Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex

This first in vivo antitumour activity for an organometallic osmium arene complex, [Os(eta(6)-p-cym)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF(6), is reported. The complex delays the growth of HCT116 human colon cancer xenografts in mice, with negligible toxicity. Its activity appears to involve redox mechanisms and its potency towards A2780 ovarian and A549 lung cancer cells is increased significantly in combination with L-buthionine-sulfoximine

P-glycoprotein and metallothionein expression and resistance to chemotherapy in osteosarcoma.

The expression of the drug resistance (DR) mediators P-glycoprotein (P-gp) and the metallothioneins (MT) was assessed immunohistochemically in biopsy material from patients with high-grade malignant osteosarcoma (OS). No significant difference was found in survival rate between expressors of both P-gp and MT and non-expressors. Thus, it was concluded that lack of expression of these two drug resistance-related proteins does not appear to confer any advantage in terms of patient survival in osteosarcoma

Potent organometallic osmium compounds induce mitochondria-mediated apoptosis and S-phase cell cycle arrest in A549 non-small cell lung cancer cells

YesThe problems of acquired resistance associated with platinum drugs may be addressed by chemotherapeutics based on other transition metals as they offer the possibility of novel mechanisms of action. In this study, the cellular uptake and induction of apoptosis in A549 human non-small cell lung cancer cells of three promising osmium(II) arene complexes containing azopyridine ligands,[Os(Z6-arene)( p-R-phenylazopyridine)X]PF6, where arene is p-cymene or biphenyl, R is OH or NMe2, and X is Cl or I, were investigated. These complexes showed time-dependent (4–48 h) potent anticancer activity with highest potency after 24 h (IC50 values ranging from 0.1 to 3.6 mM). Cellular uptake of the three compounds as quantified by ICP-MS, was independent of their log P values (hydrophobicity). Furthermore, maximum cell uptake was observed after 24 h, with evident cell efflux of the osmium after 48 and 72 h of exposure, which correlated with the corresponding IC50 values. The most active compound 2, [Os(Z6-p-cymene)(NMe2-phenylazopyridine)I]PF6, was taken up by lung cancer cells pre-dominately in a temperature-dependent manner indicating that energy-dependent mechanisms are important in the uptake of 2. Cell fractionation studies showed that all three compounds accumulated mainly in cellular membranes. Furthermore, compound 2 induced apoptosis and caused accumulation in the S-phase of the cell cycle. In addition, 2 induced cytochrome c release and alterations in mito-chondrial membrane potential even after short exposure times, indicating that mitochondrial apoptotic pathways are involved. This study represents the first steps towards understanding the mode of action of this promising class of new osmium-based chemotherapeutics

The evaluation of selected ghanaian medicinal plants for cytotoxic activites

Cancer is still responsible for many deaths worldwide. Therefore, the need for an effective management, treatment and cure of cancer is undoubtedly crucial. In Ghana, several plants or herbal products are used by traditional healers for the management and/or the treatment of various cancers. However, the efficacies of these plant products as anticancer agents are often ill defined. In this study, the methanolic extracts of ten plant species were evaluated for cytotoxicity against three human cancer cell lines, DLD- 1, MCF-7 and M14, using the MTT assay. Extracts of Adenia lobata root, Clerodendrum capitatum leaves, Garcinia kola stem bark, Plumbago zeylanica leaves and Vernonia conferta root, showed relatively low cytotoxic activities while extracts of Ficus asperifolia leaves, Paullinia pinnata root and Thonningia sanguinea root exhibited moderate activity (IC50 values 40 – 55μg/ml against at least one of the three cell lines). Croton membranaceus root extract exhibited markedly higher cytotoxic activities, particularly against the DLD-1 and MCF-7 cells (IC50 = 16.0 and 17.4μg/ml respectively), while Zanthoxylum xanthoxyloides bark extract was 2-3 fold more active against DLD-1 cells (IC50 = 16μg/ml), than against the other cell lines. These results lend some support for the use of these species in traditional medicines for the treatment of cancer, especially for C. membranaceus and Z. xanthoxyloides.Journal of Science & Technology (Ghana) Vol. 27 (2) 2007: pp. 16-2

The Effect of Polysialic Acid Expression on Glioma Cell Nano-mechanics

YesPolysialic acid (PolySia) is an important carbohydrate bio-polymer that is commonly over-expressed on tumours of neuroendocrine origin and plays a key role in tumour progression. PolySia exclusively decorates the neural cell adhesion molecule (NCAM) on tumour cell membranes, modulating cell-cell interactions, motility and invasion. In this preliminary study, we examine the nano-mechanical properties of isogenic C6 rat glioma cells - transfected cells engineered to express the enzyme polysialyltransferase ST8SiaII, which synthesises polySia (C6-STX cells) and wild type cells (C6-WT). We demonstrate that polySia expression leads to reduced elastic and adhesive properties but also more visco-elastic compared to non-expressing wild type cells. Whilst differences in cell elasticity between healthy and cancer cells is regularly assigned to changes in the cytoskeleton, we show that in this model system the change in properties at the nano-level is due to the polySia on the transfected cell membrane surface

