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Sample records for complexes potent antitumor

  1. Gamma-lactone-Functionalized antitumoral acetogenins are the most potent inhibitors of mitochondrial complex I.

    PubMed

    Tormo, J R; Estornell, E; Gallardo, T; González, M C; Cavé, A; Granell, S; Cortes, D; Zafra-Polo, M C

    2001-03-12

    To study the relevance of the terminal alpha,beta-unsaturated gamma-methyl-gamma-lactone moiety of the antitumoral acetogenins of Annonaceae for potent mitochondrial complex I inhibition, we have prepared a series of semisynthetic acetogenins with modifications only in this part of the molecule, from the natural rolliniastatin-1 (1) and cherimolin-1 (2). Some of the hydroxylated derivatives (1b, 1d and 1e) in addition to two infrequent natural beta-hydroxy gamma-methyl gamma-lactone acetogenins, laherradurin (3) and itrabin (4), are more potent complex I inhibitors than any other known compounds.

  2. Synthesis, Structural Characterization, and Cytotoxic Activity of Novel Paramagnetic Platinum Hematoporphyrin IX Complexes: Potent Antitumor Agents

    PubMed Central

    Gencheva, G.; Tsekova, D.; Gochev, G.; Momekov, G.; Tyuliev, G.; Skumryev, V.; Karaivanova, M.; Bontchev, P. R.

    2007-01-01

    Three novel stable Pt(III) complexes with distorted octahedral structure and (dz2)1 ground state have been obtained in the course of Pt(II)-hematoporphyrin IX ((7,12-bis(1-hydroxyethyl)-3,8,13,17-tetramethyl-21H-23H-porphyn-2,18-dipropionic acid), Hp) interaction in alkaline aqueous medium and aerobic conditions. A redox interaction also takes place together with the complexation process leading to the formation of Pt(III) species and organic radicals. The processes in the reaction system and the structure of the complexes formed cis-[Pt(III)(NH3)2(Hp−3H)(H2O)2]⋅H2O 1, [Pt(III)(Hp−3H)(H2O)2]⋅H2O 2, and [Pt((O,O)Hp−2H)Cl(H2O)3] 3, were studied by UV-Vis, IR, EPR and XPS spectra, thermal (TGS, DSC), potentiometric and magnetic methods. The newly synthesized complexes show promising cytotoxic activity comparable with that of cis-platin in in vitro tests against a panel of human leukemia cell lines. The observed cytotoxicity of the complex 2 against SKW-3 cells (KE-37 derivative) is due to induction of cell death through apoptosis. PMID:18309370

  3. Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity.

    PubMed

    Turkson, James; Zhang, Shumin; Palmer, Jay; Kay, Heidi; Stanko, Joseph; Mora, Linda B; Sebti, Said; Yu, Hua; Jove, Richard

    2004-12-01

    DNA-alkylating agents that are platinum complexes induce apoptotic responses and have wide application in cancer therapy. The potential for platinum compounds to modulate signal transduction events that contribute to their therapeutic outcome has not been extensively examined. Among the signal transducer and activator of transcription (STAT) proteins, Stat3 activity is frequently up-regulated in many human tumors. Various lines of evidence have established a causal role for aberrant Stat3 activity in malignant transformation and provided validation for its targeting in the development of small-molecule inhibitors as novel cancer therapeutics. We report here that platinum-containing compounds disrupt Stat3 signaling and suppress its biological functions. The novel platinum (IV) compounds, CPA-1, CPA-7, and platinum (IV) tetrachloride block Stat3 activity in vitro at low micromolar concentrations. In malignant cells that harbor constitutively activated Stat3, CPA-1, CPA-7, and platinum (IV) tetrachloride inhibit cell growth and induce apoptosis in a manner that reflects the attenuation of persistent Stat3 activity. By contrast, cells that do not contain persistent Stat3 activity are marginally affected or are not affected by these compounds. Moreover, CPA-7 induces the regression of mouse CT26 colon tumor, which correlates with the abrogation of persistent Stat3 activity in tumors. Thus, the modulation of oncogenic signal transduction pathways, such as Stat3, may be one of the key molecular mechanisms for the antitumor effects of platinum (IV)-containing complexes.

