No / Group IV metal complexes have previously shown promise as novel anticancer agents. Here, we discuss the mechanistic and cytotoxic nature of a series of group IV b-diketonate coordination complexes. Clear evidence that the ligands are exchangeable on the metal centre and that the b-diketonate ligands can act as potential drug delivery vehicles of the group IV metal ions was obtained. When evaluated for the cytotoxicity against human colon adenocarcinoma (HT-29) and human breast adenocarcinoma (MCF-7) cell lines, a general trend of decreasing potency down the group IV metals was observed. The most promising results obtained were for the hafnium complexes, with the tris diphenyl b-diketonate hafnium complex exhibiting IC50 values of 4.9 0.9 mm and 3.2 0.3 mm against HT-29 and MCF-7, respectively, which are comparable with the activity of cisplatin against the same cell lines. This tri b-diketonate hafnium complex is the first to show potent in vitro cytotoxic activity. The results reported show that ligand design has a significant effect on the cytotoxic potential of the complexes, and that these group IV complexes warrant further evaluation as novel metal-containing anticancer agents.

Yes / Condensation of a pyridyl-2-carbaldehyde derivative with 2-(bromoethyl)amine hydrobromide gave tetracyclic pyrido[1,2-a]pyrido[1’,2’:3,4]imidazo-[2,1-c]-6,7-dihydropyrazinium dications in excellent yields. Crystal structures and NOE data demonstrated the helical character of the dications, the dihedral angles between the two pyrido groups ranging from 28–458. An intermediate in the synthesis was also characterized. A much brighter emission compared to literature helicenes has been found, with quantum yields as high as 60% in the range of l=460– 600 nm. Preliminary cytotoxicity studies against HT-29 cancer cells demonstrated moderate-to-good activity, with IC50 values 12–30x that of cisplatin.

No / Various saponins, plant glycosides with favorable anti-tumorigenic properties, have been used to inhibit tumor cell growth by cell cycle arrest and apoptosis with IC50 values of up to 0.2 μM. We describe several groups of saponins (dioscins, saikosaponins, julibrosides, soy saponins, ginseng saponins and avicins) currently investigated for their use in tumor therapy. We focus on cellular and systemic mechanisms of tumor cell growth inhibition both in vitro and in vivo, combinational approaches with saponins and conventional tumor treatment strategies, and successful syntheses of saponins. The increasing interest in saponins for tumor therapy is very promising for the future development of sophisticated anti-cancer drugs.

Yes / Herein, we report 31 new β-diketonate titanium compounds of the type [Ti(O,O)2X2], whereby O,O = asymmetric or symmetric β-diketonate ligand and X = Cl, Br, OEt or OiPr. Thirteen new crystal structures are discussed and show that these octahedral species all adopt cis geometries in the solid state. These compounds have been tested for their cytotoxicity using SRB and MTT assays, showing several of the compounds are as potent as cisplatin against a range of tumour cell lines. Results also show the [Ti(O,O)2Br2] complexes are more potent than [Ti(O,O)2Cl2], [Ti(O,O)2(OEt)2] and [Ti(O,O)2(OiPr)2]. Using a simple symmetrical heptane-3,5-dione (O,O) ligand bound to titanium, we observed more than a 50-fold increase in potency with the [Ti(O,O)2Br2] (28) when compared to [Ti(O,O)2Cl2] (27). One of the more potent compounds (6) has been added to three different sixmers of DNA, in order to analyse the potential DNA binding of the compound. NMR studies have been carried out on the compounds, in order to understand the structural properties and the species formed in solution during the in vitro cell assays.

Yes / A library of new bis-picolinamide ruthenium(III) dihalide complexes of the type RuX2L2 (X = Cl or I and L = picolinamide) have been synthesised and characterised. They exhibit different picolinamide ligand binding modes, whereby one ligand is bound (N,N) and the other bound (N,O). Structural studies reveal a mixture of cis and trans isomers for the RuCl2L2 complexes but upon a halide exchange reaction to RuI2L2, only single trans isomers are present. High cytotoxic activity against human cancer cell lines was observed, with potencies for some complexes similar to or better than cisplatin. Conversion to RuI2L2 substantially increased activity towards cancer cell lines by >12-fold. The RuI2L2 complexes displayed potent activity against the A2780cis (cisplatin-resistant human ovarian cancer) cell line, with >4-fold higher potency than cisplatin. Equitoxic activity was observed against normoxic and hypoxic cancer cells, indicating the potential to eradicate both the hypoxic and aerobic fractions of solid tumours with similar efficiency. Selected complexes were also tested against non-cancer ARPE-19 cells. The RuI2L2 complexes are more potent than the RuCl2L2 analogues, and also more selective towards cancer cells with a selectivity factor >7-fold.

