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Background: α-Aminophosphonates are potentially biologically active species. Objective: We wished to compare the synthetic methods and evaluate the effect of the α- aminophosphonates on sarcoma cell lines. Methods: We investigated microwave-assisted Kabachnik–Fields and Pudovik reactions, as well as substitutions, and applied in vitro cytotoxicity screening. Results: The Kabachnik–Fields condensation and the Pudovik reaction were found to be the most suitable regarding efficiency. Surprisingly, the multidrug resistant (MDR) uterine sarcoma (Mes-Sa/Dx5) cell line was the most susceptible to the aminophosphonates tested. Conclusions: α-Aminophosphonates may indeed display anticancer effect. Substituents in the para position of the phenyl ring have an impact on the activity: the 4-Me and 4-Cl derivatives were more toxic to all cell lines as compared to the 4-H and 4-MeO species.

Supplementary Figure 1: MDR-selective toxicity of NSC297366 in additional MDR cell lines

Structure of the compounds analyzed in this study

Supplementary tables and figures, supplementary materials and methods

Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366–iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance.Significance:Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a “double-edged sword” that can be turned against resistant cancer.

A recently proposed strategy to overcome multidrug resistance (MDR) in cancer is to target the collateral sensitivity of otherwise resistant cells. We designed a library of 120 compounds to explore the chemical space around previously identified 8-hydroxyquinoline-derived Mannich bases with robust MDR-selective toxicity. We included compounds to study the effect of halogen and alkoxymethyl substitutions in R5 in combination with different Mannich bases in R7, a shift of the Mannich base from R7 to R5, as well as the introduction of an aromatic moiety. Cytotoxicity tests performed on a panel of parental and MDR cells highlight a strong influence of experimentally determined p

Aims: Due to their significant biological activity, thiosemicarbazones (TSCs) are promising candidates for anticancer therapy. In part, the efficacy of TSCs is linked to their ability to chelate essential metal ions such as copper and iron. Triapine, the best-studied anticancer TSC, has been tested clinically with promising results in hematological diseases. During the past few years, a novel subclass of TSCs with improved anticancer activity was found to induce paraptosis, a recently characterized form of cell death. The aim of this study was to identify structural and chemical properties associated with anticancer activity and paraptosis induction of TSCs. Results: When testing a panel of structurally related TSCs, compounds with nanomolar anticancer activity and paraptosis-inducing properties showed higher copper(II) complex solution stability and a slower reduction rate, which resulted in reduced redox activity. In contrast, TSCs with lower anticancer activity induced higher levels of superoxide that rapidly stimulated superoxide dismutase expression in treated cells, effectively protecting the cells from drug-induced redox stress. Innovation: Consequently, we hypothesize that in the case of close Triapine derivatives, intracellular reduction leads to rapid dissociation of intracellularly formed copper complexes. In contrast, TSCs characterized by highly stable, slowly reducible copper(II) complexes are able to reach new intracellular targets such as the endoplasmic reticulum-resident protein disulfide isomerase. Conclusion: The additional modes of actions observed with highly active TSC derivatives are based on intracellular formation of stable copper complexes, offering a new approach to combat (drug-resistant) cancer cells.

The experiments were set up in large parcels at the Fleischmann Rudolf Research Institute of Eszterházy Károly University located in Kompolt. We carried out measurements by using a Penetronik penetrometer (electrical soil cone penetrometer) at the experimental site, where brown grassland soil as well as clay washed brown forest soil are the typical soil types. The device used primarily serves to investigate the physical and water management properties of soils suitable for agricultural cultivation. The instrument is a hand-operated tool for registering soil mechanical resistance in Newtons (0-1000 N) and also the moisture content of the topsoil (%) at the same time. The recording of the location of the measurement is made by the built-in GPS, and the results of the measurements are saved to the SD card of the device. The device’s data acquisition unit allows direct reading of measurement results, serial measurements and computer processing of results (0-70 cm). Taking our objectives into consideration, we defined the location of measuring points with various numbers according to the properties of the examined fields. Besides designating measuring points at a distance of 0, 5, 10, 15, 20 and 30 m from the edge of the fields, we designated two more in the middle of each field in all cases. The examined crop species included sand oats (Avena strigosa), baltacim (Onobrychis viciifolia) as well as common vetch (Vicia sativa L.) with oats as a companion crop. Summing up the measurement results, we have made the following statements: Low soil resistance (127-131 N) was experienced after soil loosening and oat-vetch with higher, well-preserved soil moisture content observed at each level, where the 50% moisture content of the soil started at the layer of 27 cm depth. Moderate soil resistance values (150-168 N) were manifested in the case of soil tillage with loosening and ploughing after sand oats. In this case, the 50 % soil moisture content was observed at the layer of 38 cm depth. Higher soil resistance values were found (171-196 N) in the case of 2 and 3-year-old crops of baltacim, respectively, where the 50 % soil moisture content was recorded from the layer of 58 cm depth. Based on the results, we consider it important to develop and improve soil tillage systems

Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η5-C5Me5) and Ru(η6-p-cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.

The earth's population is growing steadily, currently accounting for about 7.3 billion people. Population growth causes food demand to rise, approximately 36 million people die each year due to starvation or related diseases. One solution to this problem is the continuous examination and development of the agricultural economy. In this study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI -TOF MS) were used to analyse of sunflower, soybean and hemp. In order to analyse the protein of maize, this method has already been applied. However, for sunflower, soy and hemp, it is necessary to develop a sample preparation method. Choosing the optimal matrix solution for ionization the traget molecule is an essential part of developing the method. Our aim is to compare two different matrix solutions (α-HCCA, SA matrix), based on the properties (intensity, noise ratio, value of spectra) of the spectra.

Membrane transporters play an important role in the absorption, distribution, metabolism and excretion of drugs. The cellular accumulation of many drugs is the result of the net function of efflux and influx transporters. Efflux transporters such as P-glycoprotein/ABCB1 have been shown to confer multidrug resistance in cancer. Although expression of uptake transporters has been confirmed in cancer cells, their role in chemotherapy response has not been systematically investigated. In the present study we have adapted a fluorescence-based cytotoxic assay to characterize the influence of key drug-transporters on the toxicity of approved anticancer drugs. Co-cultures of fluorescently labeled parental and transporter-expressing cells (expressing ABCB1, ABCG2 or OATP2B1) were screened against 101 FDA-approved anticancer drugs, using a novel, automated, triple fluorescence-based cytotoxicity assay. By measuring the survival of parental and transporter-expressing cells in co-cultures, we identify those FDA-approved anticancer drugs, whose toxicity is influenced by ABCB1, ABCG2 or OATP2B1. In addition to confirming known substrates of ABCB1 and ABCG2, the fluorescence-based cytotoxicity assays identified anticancer agents whose toxicity was increased in OATP2B1 expressing cells. Interaction of these compounds with OATP2B1 was verified in dedicated transport assays using cell-impermeant fluorescent substrates. Understanding drug-transporter interactions is needed to increase the efficacy of chemotherapeutic agents. Our results highlight the potential of the fluorescence-based HT screening system for identifying transporter substrates, opening the way for the design of therapeutic approaches based on the inhibition or even the exploitation of transporters in cancer cells. Electronic supplementary material The online version of this article (10.1007/s00204-019-02417-6) contains supplementary material, which is available to authorized users.

We synthesized substituted benzaldehyde derived α-hydroxyphosphonates (αOHP), α-hydroxyphosphonic acids (αOHPA) and α-phosphinoyloxyphosphonates (αOPP) and characterized their cytotoxicity against a panel of cancer cell lines. A library containing 56 analogues was screened against Mes-Sa parental and Mes-Sa/Dx5 multidrug resistant uterine sarcoma cell lines, using a fluorescence-based cytotoxicity assay. The cytotoxicity screening revealed that dibenzyl-αOHPs and dimethyl-α-diphenyl-OPPs were the most active clusters, which encouraged us to synthesize further dibenzyl-α-diphenyl-OPP derivatives that elicited pronounced cell killing. Further structure–activity relationships showed the relevance of hydrophobicity and the position of substituents on the main benzene ring as determinants of toxicity. The most active analogs proved to be equally, or even more toxic to the multidrug resistant (MDR) cell line Mes-Sa/Dx5, suggesting these compounds may overcome P-glycoprotein mediated multidrug resistance by evading the drug transporter.