RGD-Binding Integrins in Head and Neck Cancers

YesAlterations in integrin expression and function promote tumour growth, invasion, metastasis and neoangiogenesis. Head and neck cancers are highly vascular tumours with a tendency to metastasise. They express a wide range of integrin receptors. Expression of the αv and β1 subunits has been explored relatively extensively and linked to tumour progression and metastasis. Individual receptors αvβ3 and αvβ5 have proved popular targets for diagnostic and therapeutic agents but lesser studied receptors, such as αvβ6, αvβ8, and β1 subfamily members, also show promise. This review presents the current knowledge of integrin expression and function in squamous cell carcinoma of the head and neck (HNSCC), with a particular focus on the RGD-binding integrins, in order to highlight the potential of integrins as targets for personalised tumour specific identification and therapy

An efficient assay for identification and quantitative evaluation of potential polysialyltransferase inhibitors

YesThe polysialyltransferases (polySTs) catalyse the polymerisation of polysialic acid, which plays an important role in tumour metastasis. While assays are available to assess polyST enzyme activity, there is no methodology available specifically optimised for identification and quantitative evaluation of potential polyST inhibitors. The development of an HPLC-fluorescence-based enzyme assay described within includes a comprehensive investigation of assay conditions, including evaluation of metal ion composition, enzyme, substrate and acceptor concentrations, temperature, pH, and tolerance to DMSO, followed by validation using known polyST inhibitors. Thorough analysis of each of the assay components provided a set of optimised conditions. Under these optimised conditions, the experimentally observed Ki value for CMP, a competitive polyST inhibitor, was strongly correlated with the predicted Ki value, based on the classical Cheng-Prusoff equation [average fold error (AFE) = 1.043]. These results indicate that this assay can provide medium-throughput analysis for enzyme inhibitors with high accuracy, through determining the corresponding IC50 values with substrate concentration at the KM, without the need to perform extensive kinetic studies for each compound. In conclusion, an in vitro cell-free assay for accurate assessment of polyST inhibition is described. The utility of the assay for routine identification of potential polyST inhibitors is demonstrated, allowing quantitative measurement of inhibition to be achieved, and exemplified through assessment of full competitive inhibition. Given the considerable and growing interest in the polySTs as important anti-metastatic targets in cancer drug discovery, this is a vital tool to enable preclinical identification and evaluation of novel polyST inhibitors.Yorkshire Cancer Research, Wellcome Trus

A proteomic investigation to discover candidate proteins involved in novel mechanisms of 5-fluorouracil resistance in colorectal cancer

YesOne of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.Sadr ul-Shaheed and the University of Bradford Proteomics Facility were supported by Yorkshire Cancer Research, UK (Cancer Medicine Discovery II, grant B381PA)

はじめに : 人文社会科学研究科研究プロジェクト報告書第237集『起業家教育に関する実践的研究』

千葉大学大学院人文社会科学研究科研究プロジェクト報告書第237集『起業家教育に関する実践的研究』 藤川 大祐 編“A Practical Study About Entrepreneurship education Report on Research Project No.23

The contrasting chemical reactivity of potent isoelectronic iminopyridine and azopyridine osmium(ii) arene anticancer complexes

A wide variety of steric and electronic features can be incorporated into transition metal coordination complexes, offering the prospect of rationally-designed therapeutic agents with novel mechanisms of action. Here we compare the chemical reactivity and anticancer activity of organometallic OsII complexes [Os(η6-arene)(XY)Z]PF6 where arene = p-cymene or biphenyl, XY = N,N′-chelated phenyliminopyridine or phenylazopyridine derivatives, and Z = Cl or I. The X-ray crystal structure of [Os(η6-p-cym)(Impy-OH)I]PF6·0.5CH2Cl2·H2O (Impy-OH = 4-[(2-pyridinylmethylene)amino]-phenol) is reported. Like the azopyridine complexes we reported recently (Dalton Trans., 2011, 40, 10553–10562), some iminopyridine complexes are also potently active towards cancer cells (nanomolar IC50 values). However we show that, unlike the azopyridine complexes, the iminopyridine complexes can undergo aquation, bind to the nucleobase guanine, and oxidize coenzyme nicotine adenine dinucleotide (NADH). We report the first detection of an Os-hydride adduct in aqueous solution by 1H NMR (−4.2 ppm). Active iminopyridine complexes induced a dramatic increase in the levels of reactive oxygen species (ROS) in A549 lung cancer cells. The anticancer activity may therefore involve interference in the redox signalling pathways in cancer cells by a novel mechanism