Yes / Cancer is now the second-leading cause of mortality and morbidity, behind only heart disease, necessitating urgent development of (chemo)therapeutic interventions to stem the growing burden of cancer cases and cancer death. Plants represent a credible source of promising drug leads in this regard, with a long history of proven use in the indigenous treatment of cancer. This study therefore investigated Anacardium occidentale, one of the plants in a Nigerian Traditional Medicine formulation commonly used to manage cancerous diseases, for cytotoxic activity. Bioassay-guided fractionation, spectroscopy, Alamar blue fluorescence-based viability assay in cultured HeLa cells and microscopy were used. Four compounds: zoapatanolide A (1), agathisflavone (2), 1, 2-bis (2,6-dimethoxy-4-methoxybenzoyl) ethane (Anacardicin, 3) and methyl gallate (4) were isolated, with the most potent being zoapatanolide A with an IC50 value of 36.2 ± 9.8 μM in the viability assay. To gain an insight into the likely molecular basis of their observed cytotoxic effects, Autodock Vina binding free energies of each of the isolated compounds with seven molecular targets implicated in cancer development (MAPK8, MAPK10, MAP3K12, MAPK3, MAPK1, MAPK7 and VEGF), were calculated. Pearson correlation coefficients were obtained with experimentally-determined IC50 in the Alamar blue viability assay. While these compounds were not as potent as a standard anti-cancer compound, doxorubicin, the results provide reasonable evidence that the plant species contains compounds with cytotoxic activity. This study provides some evidence of why this plant is used ethnobotanically in anti-cancer herbal formulations and justifies investigating Nigerian medicinal plants highlighted in recent ethno-botanical surveys. / This work was supported by a British Council Researcher Links Travel Grant 2013 to TBJ, a South Africa’s National Research Foundation (NRF) Grant No 98345, 2016 to FRVH and an academic staff funding provided to AAF by the School of Pharmacy, University of Bradford, UK.

Yes / The synthesis and characterization of three aromatic oligoamides, constructed from the same pyridyl carboxamide core but incorporating distinct end groups of acetyl (Ac) 1, tert-butyloxycarbonyl (Boc) 2 and amine 3 is reported. Single crystal X-ray diffraction analysis of 1-3 and a dimethylsulfoxide (DMSO) solvate of 2 (2-DMSO), has identified the presence of a range of intra- and intermolecular interactions including N-H⋯N, N-H⋯O=C and N-H⋯O=S(CH3)2 hydrogen-bonding interactions, C-H⋯π interactions and off-set, face-to-face stacking π-π interactions that support the variety of slipped stack, herringbone and cofacial crystal packing arrangements observed in 1-3. Additionally, the cytotoxicity of this series of aromatic oligoamides was assessed against two human ovarian (A2780 and A2780cisR), two human breast (MCF-7 and MDA-MB-231) cancerous cell lines and one non-malignant human epithelial cell line (PNT-2), to investigate the influence of the terminal functionality of these aromatic oligoamides on their biological activity. The chemosensitivity results highlight that modification of the terminal group from Ac to Boc in 1 and 2 leads to a 3-fold increase in antiproliferative activity against the cisplatin-sensitive ovarian carcinoma cell line, A2780. The presence of the amine termini in 3 gave the only member of the series to display activity against the cisplatin-resistance ovarian carcinoma cell line, A2780cisR. Compound 2 is the lead candidate of this series, displaying high selectivity towards A2780 cancer cells when compared to non-malignant PNT-2 cells, with a selectivity index value >4.2. Importantly, this compound is more selective towards A2780 (cf. PNT-2) than the clinical platinum drugs oxaliplatin by > 2.6-fold and carboplatin by > 1.6-fold. / University of Bradford Development Fund; University of Birmingham - Birmingham Fellowship; UKRI Future Leaders Fellowship (MR/T041315/1); UKRI Future Leaders Fellowship (MR/S035486/2)

No description available.