The effects of soil bacteria treatments on barley and wheat (1. treatment: stubble decomposers + soil inoculators; 2. stubble decomposers + soil regenerators; 3. control) were studied at the Agricultural Research Institute in Kompolt on spectral vegetation indices which are closely related to photochemical processes and photosynthetic pigments in barley and wheat leaves. We appliedin vivofield measurements: SPAD 502 relative chlorophyll meter and ASD Field Spec Pro 3 spectroradiometer. This work presents the results of the experiments in 2019, moreover, we compared them with our previously published investigations on several other crops (maize, sunflower, rape, barley) carried out in 2017 and 2018. In 2019 despite the significant level of the standard deviation of data in field conditions, treated (mainly with stubble decomposers + soil inoculators) wheat leaves could be characterized by significantly higher chlorophyll and water content, higher photochemical efficiency, and lower carotenoid content. In the case of barley due to the large standard deviation of data, we couldn’t reveal the beneficial effects of treatments by these methods. Due to the very rainy spring in 2019 some experimental plots - like K9 with barley – wre covered by inland water, which negatively influenced living conditions of soil bacteria. Despite this unfavourable conditions, the first treatment resulted in an 18.9% higher yield of barley and 27.8% higher yield of wheat, while the second treatment increased barley yield with 28.9% and wheat yield with 27.7%. In the case of wheat, spectral vegetation indices could indicate beneficial effects of soil bacteria treatments at the beginning of flowering, similarly to our results in 2017 and 2018 in case of maize, sunflower, rape, and barley.

The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure&ndash, activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells.

The Fleischmann Rudolf Research Institute in Kompolt is not only famous for plant breeding but the institute also surveys the effects of different nutrient supply methods since 1918. In 2017, we joined this research supported by EFOP 3.6.1 project. Our aim was to investigate photochemical processes – which is one of the most determinant in case of yield – of crops by in vivo field measurements. We measured the chlorophyll content of leaves using Minolta SPAD 502. We used miniPAM fluorometer to determine actual photochemical efficiency and non-photochemical quenching of PSII during natural light conditions and also to evaluate the pigment (chlorophylls and carotenoids) and water content of leaves we applied field spectrophotometer (ASD FieldSpecPro 3). We utilized these methods by various treatments (1. treatment with soil bacteria + head and base fertilizer; 2. treated by only head fertilizer; 3. treated by only base-fertilizer) in field experiment of autumn wheat (4.1–2.43–1.19 ha) in June, 2017. The difference between treatments was clearly detectable. In the case of the first treatment, physiological processes were more intense and the ripening occurred earlier. The obtained yield was the highest in the case of the area treated by soil bacterial. Based on the results, the first treatment can be recommended in practice.

Cyclic NGR peptides as homing devices are good candidates for the development of drug conjugates for targeted tumor therapy. In our previous study we reported that the Dau=Aoa-GFLGK(c[KNGRE]-GG-)-NH2 conjugate has a significant antitumor activity against both CD13+ HT-1080 human fibrosarcoma and CD13− but integrin positive HT-29 human colon adenocarcinoma cells. However, it seems that the free ε-amino group of Lys in the cycle is not necessary for the biological activity. Therefore, we developed novel cyclic NGR peptide–daunomycin conjugates in which Lys was replaced by different amino acids (Ala, Leu, Nle, Pro, Ser). The exchange of the Lys residue in the cycle simplified the cyclization step and resulted in a higher yield. The new conjugates showed lower chemostability against deamidation of Asn than the control compound, thus they had lower selectivity to CD13+ cells. However, the cellular uptake and cytotoxic effect of Dau=Aoa-GFLGK(c[NleNGRE]-GG-)-NH2 was higher in comparison to the control especially on HT-29 cells. Therefore, this conjugate is more suitable for drug targeting with dual targeting property.

