounds differentially affect biological processes.
Publications

Hübner, D.; Kaluđerović, M. R.; Gómez-Ruiz, S.; Kaluđerović, G. N. Anionic chlorido(triphenyl)tin(IV) bearing N-phthaloylglycinato or 1,2,4-benzenetricarboxylato 1,2-anhydride ligands: potential cytotoxic and apoptosis-inducing agents against several types of cancer Chem Biol Drug Des 89, 628-633, (2017) DOI: 10.1111/cbdd.12885

Two ionic triphenyltin(IV) chloride carboxylate compounds of the formula [NHEt3][Ph3SnCl(L)] [LH = N-phthaloylglycine (P-GlyH), 1; 1,2,4-benzenetricarboxylic 1,2-anhydride (BTCH), 2] were tested for the in vitro activity against 518A2 (melanoma), FaDu (head and neck carcinoma), HT-29 (colon cancer), MCF-7 (breast carcinoma), and SW1736 (thyroid cancer) cell lines. The ammonium salts of the carboxylic acids are found to be not active, while anionic [Ph3SnCl(L)]− exhibited high cytotoxicity in nM range, both higher activity and selectivity than cisplatin. Compounds 1 and 2 are inducing apoptosis, which was proved with the morphological and biochemical features such as membrane blebbing, translocation of phosphatidylserine, and DNA fragmentation. Thus, accumulation of cells in sub-G1 phase is observed. Both anionic organotin(IV) compounds showed potent cytotoxic and apoptotic properties against five cancer cell lines of various histogenetic origin.
Publications

Kaluđerović, G. N.; Bulatović, M.; Krajnović, T.; Paschke, R.; Zmejkovski, B. B.; Maksimović-Ivanić, D.; Mijatović, S. (18-Crown-6)potassium(I) Trichlorido[28-acetyl-3-(tris-(hydroxylmethyl)amino-ethane)betulinic ester-κN]platinum(II): Synthesis and In Vitro Antitumor Activity Inorganics 5, 56, (2017) DOI: 10.3390/inorganics5030056

Synthesis of platinum(II) conjugate with acetylated betulinic acid tris(hydroxymethyl)aminomethane ester (BATRIS) is presented (BATRISPt). HR-ESI-MS and multinuclear NMR spectroscopy, as well as elemental analysis were used for characterization of BATRISPt. Cytotoxicity (3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), crystal violet (CV), and sulforhodamine B (SRB) assays) of BA, BATRIS, BATRISPt, and cisplatin were assessed on seven different tumor cell lines: melanoma B16, colon HCT116 and DLD-1, adenocarcinoma HeLa, breast MCF-7, and anaplastic thyroid tumor 8505C and SW1736; as well as normal MRC-5 fibroblasts. Furthermore, the effect of the mentioned compounds on the apoptosis (Annexin V/PI assay) and autophagy induction (acridine orange (AO) assay) as well as caspase 3, 8, and 9 activation were investigated on the selected B16 melanoma cell line. BATRISPt showed lower activity than BA, BATRIS, or cisplatin. All tested compounds triggered apoptosis in B16 cells. Induction of autophagy was observed in B16 cells exposed only to BATRIS. On the other hand, new conjugate activates caspases 8 and 9 in B16 cells with higher impact than BATRIS or cisplatin alone.
Publications

Zmejkovski, B. B.; Pantelić, N.; Filipović, L.; Aranđelović, S.; Radulović, S.; Sabo, T. J.; Kaluđerović, G. N. In Vitro Anticancer Evaluation of Platinum(II/IV) Complexes with Diisoamyl Ester of (S,S)-ethylenediamine-N,N’-di-2-propanoic Acid Anti-Cancer Agents Med Chem 17, 1136-1143, (2017) DOI: 10.2174/1871520616666161207155634

Platinum(II) and platinum(IV) complexes [PtCln{(S,S)-(i-Am)2eddip}] (n = 2, 4: 1, 2, respectively; (S,S)-(i-Am)2eddip = O,O’-diisoamyl-(S,S)-ethylenediamine-N,N’-di-2-propanoate) were synthesized and characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and mass spectrometry. Quantum chemical calculations were used to predict formed isomers of 1 and 2. Furthermore, reduction of 2 with ascorbic acid was followed by time-dependant 13C NMR spectroscopy in order to enable assignation of the formed isomers for complex 1. In vitro cytotoxic activity was determined for 1 and 2 on a panel of five human tumor cell lines derived from cervix adenocarcinoma (HeLa), alveolar basal adenocarcinoma (A549), breast adenocarcinoma (MDA-453), colorectal cancer (LS 174), erythromyeloblastoid leukemia (K562), as well as one non-malignant human lung fibroblast cell line (MRC-5), using MTT assay. Both complexes exhibited high (2 against K562: IC50 = 5.4 µM), more active than cisplatin, to moderate activity (1). Both complexes caused considerable decrease of cell number in K562 cells in G1, S and G2 phases, concordantly increasing subpopulation in sub-G1 fraction. Morphological analysis of K562 cell death induced by platinum(II/IV) complexes indicate apoptosis. 
Publications