Cancer immunotherapy is an encompassing term referring to therapeutic strategies that aim to boost the immune system to fight cancer. These strategies include administering immune cells that have been altered to have greater anti-tumor activity or using biologics and small molecules that target immune components to also promote tumor clearance. Natural Killer (NK) cells are cells of the innate immune system that recognize and kill abnormal cells such as cancer cells and play an important role in the anti-tumor response. Because of their crucial role in tumor immunity, NK cells are prime targets for immunotherapies. Repurposing small molecule drugs is an attractive strategy to identify new immunotherapies from already approved drugs. Here, we screened 1,200 approved drugs from the Prestwick Chemical Library to identify drugs that increase NK cell cytotoxicity. We used a high-throughput luciferase-release cytotoxicity assay to measure the killing of the myeloid leukemia cell line, K562 cells expressing nano luciferase (NL) by NK92 cells, a human NK cell line. From the drug candidates identified from the screening assay, the antibiotic colistin sulfate increased cytotoxicity of the NK92 cell line and unstimulated human NK cells towards K562-NL cells. This increase in NK cytotoxicity was short-lived as pre-treating NK92 cells with colistin for 1 hour or 24 hours did not increase cytotoxicity. Also, we show pre-treating K562-NL target cells with colistin does not sensitize them to NK-mediated killing. Further studies are needed to uncover the mechanism of action of colistin, thus contributing to knowledge of fundamental NK cell biology regarding NK cell cytotoxicity which will aid in identifying additional small molecule drugs that enhance NK cell activity.