Economically, one of our most important crop is the sunflower. Regarding its production it is essential to use top quality seeds. As the conditions of seed certification and the certification parameters are regulated by laws and ordinances, it is highly important to farmers and seed producers to detect seeds of low quality or dubious origins.Nowadays, the examination of the cultivar homogenity of sunflower is based on a reference method of the International Seed Testing Association Rules International (ISTA), Chapter 8. This standard reference method uses ultrathin poliakrilamid isoelectric focusing gel electrophoresis (IEF-UTL, or simply IEF). With this work we have set out to compare the results of MALDI-TOF to the test results – used as reference results – achieved by this reference method. The aim is to develop a new, quick, cheap and reliable method. In this article I summarized the results of some of the experiments that will provide basis for my further work.During our previous experiments we have concluded that out of four extracting agents we can get the most protein markers using NaCl acid buffer, 1 propanol buffer.

Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)–overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1−/−;p53−/− spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer. Mol Cancer Ther; 16(1); 45–56. ©2016 AACR.

The aim of this study is to analyze the position of the Hungarian Party to the Romania’s Hungarian peasantry. I intend to analyze the party elite position on this issue and the importance the Hungarian peasants represented to this political elite. I will analyze then the election campaign made by the Hungarian Party in the rural areas, approached methods to the peasantry by the candidates and the effectiveness of this election campaign. I will also analyze the position of the Hungarian peasantry to the Hungarian Party (sympathy for the Hungarian Party or to other political parties) and its participation in the inter-war elections.

The RASopathy consortium was built from research groups of the Budapest University of Technology and Economics, Eötvös Loránd University, Semmelweis University and two startups: KINETO Lab Ltd. and Fototronic Ltd. The goal was to design and test novel covalent and allele-specific KRAS small molecular inhibitors. KRAS is the most frequently mutated human oncogene which was unsuccessfully targeted until recently. The consortium established G12C-expressing bacterial and human cancer cell models (homo- and heterozygous variants) of lung, colorectal and pancreatic tumors. Using covalent fragment and acrylamide warhead libraries we were able to select novel candidates of small molecular G12C-specific inhibitors which were compared to published best-in-class drug candidates.Az NVKP pályázati konstrukció keretében 2017-ben kezdte meg közös munkáját a Semmelweis Egyetem, a Budapesti Mûszaki és Gazdaságtudományi Egyetem, az Eötvös Loránd Tudományegyetem és két innovatív vállalkozás, a KINETO Lab Kft. és a Fototronic Kft. Fõ célkitûzésünk az emberi rosszindulatú daganatokban nagy gyakorisággal károsodott KRAS fehérje onkogén mutánsainak célzott támadása, allélspecifikus inhibitorok fejlesztése. Az emberi RAS fehérje és annak izoformái (HRAS, KRAS) kiemelkedõ szerepet játszanak a jelátvitelben, helyes mûködésük az életképesség fenntartásához elengedhetetlen, egyes pontmutációik azonban a jelpálya túlzott erõsítését váltják ki, ami tumorok képzõdését okozza. Kidolgoztuk a KRAS G12C mutáns fehérjét expresszáló bakteriális rendszert, homo- és heterozigóta emberi tüdõ-, vastagbél- és pankreászrák-sejtvonalakat. Potenciális új inhibitor tervezéséhez kovalens fragmens és akrilamid-fej könyvtárakat használtunk. Referenciaként a jelenlegi legjobb kovalens inhibitorokat használva számos új gyógyszerjelölt kismolekulájú inhibitort azonosítottunk, amelyek G12C KRAS- és daganatsejt-specifikusnak bizonyultak.

Background Homologous recombination (HR) repair deficiency arising from defects in BRCA1 or BRCA2 is associated with characteristic patterns of somatic mutations. In this genetic study, we ask whether inactivating mutations in further genes of the HR pathway or the DNA damage checkpoint also give rise to somatic mutation patterns that can be used for treatment prediction. Results Using whole genome sequencing of an isogenic knockout cell line panel, we find a universal HR deficiency-specific base substitution signature that is similar to COSMIC signature 3. In contrast, we detect different deletion phenotypes corresponding to specific HR mutants. The inactivation of BRCA2 or PALB2 leads to larger deletions, typically with microhomology, when compared to the disruption of BRCA1, RAD51 paralogs, or RAD54. Comparison with the deletion spectrum of Cas9 cut sites suggests that most spontaneously arising genomic deletions are not the consequence of double-strand breaks. Surprisingly, the inactivation of checkpoint kinases ATM and CHK2 has no mutagenic consequences. Analysis of tumor exomes with biallelic inactivating mutations in the investigated genes confirms the validity of the cell line models. We present a comprehensive analysis of sensitivity of the investigated mutants to 13 therapeutic agents for the purpose of correlating genomic mutagenic phenotypes with drug sensitivity. Conclusion Our results suggest that no single genomic mutational class shows perfect correlation with sensitivity to common treatments, but the contribution of COSMIC signature 3 to base substitutions, or a combined measure of different features, may be reasonably good at predicting platinum and PARP inhibitor sensitivity.