  4. BAY 87-2243, a highly potent and selective inhibitor of hypoxia-induced gene activation has antitumor activities by inhibition of mitochondrial complex I

    PubMed Central

    Ellinghaus, Peter; Heisler, Iring; Unterschemmann, Kerstin; Haerter, Michael; Beck, Hartmut; Greschat, Susanne; Ehrmann, Alexander; Summer, Holger; Flamme, Ingo; Oehme, Felix; Thierauch, Karlheinz; Michels, Martin; Hess-Stumpp, Holger; Ziegelbauer, Karl

    2013-01-01

    The activation of the transcription factor hypoxia-inducible factor-1 (HIF-1) plays an essential role in tumor development, tumor progression, and resistance to chemo- and radiotherapy. In order to identify compounds targeting the HIF pathway, a small molecule library was screened using a luciferase-driven HIF-1 reporter cell line under hypoxia. The high-throughput screening led to the identification of a class of aminoalkyl-substituted compounds that inhibited hypoxia-induced HIF-1 target gene expression in human lung cancer cell lines at low nanomolar concentrations. Lead structure BAY 87-2243 was found to inhibit HIF-1α and HIF-2α protein accumulation under hypoxic conditions in non-small cell lung cancer (NSCLC) cell line H460 but had no effect on HIF-1α protein levels induced by the hypoxia mimetics desferrioxamine or cobalt chloride. BAY 87-2243 had no effect on HIF target gene expression levels in RCC4 cells lacking Von Hippel–Lindau (VHL) activity nor did the compound affect the activity of HIF prolyl hydroxylase-2. Antitumor activity of BAY 87-2243, suppression of HIF-1α protein levels, and reduction of HIF-1 target gene expression in vivo were demonstrated in a H460 xenograft model. BAY 87-2243 did not inhibit cell proliferation under standard conditions. However under glucose depletion, a condition favoring mitochondrial ATP generation as energy source, BAY 87-2243 inhibited cell proliferation in the nanomolar range. Further experiments revealed that BAY 87-2243 inhibits mitochondrial complex I activity but has no effect on complex III activity. Interference with mitochondrial function to reduce hypoxia-induced HIF-1 activity in tumors might be an interesting therapeutic approach to overcome chemo- and radiotherapy-resistance of hypoxic tumors. PMID:24403227

  5. Reactions of potent antitumor complex trans-[Ru(III)Cl4(indazole)2]- with a DNA-relevant nucleobase and thioethers: insight into biological action.

    PubMed

    Egger, Alexander; Arion, Vladimir B; Reisner, Erwin; Cebrián-Losantos, Berta; Shova, Sergiu; Trettenhahn, Günter; Keppler, Bernhard K

    2005-01-10

    Reactions of the complex trans-[RuCl(4)(Hind)(2)](-) (Hind = indazole), which is of clinical relevance today, with both the DNA model nucleobase 9-methyladenine (made) and the thioethers R(2)S (R = Me, Et), as models of the methionine residue in biological molecules possibly acting as nitrogen-competing sulfur-donor ligands for ruthenium atom, have been investigated to get insight into details of mechanism leading to antitumor activity. Three novel ruthenium complexes, viz., [Ru(III)Cl(3)(Hind)(2)(made)], 1, [Ru(II)Cl(2)(Hind)(2)(Me(2)S)(2)], 2, and [Ru(II)Cl(2)(Hind)(2)(Et(2)S)(2)], 3, have been isolated as solids. Oxidation of 2 and 3 with hydrogen peroxide in the presence of 12 M HCl in chloroform afforded the monothioether adducts, viz., [Ru(III)Cl(3)(Hind)(2)(Me(2)S)], 4, and [Ru(III)Cl(3)(Hind)(2)(Et(2)S)], 5. By dissolution of 2 or 3 in DMSO, replacement of both R(2)S ligands by DMSO molecules occurred with isolation of trans,trans,trans-[Ru(II)Cl(2)(Hind)(2)(DMSO)(2)], 6. The products were characterized by elemental analysis, IR, UV-vis, electrospray mass spectrometry, cyclic voltammetry, and X-ray crystallography (1.CH(2)Cl(2).CH(3)OH and 1.1.1H(2)O.0.9CH(3)OH, 2, and 5). The first crystallographic evidence for the monofunctional coordination of the 9-methyladenine ligand to ruthenium via N7 and the self-pairing of the complex molecules via H-bonding, using the usual Watson-Crick pairing donor and acceptor sites of two adjacent 9-methyladenine ligands, is reported. The electrochemical behavior of 1-5 has been studied in DMF and DMSO by cyclic voltammetry. The redox potential values have been interpreted on the basis of the Lever's parametrization method. The E(L) parameter was estimated for 9-methyladenine at 0.18 V, showing that this ligand behaves as a weaker net electron donor than imidazole (E(L) = 0.12 V). The kinetics of the reductively induced stepwise replacement of chlorides by DMF in 4 and 5 were studied by digital simulation of the cyclic

