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Hyssopus officinalisL. is a well-known aromatic plant used in traditional medicine and the foodand cosmetics industry. The aim of this study is to assess the antioxidant, genotoxic, antigenotoxic andcytotoxic properties of characterized hyssop essential oils and methanol extracts. Chemical compositionwas analyzed by gas chromatography - mass spectrometry (GC-MS) and liquid chromatography with diodearray detection and mass spectrometry (LC-DAD-MS), respectively. Antioxidant activity was examinedby 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) tests; genotoxicand antigenotoxic activity were examined by the comet assay, while cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide dye (MTT) test against tumor cell lines (SW480,MDA-MB 231, HeLa) and non-transformed human lung fibroblast cell lines (MRC-5). The essential oilswere rich in monoterpene hydrocarbons (e.g., limonene; 7.99–23.81%), oxygenated monoterpenes (1,8-cineole; 38.19–67.1%) and phenylpropanoids (methyl eugenol; 0.00–28.33%). In methanol extracts, the mostabundant phenolics were chlorogenic and rosmarinic acid (23.35–33.46 and 3.53–17.98 mg/g, respectively).Methanol extracts expressed moderate to weak antioxidant activity (DPPH IC50= 56.04–199.89μg/mL,FRAP = 0.667–0.959 mmol Fe2+/g). Hyssop preparations significantly reduced DNA damage in humanwhole blood cells, induced by pretreatment with hydrogen peroxide. Methanol extracts exhibited selectiveand potent dose- and time-dependent activity against the HeLa cell line. Results of the current studydemonstrated notableH.officinalismedicinal potential, which calls for further investigation.

Aim: Newly synthesized platinum(IV) complexes with ethylenediamine-N,N’-diacetate ligands (EDDA-type) (butyl-Pt and pentyl-Pt) were investigated against two cancer (A549 lung, and HTB 140 melanoma) and one non-cancerous (MRC-5 embryonic lung fibroblast) human cell lines. Materials and Methods: The effects of these agents were compared with those of cisplatin after 6-, 24- and 48-h treatment. Sulforhodamine-B (SRB) assay was performed to estimate the cytotoxic effect, while the inhibitory effect on cell proliferation was measured using 5-bromo-2,-deoxyuridine (BrdU) incorporation assay. Cell cycle analysis was performed by flow cytometry. Type of cell death induced by these agents was determined by electrophoretic analysis of DNA, flow cytometry and by western blot analysis of proteins involved in induction of apoptosis. The effects of gamma irradiation, alone and in combination with platinum-based compounds, were examined by clonogenic and SRB assays. Results: All examined platinum-based compounds had inhibitory and antiproliferative effects on A549 cells, but not on HTB140 and MRC-5 cells. Butyl-Pt, pentyl-Pt and cisplatin arrested the cell cycle in the S-phase and induced apoptotic cell death via regulation of expression of B-cell lymphoma 2 (BCL2) and BCL2-associated X (BAX) proteins. Platinum-based compounds increased the sensitivity of A549 cells to gamma irradiation. Butyl-Pt and pentyl-Pt showed better antitumour effects against A549 cells than did cisplatin, by interfering in cell proliferation and the cell cycle, and by triggering apoptosis. Conclusion: The effects of gamma irradiation on tumour cells may be amplified by pre-treatment of cells with platinum-based compounds.

In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation [K sv = (3.7 ± 0.1) and (3.4 ± 0.1) × 10 3 M −1 , respectively], an intercalative mode also confirmed through viscosity measurements. K a values, obtained as result of fluorescence titration of BSA with D13 and D15 [K a = (4.2 ± 0.2) and (2.6 ± 0.2) × 10 5 M, respectively], support the fact that a sign

Izvod: Chelidonium majus L. (Papaveraceae) u tradicionalnoj medicini ima primenu u lečenju širokog spektra različitih bolesti. Farmakološka svojstva ove biljke predmet su velikog broja in vitro i in vivo istraživanja, kao i kliničkih studija. Međutim, najveći broj istraživanja, naročito antitumorskog dejstva, usmeren je na ispitivanje biološke aktivnosti pojedinačno izolovanih alkaloida i flavonoida. Antitumorsko dejstvo celog ekstrakta nije dovoljno ispitano. U ovoj disertaciji opisano je direktno citotoksično dejstvo ekstrakta na humanim tumorskim ćelijskim linijama dojke (MDA-MB-231, MCF7), kolona (HCT116, SW480) i pluća (A549, H460) i diferencijalna citotoksičnost u odnosu na normalne ćelije, fibroblaste (MRC-5). Opisano je i indirektno antitumorsko dejstvo, odnosno uticaj ekstrakta na sposobnost migracije i radiosenzitivnost malignih ćelija. Ispitivani ekstrakt Chelidonium majus pokazuje vremenski- i dozno-zavisan citotoksični efekat na svim ispitivanim tumorskim ćelijskim linijama, uz dobru selektivnost prema ovim malignim ćelijama u odnosu na zdrave, netransformisane ćelije (fibroblaste). Analiza protočnom citometrijom pokazala je da ekstrakt uzrokuje zastoj u G2/M fazi ćelijskog ciklusa, kao i da indukuje apoptozu, što je potvrđeno određivanjem proteina uključenih u apoptozu i analizom morfoloških promena, karakterističnim za ovaj proces na A549 ćelijama. Utvrđeno je sinergističko dejstvo ekstrakta i doksorubicina, zavisno od tumorske ćelijske linije koja se tretira i od primenjene doze doksorubicina. Ekstrakt je inhibirao migraciju A549, HCT116 i MDA-MB 231 ćelija i povećao osetljivost ove tri ćelijske linije na γ-zračenje, čime je pokazano da ispoljava i indirektna antitumorska dejstva. Dobijeni rezultati pokazuju da ekstrakt ispoljava direktno i indirektno antitumorsko dejstvo u in vitro uslovima, te bi ovaj potencijal trebalo ispitati u in vivo sistemu., Chelidonium majus L. (Papaveraceae) is widely used in alternative medicine for treatment of various disorders. The pharmacological properties of the plant were the subject of numerous in vitro and in vivo investigations as well as clinical studies. However, most research, especially of antitumor activity, were focused on the assessment of biological activities of isolated alkaloids and flavonoids, while there are only a few studies that examine properties of the whole extract In this dissertation ethanol extract of Chelidonium majus was evaluated for its anti-cancer properties on six human cancer cell lines: breast (MDA-MB-231, MCF7), colon (HCT116, SW480) and lung (A549, H460) tumor cell lines and differential cytotoxicity as compared to normal cells, fibroblasts (MRC -5) was estimated. Also, indirect antitumor activity, i.e. effect on migration and radiosensitivity of cancer cells were investigated. Chelidonium majus extract showed selective time- and dose-dependent increase of cytotoxicity in all six cell lines, with individual cell line sensitivities. Extract promoted cell cycle arrest and induced apoptosis, as demonstrated by flow cytometric analysis of apoptosis-related proteins and by assessment of morphological changes typical for apoptosis. Cotreatment with doxorubicin enhanced cytotoxicity of the drug. Inhibitory effect on migration was shown with non-toxic extract concentration on A549, HCT116 and MDA-MB 231 cells. Also, pretreatment with low concentrations of extract increased sensitivity of these cell lines to γ-radiation. These results indicate possible usefulness of Chelidonium majus crude extract in antitumor therapy, whether through its direct cytotoxic effect, by prevention of metastasis, or as adjuvant therapy. Therefore, this potential should be examined in the in vivo system.