Clinical evidence shows that following initial response to treatment, drug-resistant cancer cells frequently evolve and, eventually, most tumors become resistant to all available therapies. We compiled a focused library consisting of >500 commercially available or newly synthetized 8-hydroxyquinoline (8OHQ) derivatives whose toxicity is paradoxically increased rather than decreased by the activity of P-glycoprotein (Pgp), a transporter conferring multidrug resistance (MDR). Here, we deciphered the mechanism of action of NSC297366 that shows exceptionally strong Pgp-potentiated toxicity. Treatment of cells with NSC297366 resulted in changes associated with the activity of potent anticancer iron chelators. Strikingly, iron depletion was more pronounced in MDR cells due to the Pgp-mediated efflux of NSC297366–iron complexes. Our results indicate that iron homeostasis can be targeted by MDR-selective compounds for the selective elimination of multidrug resistant cancer cells, setting the stage for a therapeutic approach to fight transporter-mediated drug resistance. Significance: Modulation of the MDR phenotype has the potential to increase the efficacy of anticancer therapies. These findings show that the MDR transporter is a “double-edged sword” that can be turned against resistant cancer.

ABC multidrug transporters are key players in cancer multidrug resistance and in determining the ADME-Tox properties of drugs and xenobiotics. The most sensitive and specific detection of these transporters is based on functional assays. Assessment of the transporter-dependent reduction of cellular uptake of the fluorescent dyes, such as Hoechst 33342 (Ho) and more recently DyeCycle Violet (DCV), have been widely advocated for the characterization of both ABCB1 and ABCG2 multidrug transporters. Detailed comparison of these supravital DNA-binding dyes revealed that DCV is less toxic to ABCG2- and ABCB1-expressing cells than Ho. ATPase measurements imply that DCV and Ho are similarly handled by ABCB1, whereas ABCG2 seems to transport DVC more effectively. In addition, we have developed an image-based high content microscopy screening method for simultaneous in situ measurement of the cellular activity and expression of the ABCG2 multidrug transporter. We demonstrated the applicability of this method for identifying ABCG2-positive cells in heterogeneous cell population by a single dye uptake measurement. These results may promote multidrug transporter studies at a single cell level and allow the quantitative detection of clinically important drug-resistant sub-populations. © 2016 International Society for Advancement of Cytometry.

Com breeding can be successful only on a broad base of genetic material. The expansion of breeding aims includes the research of germplasm materials. In our experiments, we examined 11 blue, purple and red exotic com varieties on two locations in Hungary. We conducted a complex study to obtain more information. We studied several morphological and phenological features and determined the most important qualitative parameters (protein, fat, ash). Results show that there are great opportunities in exotic com varieties. Their quality exceeds that of the yellow ones in many cases. There are significant differences in yield and nutritional parameters. The favourable nutritional composition is not coupled with great productivity. Based on their flowering time and their agronomical features, they can be cultivated under Hungarian conditions as well. They match the new breeding aims, so they can be used as functional food or energy plants. The cultivation of alternative crops has an important role in world agriculture. Their market share is continuously growing in the food industry rector.