  6. Antitumor effect of arabinogalactan and platinum complex.

    PubMed

    Starkov, A K; Zamay, T N; Savchenko, A A; Ingevatkin, E V; Titova, N M; Kolovskaya, O S; Luzan, N A; Silkin, P P; Kuznetsova, S A

    2016-03-01

    The article presents the results of investigation of antitumor properties of platinum-arabinogalactan complex. We showed the ability of the complex to inhibit the growth of Ehrlich ascites tumor cells. It is found that the distribution of the platinum-arabinogalactan complex is not specific only for tumor cells in mice. The complex was found in all tissues and organs examined (ascites cells, embryonic cells, kidney, and liver). The mechanism of action of the arabinogalactan-platinum complex may be similar to cisplatin as the complex is able to accumulate in tumor cells.

  7. Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics.

    PubMed

    Le, V H; Inai, M; Williams, R M; Kan, T

    2015-02-01

    The ecteinascidin family comprises a number of biologically active compounds, containing two to three tetrahydroisoquinoline subunits. Although isolated from marine tunicates, these compounds share a common pentacyclic core with several antimicrobial compounds found in terrestrial bacteria. Among the tetrahydroisoquinoline natural products, ecteinascidin 743 (Et-743) stands out as the most potent antitumor antibiotics that it is recently approved for treatment of a number of soft tissue sarcomas. In this article, we will review the backgrounds, the mechanism of action, the biosynthesis, and the synthetic studies of Et-743. Also, the development of Et-743 as an antitumor drug is discussed.

  8. Green synthesis and characterization of gold nanoparticles using extract of anti-tumor potent Crocus sativus

    NASA Astrophysics Data System (ADS)

    Vijayakumar, R.; Devi, V.; Adavallan, K.; Saranya, D.

    2011-12-01

    In the present study, we have explored anti-tumor potent Crocus sativus (saffron) as a reducing agent for one pot size controlled green synthesis of gold nanoparticles (AuNps) at ambient conditions. The nanoparticles were characterized using UV-vis, scanning electron microscope (SEM), high resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD) and FTIR analysis. The prepared AuNPs showed surface Plasmon resonance centered at 549 nm with average particle size of 15±5 nm. Stable, spherical and triangular crystalline AuNPs with well-defined dimensions were synthesized using anti-tumor potent Crocus sativus (saffron). Crystalline nature of the nanoparticles is confirmed from the HR-TEM, SAED and SEM images, and XRD patterns. From the FTIR spectra it is found that the biomolecules are responsible for capping in gold nanoparticles.