Pantelić, N.; Zmejkovski, B. B.; Kolundžija, B.; Crnogorac, M. Đ.; Vujić, J. M.; Dojčinović, B.; Trifunović, S. R.; Stanojković, T. P.; Sabo, T. J.; Kaluđerović, G. N. In vitro antitumor activity, metal uptake and reactivity with ascorbic acid and BSA of some gold(III) complexes with N,N′-ethylenediamine bidentate ester ligands J Inorg Biochem 172, 55-66, (2017) DOI: 10.1016/j.jinorgbio.2017.04.001

Four novel gold(III) complexes of general formulae [AuCl2{(S,S)-R2eddl}]PF6 (R2eddl = O,O′-dialkyl-(S,S)-ethylenediamine-N,N′-di-2-(4-methyl)pentanoate, R = n-Pr, n-Bu, n-Pe, i-Bu; 1–4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N′-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24 h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC50: 5.04–6.51 μM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner.
Publications

Janković-Tomanikć, M.; Todorović, D.; Stanivuković, Z.; Perić Mataruga, V.; Wessjohann, L. A.; Kaluđerović, G. N. Mesoporous silica nanoparticles SBA-15 loaded with emodin upregulate the antioxidative defense of Euproctis chrysorrhoea  (L.) larvae. Turk J Biol 41, 935-942, (2017) DOI: 10.3906/biy-1705-76

The study presented here aims to elucidate the effects of emodin (EO = 1,3,8-trihydroxy-6-methylanthraquinone) in its free form and when loaded into a mesoporous silica nanocarrier SBA-15 (→ SBA-15|EO) on the activities of the main antioxidative enzymes, superoxide dismutase, catalase, glutathione S-transferase, and glutathione reductase, in larvae of a polyphagous insect pest, the browntail moth Euproctis chrysorrhoea (L.). The results show that only SBA-15|EO upregulates the activities of the tested antioxidative enzymes. These results point to significant differences in the effectiveness of the compound in the free versus the loaded form.
Publications

Paudel, G.; Bilova, T.; Schmidt, R.; Greifenhagen, U.; Berger, R.; Tarakhovskaya, E.; Stöckhardt, S.; Balcke, G. U.; Humbeck, K.; Brandt, W.; Sinz, A.; Vogt, T.; Birkemeyer, C.; Wessjohann, L.; Frolov, A Osmotic stress is accompanied by protein glycation in Arabidopsis thaliana J. Exp. Bot. 67, 6283-6295, (2016) DOI: 10.1093/jxb/erw395

Among the environmental alterations accompanying oncoming climate changes, drought is the most important factor influencing crop plant productivity. In plants, water deficit ultimately results in the development of oxidative stress and accumulation of osmolytes (e.g. amino acids and carbohydrates) in all tissues. Up-regulation of sugar biosynthesis in parallel to the increasing overproduction of reactive oxygen species (ROS) might enhance protein glycation, i.e. interaction of carbonyl compounds, reducing sugars and α-dicarbonyls with lysyl and arginyl side-chains yielding early (Amadori and Heyns compounds) and advanced glycation end-products (AGEs). Although the constitutive plant protein glycation patterns were characterized recently, the effects of environmental stress on AGE formation are unknown so far. To fill this gap, we present here a comprehensive in-depth study of the changes in Arabidopsis thaliana advanced glycated proteome related to osmotic stress. A 3 d application of osmotic stress revealed 31 stress-specifically and 12 differentially AGE-modified proteins, representing altogether 56 advanced glycation sites. Based on proteomic and metabolomic results, in combination with biochemical, enzymatic and gene expression analysis, we propose monosaccharide autoxidation as the main stress-related glycation mechanism, and glyoxal as the major glycation agent in plants subjected to drought. 
Publications

Bensing, C.; Mojić, M.; Gómez-Ruiz, S.; Carralero, S.; Dojčinović, B.; Maksimović-Ivanić, D.; Mijatović, S.; Kaluđerović, G. N. Evaluation of functionalized mesoporous silica SBA-15 as a carrier system for Ph3Sn(CH2)3OH against the A2780 ovarian carcinoma cell line Dalton T. 45, 18984-18993, (2016) DOI: 10.1039/C6DT03519A

SBA-15|Sn3, a mesoporous silica-based material (derivative of SBA-15) loaded with an organotin compound Ph3Sn(CH2)3OH (Sn3), possesses improved antitumor potential against the A2780 high-grade serous ovarian carcinoma cell line in comparison to Sn3. It is demonstrated that both the compound and the nanostructured material are internalized by the A2780 cells. A similar mode of action of Sn3 and SBA-15|Sn3 against the A2780 cell line was found. Explicitly, induction of apoptosis, caspase 2, 3, 8 and 9 activation, accumulation of cells in the hypodiploid phase as well as accumulation of ROS were observed. Interestingly, Sn3 loaded in the mesoporous silica-based material needed to reach a concentration 3.5 times lower than the IC50 value of the Sn3 compound, pointing out a higher effect of the SBA-15|Sn3 than Sn3 alone. Clonogenic potential, growth in 3D culture as well as mobility of cells were disturbed in the presence of SBA-15|Sn3. Such behavior could be associated with the suppression of p-38 MAPK. Less profound effect of Sn3 compared to SBA-15|Sn3 could be attributed to a different regulation of p-38 and STAT-3, which are mainly responsible for an appropriate cellular response to diverse stimuli or metastatic properties.

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