Triapine, which is currently tested in a clinical phase III trial, is the best-studied thiosemicarbazone (TSC) for anticancer therapy. With regard to the mode of action, anticancer activity of TSCs is frequently linked to their ability to chelate essential metal ions such as copper and iron. As Triapine monotherapy showed promising results mainly against hematological diseases, novel TSC derivatives have been developed and clinically investigated for their activity against solid tumors. These novel TSCs belong to a subclass with enhanced anticancer activity in vitro and in vivo which were recently discovered to induce paraptosis, a form of programmed but caspase-independent cell death. As these TSCs are characterized by a up to 1000-fold higher activity in cell culture compared to Triapine, the aim of this study was to elucidate the mechanism of action as well as the underlying structural and chemical requirements of these effects. For this purpose, a panel of structurally related Triapine derivatives was examined for anticancer activity (as metal-free ligand and copper(II) complex), paraptosis-inducing potential as well as solution stability and redox properties of their copper(II) complexes. Correlation studies between these chemical and biological properties revealed that the increased anticancer activity and paraptosis-inducing potential of the nanomolar active TSCs is related to a higher copper(II) complex solution stability and slower reduction rate. Unexpectedly, the TSCs with lower activity produced higher superoxide levels in a cell-free setting. This paradox could be explained by their lower copper(II) complex stability and increased readiness to be reduced, which resulted in a fast reduction of intracellular complexes and release of the metal-free ligand. Although this process resulted in the generation of superoxide, cell damage seemed to be prevented by rapid upregulation of the superoxide dismutase (in vitro and in vivo). In contrast, the copper complexes of the highly active TSCs are stable enough to reach intracellular targets such as the ER-resident protein disulfide isomerase, whose inhibition is crucial for paraptosis induction by TSCs. In conclusion, copper complex stability is a crucial parameter of TSC activity, influencing the (intracellular) formation or dissociation of copper complexes. This intracellular stability of complexes, affects their mechanism of action as well as cell death induction. Overall, this study points out the importance of the redox parameters in order to understand and predict the TSC anticancer activity as well as their mechanism of action and, thereby, will pave the way for the development of improved anticancer agents. Citation Format: Sonja Hager, Veronika F. Pape, Vivien Pósa, Bianca Montsch, Lukas Uhlik, Gergely Szakàcs, Szilárd Tóth, Nikolett Jabronka, Bernhard K. Keppler, Walter Berger, Christian R. Kowol, Éva A. Enyedy, Petra Heffeter. Improved activity and paraptosis-induction of anticancer thiosemicarbazones requires high copper(II) complex stability and slow reduction kinetics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1939.

Drug resistant tuberculosis (TB) is a major worldwide health problem. In addition to the bacterial mechanisms, human drug transporters limiting the cellular accumulation and the pharmacological disposition of drugs also influence the efficacy of treatment. Mycobacterium tuberculosis topoisomerase-I (MtTopo-I) is a promising target for antimicrobial treatment. In our previous work we have identified several hit compounds targeting the MtTopo-I by in silico docking. Here we expand the scope of the compounds around three scaffolds associated with potent MtTopo-I inhibition. In addition to measuring the effect of newly generated compounds on MtTopo-I activity, we characterized the compounds' antimicrobial activity, toxicity in human cells, and interactions with human multidrug transporters. Some of the newly developed MtTopo-I inhibitors have strong antimicrobial activity and do not harm mammalian cells. Moreover, our studies revealed significant human ABC drug transporter interactions for several MtTopo-I compounds that may modify their ADME-Tox parameters and cellular effects. Promising new drug candidates may be selected based on these studies for further anti-TB drug development.

Im Artikel wird es versucht, die Erscheinungen der estnischen Sprache, die zur Movierung (Motion) zugeordnet werden konnen, im ostseefinnischen und europaischen Kontext diachronisch in ihrer Dynamik zu beschreiben. Es wird eine Antwort auf die Frage gesucht, ob das Fehlen der Kategorie des grammatischen Genus im Estnischen die Movierung als Mittel der Wortschatzerweiterung zulasst. Auf der Grundlage der Grammatik Johannes Gutslaffs wird bewiesen, dass im Estnischen das Wortbildungssuffix -ik auch fur Bildung der Feminina gedient hat. Die erwiesene uralte ostseefinnische Gendermarkierung (genauer: die Markierung des Sexus) hangt mit der Markierung der stereotypisch geringen Grose der Frau zusammen. Die Sexusneutralisierung des Suffixes hatte im 18. Jahrhundert ihren Anfang. Deren Grund war eine komplizierte Abfolge von Bedeutungsveranderungen von bestimmten Lexemen.