  9. Attraction and activation of dendritic cells at the site of tumor elicits potent antitumor immunity.

    PubMed

    Lapteva, Natalia; Aldrich, Melissa; Rollins, Lisa; Ren, Wenhong; Goltsova, Tatiana; Chen, Si-Yi; Huang, Xue F

    2009-09-01

    Tumor cells harbor unique genetic mutations, which lead to the generation of immunologically foreign antigenic peptide repertoire with the potential to induce individual tumor-specific immune responses. Here, we developed an in situ tumor vaccine with the ability to elicit antitumor immunity. This vaccine comprised an E1B-deleted oncolytic adenovirus expressing beta-defensin-2 (Ad-BD2-E1A) for releasing tumor antigens, recruiting and activating plasmacytoid dendritic cells (pDCs). Intratumoral injections of Ad-BD2-E1A vaccine inhibited primary breast tumor growth and blocked naturally occurring metastasis in mice. Ad-BD2-E1A vaccination induced potent tumor-specific T-cell responses. Splenic and intratumoral DCs isolated from Ad-BD2-E1A-immunized mice were able to stimulate or promote the differentiation of naive T cells into tumor-specific cytotoxic T cells. We further found that the increased numbers of mature CD45RA(+)CD8alpha(+)CD40(+) pDCs infiltrated into Ad-BD2-E1A-treated tumors. The antitumor effect of Ad-BD2-E1A vaccination was abrogated in toll-like receptor 4 (TLR4) deficient mice, suggesting the critical role of TLR4 in the induction of antitumor immunity by Ad-BD2-E1A. The results of this study indicate that in situ vaccination with the oncolytic BD2-expressing adenovirus preferentially attracts pDCs and promotes their maturation, and thus elicits potent tumor-specific immunity. This vaccine represents an attractive therapeutic strategy for the induction of individualized antitumor immunity.

  10. CHS 828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo.

    PubMed

    Hjarnaa, P J; Jonsson, E; Latini, S; Dhar, S; Larsson, R; Bramm, E; Skov, T; Binderup, L

    1999-11-15

    A new class of recently discovered antineoplastic agents, the pyridyl cyanoguanidines, exert a potent antitumor activity in rodents after oral administration. Optimization in vitro and in vivo has resulted in the selection of the lead candidate CHS 828 (N-(6-chlorophenoxyhexyl)-N'cyano-N"-4-pyridylguanidine). CHS 828 was found to exert potent cytotoxic effects in human breast and lung cancer cell lines, with lesser effects on normal fibroblasts and endothelial cells. In a study using a panel of cell lines with different resistance patterns, the effects of CHS 828 showed a low correlation with the activity patterns of known anticancer agents, and no sensitivity to known mechanisms of multidrug resistance was observed. In nude mice bearing human tumor xenografts, CHS 828, at doses from 20 to 50 mg/kg/day p.o., inhibited the growth of MCF-7 breast cancer tumors and caused regression of NYH small cell lung cancer tumors. Oral administration of CHS 828 once weekly improved efficacy without increasing toxicity. CHS 828 was found to compare favorably with established chemotherapeutic agents such as cyclophosphamide, etoposide, methotrexate, and paclitaxel. In mice with NYH tumors, long-term survival (>6 months) was observed after treatment with CHS 828 was stopped. In conclusion, CHS 828 is an effective new antitumor agent, with a potentially new mechanism of action. CHS 828 is presently being tested in Phase I clinical trials in collaboration with the European Organization for Research and Treatment of Cancer.

  11. Methylenedioxy- and ethylenedioxy-fused indolocarbazoles: potent human topoisomerase I inhibitors and antitumor agents.

    PubMed

    Zembower, David E; Xie, Yongping; Koohang, Ali; Kuffel, Mary J; Ames, Matthew M; Zhou, Yasheen; Mishra, Rama; Mar, Aye Aye; Flavin, Michael T; Xu, Ze-Qi