Lau Wing-Ngar Vivian. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 135-144). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.ii / Abbreviations --- p.vi / List of figures --- p.viii / List of tables --- p.xi / Contents --- p.xiii / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General introduction --- p.1 / Chapter 1.2 --- Roadside air pollution worldwide and in Hong Kong --- p.2 / Chapter 1.2.1 --- Air quality in Hong Kong --- p.3 / Chapter 1.3 --- Characteristics of particulate matter --- p.9 / Chapter 1.4 --- Composition and sources of particulate matter --- p.11 / Chapter 1.5 --- Toxic effects of particulate matter --- p.12 / Chapter 1.5.1 --- Lung injury --- p.12 / Chapter 1.5.2 --- Cardiovascular injury --- p.15 / Chapter 1.5.3 --- Mutagenesis and carcinogenesis --- p.16 / Chapter 1.6 --- Aims of my study --- p.16 / Chapter 2 --- Toxic Effects of Heavy Metals Ions on Selected Cultured Cell-lines --- p.18 / Chapter 2.1 --- Introduction --- p.18 / Chapter 2.1.1 --- Metals --- p.18 / Chapter 2.1.1.1 --- Cadmium --- p.22 / Chapter 2.1.1.2 --- Chromium --- p.23 / Chapter 2.1.1.3 --- Lead --- p.25 / Chapter 2.1.1.4 --- Zinc --- p.26 / Chapter 2.1.2 --- Metallothioneins --- p.28 / Chapter 2.1.3 --- p53 --- p.31 / Chapter 2.1.4 --- Tumor Necrosis Factor-alpha (TNF-α) --- p.32 / Chapter 2.1.5 --- Aims of this chapter --- p.32 / Chapter 2.2 --- Materials and methods --- p.35 / Chapter 2.2.1 --- Reagents --- p.35 / Chapter 2.2.2 --- Cultured Cell lines --- p.35 / Chapter 2.2.2.1 --- PU5-18 --- p.36 / Chapter 2.2.2.2 --- LL24 --- p.36 / Chapter 2.2.2.3 --- HBE4-E6/E7 --- p.37 / Chapter 2.2.3 --- Cytotoxicity assays --- p.37 / Chapter 2.2.4 --- ELISA assays --- p.40 / Chapter 2.2.4.1 --- ELISA assay ofp53 levels --- p.41 / Chapter 2.2.4.2 --- ELISA assay of TNF-α levels --- p.43 / Chapter 2.2.5 --- MT gene expression studies by Luciferase assay --- p.44 / Chapter 2.2.5.1 --- PCR amplification --- p.44 / Chapter 2.2.5.2 --- 5´ة End modification of PCR amplified DNA --- p.44 / Chapter 2.2.5.3 --- Ligation of DNA fragment to linearized vector --- p.46 / Chapter 2.2.5.4 --- E. coli. transformation by heat shock --- p.46 / Chapter 2.2.5.5 --- PCR sequencing --- p.47 / Chapter 2.2.5.6 --- Transfection of plasmid into HBE4-E6/E7 cells --- p.49 / Chapter 2.2.5.7 --- Data analysis --- p.50 / Chapter 2.3 --- Results and discussion --- p.51 / Chapter 2.3.1 --- Cytotoxicity assays --- p.51 / Chapter 2.3.2 --- Combination effects of metals on cytotoxicity --- p.61 / Chapter 2.3.3 --- p53 --- p.65 / Chapter 2.3.4 --- TNF-α --- p.68 / Chapter 2.3.5 --- MT gene expression studies by Luciferase assay --- p.69 / Chapter 2.4 --- Conclusion --- p.74 / Chapter 3 --- Effects of Polycyclic Aromatic Hydrocarbons (PAHs) on Cultured Cell-lines --- p.75 / Chapter 3.1 --- Introduction --- p.75 / Chapter 3.2 --- Materials and methods --- p.79 / Chapter 3.2.1 --- Reagents --- p.79 / Chapter 3.2.2 --- Cell culture --- p.79 / Chapter 3.2.3 --- AlamarBlue assay --- p.80 / Chapter 3.2.4 --- EROD assay --- p.80 / Chapter 3.3 --- Results and discussion --- p.84 / Chapter 3.4 --- Conclusion --- p.88 / Chapter 4 --- Chemical and Biological Assays on Roadside Dust --- p.89 / Chapter 4.1 --- Introduction --- p.89 / Chapter 4.1.1 --- Composition of particulate matter in Hong Kong --- p.89 / Chapter 4.1.2 --- Metal contents of particulate matter in Hong Kong --- p.91 / Chapter 4.1.3 --- Possible adverse health impacts of particulate matter --- p.94 / Chapter 4.1.3.1 --- In vitro studies using different cell models --- p.94 / Chapter 4.1.3.2 --- In vivo studies using rodents --- p.97 / Chapter 4.1.3.3 --- Epidemiological studies --- p.98 / Chapter 4.1.4 --- Aims of this chapter --- p.100 / Chapter 4.2 --- Materials and methods --- p.101 / Chapter 4.2.1 --- Sampling of roadside dust --- p.101 / Chapter 4.2.2 --- Chemical analysis of roadside dust --- p.104 / Chapter 4.2.2.1 --- Reagents --- p.104 / Chapter 4.2.2.2 --- Total metal contents --- p.105 / Chapter 4.2.2.3 --- Extractable metal contents --- p.105 / Chapter 4.2.3 --- Biological assays --- p.105 / Chapter 4.2.3.1 --- Cell models --- p.106 / Chapter 4.2.3.2 --- Pretreatment of roadside dust --- p.106 / Chapter 4.2.3.3 --- AlamarBlue assay --- p.106 / Chapter 4.2.3.4 --- ELISA assays --- p.108 / Chapter 4.2.3.5 --- Luciferase assay --- p.108 / Chapter 4.3 --- Results and discussion --- p.110 / Chapter 4.3.1 --- Total metal contents --- p.110 / Chapter 4.3.2 --- Extractable metal contents --- p.113 / Chapter 4.3.3 --- AlamarBlue assay --- p.116 / Chapter 4.3.4 --- p53 --- p.122 / Chapter 4.3.5 --- TNF-α --- p.122 / Chapter 4.3.6 --- Luciferase assay --- p.126 / Chapter 4.4 --- Conclusion --- p.129 / Chapter 5 --- General discussion and conclusion --- p.130 / Chapter 6 --- References --- p.135