There is a constant need for new therapies against multidrug-resistant (MDR) cancer. Natural compounds are a promising source of novel anticancer agents. We recently showed that protoflavones display activity in MDR cancer cell lines that overexpress the P-glycoprotein (P-gp) drug efflux pump. In this study, 52 protoflavones, including 22 new derivatives, were synthesized and tested against a panel of drug-sensitive parental cells and their MDR derivatives obtained by transfection with the human ABCB1 or ABCG2 genes, or by adaptation to chemotherapeutics. With the exception of protoapigenone, identified as a weak ABCG2 substrate, all protoflavones bypass resistance conferred by these two transporters. The majority of the compounds were found to exhibit mild to strong (up to 13-fold) selectivity against the MCF-7Dox and KB-V1 cell lines, but not to transfected MDR cells engineered to overexpress the MDR transporters. Our results suggest that protoflavones can overcome MDR cancer by evading P-gp-mediated efflux.

Success of cancer treatment is often hampered by the emergence of multidrug resistance (MDR) mediated by P-glycoprotein (ABCB1/Pgp). Doxorubicin (DOX) is recognized by Pgp and therefore it can induce therapy resistance in breast cancer patients. In this study our aim was to evaluate the susceptibility of the pegylated liposomal formulation of doxorubicin (PLD/Doxil®/Caelyx®) to MDR. We show that cells selected to be resistant to DOX are cross-resistant to PLD and PLD is also ineffective in an allograft model of doxorubicin-resistant mouse B-cell leukemia. In contrast, PLD was far more efficient than DOX as reflected by a significant increase of both relapse-free and overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. Increased survival could be explained by the delayed onset of drug resistance. Consistent with the higher Pgp levels needed to confer resistance, PLD administration was able to overcome doxorubicin insensitivity of the mouse mammary tumors. Our results indicate that the favorable pharmacokinetics achieved with PLD can effectively overcome Pgp-mediated resistance, suggesting that PLD therapy could be a promising strategy for the treatment of therapy-resistant breast cancer patients.

Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide-daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2). The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma) and CD13 negative HT-29 (human colon adenocarcinoma) cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions.

ABC multidrug transporters are key players in cancer multidrug resistance and in determining the ADME-Tox properties of drugs and xenobiotics. The most sensitive and specific detection of these transporters is based on functional assays. Assessment of the transporter-dependent reduction of cellular uptake of the fluorescent dyes, such as Hoechst 33342 (Ho) and more recently DyeCycle Violet (DCV), have been widely advocated for the characterization of both ABCB1 and ABCG2 multidrug transporters. Detailed comparison of these supravital DNA-binding dyes revealed that DCV is less toxic to ABCG2- and ABCB1-expressing cells than Ho. ATPase measurements imply that DCV and Ho are similarly handled by ABCB1, whereas ABCG2 seems to transport DVC more effectively. In addition, we have developed an image-based high content microscopy screening method for simultaneous in situ measurement of the cellular activity and expression of the ABCG2 multidrug transporter. We demonstrated the applicability of this method for identifying ABCG2-positive cells in heterogeneous cell population by a single dye uptake measurement. These results may promote multidrug transporter studies at a single cell level and allow the quantitative detection of clinically important drug-resistant sub-populations. © 2016 International Society for Advancement of Cytometry.

There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells.