    2012-11-01

    The indolo[2,3-a]carbazole alkaloids constitute an important class of natural products with interesting and diverse biological activities. A series of novel ring-fused indolocarbazoles were synthesized and evaluated for inhibition of topoisomerase I-mediated relaxation of supercoiled DNA and in vitro antitumor activity. The derivatives bearing a methylenedioxy or an ethylenedioxy ring fused onto the nonglycosylated indole (1a, 1b) demonstrated more potent anti-topoisomerase I activity. The isopropylenedioxy analogue 1c was approximately half as active as 1a, while the O-dimethoxy analogue 1d and the regioisomers 2a and 2b were essentially devoid of measurable activity, implying that the stacking with the intact DNA strand has been impeded by these compounds due to steric hindrance. The newly synthesized indolocarbazoles were screened against the NCI's 60 tumor cell lines. The order of activity, based on the mean GI50 values, is as follows: 1a > 2a ~ 1d > 1b > MCR-47 > 2b. Though in general the analogues that showed potent activity against topoisomerase I (1a, 1b) also showed potent in vitro inhibition of tumor cell growth, the antitumor activity of the anti-topoisomerase I inactive 1d and 2a were intriguing. COMPARE analyses confirmed that the topoisomerase I is the primary target for 1a and 1b; however, other target(s) or pathway(s) may also be involved, with PLD1 and MERTK suggested. Further investigation of these molecular targets against these indolocarbazoles is warranted.

  12. Design, synthesis and 3D-QSAR of beta-carboline derivatives as potent antitumor agents.

    PubMed

    Cao, Rihui; Guan, Xiangdong; Shi, Buxi; Chen, Zhiyong; Ren, Zhenhua; Peng, Wenlie; Song, Huacan

    2010-06-01

    In a continuing effort to develop novel beta-carbolines endowed with better pharmacological profiles, a series of beta-carboline derivatives were designed and synthesized based on the previously developed SARs. Cytotoxicities in vitro of these compounds against a panel of human tumor cell lines were also investigated. The results demonstrated that the N2-benzylated beta-carbolinium bromides 56-60 represented the most potent compounds with IC50 values lower than 10 microM. The application of 3D-QSAR to these compounds explored the structural basis for their biological activities. CoMFA (q2=0.513, r2=0.862) and CoMSIA (q2=0.503, r2=0.831) models were developed for a set of 47 beta-carbolines. The results indicated that the antitumor pharmacophore of these molecules were marked at position-1, -2, -3, -7 and -9 of beta-carboline ring.

  13. DNA vaccines targeting the encoded antigens to dendritic cells induce potent antitumor immunity in mice.

    PubMed

    Cao, Jun; Jin, Yiqi; Li, Wei; Zhang, Bin; He, Yang; Liu, Hongqiang; Xia, Ning; Wei, Huafeng; Yan, Jian

    2013-08-14

    Although DNA vaccine holds a great potential for cancer immunotherapy, effective long-lasting antitumoral immunity sufficient to induce durable responses in cancer patients remains to be achieved. Considering the pivotal role of dendritic cells (DC) in the antigen processing and presentation, we prepared DC-targeting DNA vaccines by fusing tumor-associated antigen HER2/neu ectodomain to single chain antibody fragment (scFv) from NLDC-145 antibody specific for DC-restricted surface molecule DEC-205 (scFvNLDC-145), and explored its antitumoral efficacy and underlying mechanisms in mouse breast cancer models. In vivo targeting assay demonstrated that scFvNLDC-145 specifically delivered DNA vaccine-encoded antigen to DC. Compared with untargeted HER2/neu DNA vaccines, vaccination with scFvNLDC-145-HER2/neu markedly promoted the HER2/neu-specific cellular and humoral immune responses with long-lasting immune memory, resulting in effective protection against challenge of HER2/neu-positive D2F2/E2 breast tumor while ineffective in parental HER2/neu-negative D2F2 breast tumor. More importantly, in combination with temporary depletion of regulatory T cells (Treg) by low-dose cyclophosphamide, vaccination with scFvNLDC-145-HER2/neu induced the regression of established D2F2/E2 breast tumor and significantly retarded the development of spontaneous mammary carcinomas in transgenic BALB-neuT mice. Our findings demonstrate that DC-targeted DNA vaccines for in vivo direct delivery of tumor antigens to DC could induce potent antigen-specific cellular and humoral immune responses and, if additional combination with systemic Treg depletion, was able to elicit an impressively therapeutic antitumoral activity, providing a rationale for further development of this approach for cancer treatment.