Sweet sorghum can be utilized for bioethanol production because it has high sugar content (14-17%). We determined the most important nutritional values of 5 silo type sorghum lines in waxy and full maturation. The examined restorer lines were: RL 4, RL 9, RL 15, RL 18, K 1. The following nutritional parameters were examined: dry material content, refractometric total sugar content, reducing sugar content. In waxy maturation 73.85-87.37% of dry matter in stalk juice makes the total sugar. Dry material content, total and reducing sugar content of stalkdecreases from waxy mature to full maturation.There are differences between lines in dry matter (SzD5%=0.76), total sugar (SzD5%=0.79), reducing sugar content (SzD5%=0.30). RL 4 performed a decrease in total sugar content from 10.07% to 10.02% during this period, reducing sugar also decreased from 4.01% to 2.47%. RL 9 performed a decrease in total sugar content from 11.76% to 11.08% during this period. Reducing sugar also decreased from 3.17% to 2.01% in the waxymaturation. RL 15 showed a total sugar content decrease from 15.43 % to 15.36%. The reducing sugar also decreased from 3.23% to 1.71% in waxy maturation. In RL 18 total mean sugar content during waxy maturation was 13.78% which dropped to 13.26% approaching full maturation. Reducing sugar also decreased from 4.11% to 2.23% in waxy mature. K 1 performed a decrease in total sugar content from 9.35% to 6.15% during this period, while reducing sugar also decreased from 1.52% to 0.77%. These lines upcoming for experiments are perspectives since having excellent stalk juice nutritional parameters they are of great or very great height and their stalks are thick-very thick, stalk medullas are wet.

Anticancer compounds are typically identified in in vitro screens. Unfortunately, the in vitro drug sensitivity of cell lines does not reflect treatment efficiency in animal models, and neither show acceptable correlation to clinical results. While cell lines and laboratory animals can be readily "cured", the treatment of malignancies remains hampered by the multidrug resistance (MDR) of tumors. Genetically engineered mouse models (GEMMs) giving rise to spontaneous tumors offer a new possibility to characterize the evolution of drug resistance mechanisms and to target multidrug resistant cancer.A tumorellenes szerek alapjául szolgáló vegyületeket többnyire in vitro kísérletekben azonosítják. Problémát jelent, hogy a szûrésekhez használt sejtvonalak érzékenysége nem mutat teljes átfedést az állatmodellek eredményeivel, illetve a klinikai tapasztalatokkal: míg a sejtvonalakat és a laboratóriumi egereket hatékonyan „gyógyíthatjuk”, a daganatos megbetegedések eredményes kezelése a terápia során rendszerint kialakuló multidrog-rezisztencia (MDR) miatt a mai napig nem megoldott. Új irányt jelentenek a genetikailag módosított egerekben kialakuló spontán tumor modellek, melyek a kemoterápiás kezelés következtében válnak ellenállóvá. A spontán fejlõdõ tumorok evolúciójának, szövettanának, terápiára adott válaszának tanulmányozása révén megismerhetõvé válnak a klinikailag releváns rezisztenciamechanizmusok, és lehetõség nyílik a multidrogrezisztens tumorokat célzó kemoterápia fejlesztésére.

All the research in Hungary and other countries in Europe focus on improving the quality of crops and increasing the competitiveness of production.In this respect, we have to advance the conventional technological elements, reduce the application of pesticides and fertilizers, and produce new varieties suitable for environmentally-sound production. In our crop breeding programs, we applied conventional and biotechnological methods (embryo rescue and double haploid methods) in order to get somaclonal and gametoclonal variations.We produced winter wheat lines (HP-31-95, HP-82-96) by traditional way, which have high baking qualities and high nutrient efficiency. Some diseases can limit the quantity and quality of a wheat crop. We examined several wheat diseases in our winter wheat candidates, and we found that our progenies have resistance to leaf rust.With respect to a serious problem was the small quantity of applied fertilizers and the other externals, our research focused onto advance a common wheat selection system, with the help of it, we can handle these problems. We have summarized that our selected progenies can compete with the registered varieties with quality and environmental respect.

The large biomass production and the low input of fertilizer needed make Miscanthus an interesting potential non-food crop with broad applications, e.g., as fuel and energy, thatching, as fiber for production in the paper and car industry as well as ethanol production. Axillary buds of Miscanthus × giganteus were placed on a shoot inducing nutrient solution (modified Murashige and Skoog, 1962) basic medium supplemented with 0.3 mg l−1 6-Benzylaminopurin. After 40 days of culturing the axillary buds, three times more shoots could be harvested. The nutrient content (N, P, K, Ca, Mg) was determined several times during the culturing. The results showed that after 35 days, nitrogen and phosphate were almost completely taken up and thereafter no shoot growth was observed. After the shoot propagation the plants were transferred into a nutrient solution for root formation and could be potted in soil, after about 14 days.