  14. Potent antitumor activity of double-regulated oncolytic adenovirus-mediated ST13 for colorectal cancer.

    PubMed

    Yu, De Bin; Zhong, Su Yang; Yang, Min; Wang, Yi Gang; Qian, Qi Jun; Zheng, Shu; Liu, Xin Yuan

    2009-04-01

    Following targeted gene virotherapy, the suppression of tumorigenicity 13 (ST13) gene was inserted into the double-regulated oncolytic adenovirus SG500 to ensure more safety and potent antitumor activity against colorectal cancer in vitro and in vivo. We generated the ST13-expressing oncolytic adenovirus SG500-ST13, with which colorectal carcinoma cell lines SW620 and HCT116, and the lung fibroblast cell line WI38, were infected. Crystal violet staining was carried out to detect the cytopathic effect in cells, and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method was used to assay cell viability. The effect of apoptosis induced by SG500-ST13 was confirmed by Hoechst staining and the TdT-mediated dUTP-biotin nick-end labeling method. To further identify the antitumor effects of SG500-ST13 on HCT116 xenografts in Balb/c nude mice, the induction of cell death was assessed by hematoxylin-eosin staining. Immunohistochemical study was also carried out.

  15. Recent Progress on C-4-Modified Podophyllotoxin Analogs as Potent Antitumor Agents

    PubMed Central

    Liu, Ying-Qian; Tian, Jing; Qian, Keduo; Zhao, Xiao-Bo; Morris-Natschke, Susan L.; Yang, Liu; Nan, Xiang; Tian, Xuan; Lee, Kuo-Hsiung

    2015-01-01

    Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure–activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates. PMID:24827545

  16. Potent antitumor activities of recombinant human PDCD5 protein in combination with chemotherapy drugs in K562 cells

    SciTech Connect

    Shi, Lin; Song, Quansheng; Zhang, Yingmei; Lou, Yaxin; Wang, Yanfang; Tian, Linjie; Zheng, Yi; Ma, Dalong; Ke, Xiaoyan; Wang, Ying

    2010-05-28

    Conventional chemotherapy is still frequently used. Programmed cell death 5 (PDCD5) enhances apoptosis of various tumor cells triggered by certain stimuli and is lowly expressed in leukemic cells from chronic myelogenous leukemia patients. Here, we describe for the first time that recombinant human PDCD5 protein (rhPDCD5) in combination with chemotherapy drugs has potent antitumor effects on chronic myelogenous leukemia K562 cells in vitro and in vivo. The antitumor efficacy of rhPDCD5 protein with chemotherapy drugs, idarubicin (IDR) or cytarabine (Ara-C), was examined in K562 cells in vitro and K562 xenograft tumor models in vivo. rhPDCD5 protein markedly increased the apoptosis rates and decreased the colony-forming capability of K562 cells after the combined treatment with IDR or Ara-C. rhPDCD5 protein by intraperitoneal administration dramatically improved the antitumor effects of IDR treatment in the K562 xenograft model. The tumor sizes and cell proliferation were significantly decreased; and TUNEL positive cells were significantly increased in the combined group with rhPDCD5 protein and IDR treatment compared with single IDR treatment groups. rhPDCD5 protein, in combination with IDR, has potent antitumor effects on chronic myelogenous leukemia K562 cells and may be a novel and promising agent for the treatment of chronic myelogenous leukemia.

  17. Potent antitumor activity of quinolone compounds with an unsaturated aminoazabicyclo group at the C-7 position of the quinolone ring.

    PubMed

    Arakawa, H; Mano, E; Hakoda, N; Yoshinari, T; Nakagawa, S; Okura, A

    1996-04-01

    Relationships between the substituents on the quinolone nucleus of 2 and related compounds and their biological activities were studied. 2, 3 and 1 carrying a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl group at the C-7 position increased the rate of formation of DNA-protein complexes in cells, and inhibited the growth of tumor cells more strongly than the compounds with other substituents. The introduction of a fluorine atom or a methoxy group at the 8-position and an amino group at the 5-position increased the activity still further. The three compounds listed were all effective against P388 leukemia in mice. Subcutaneous injection of 2 at 2 mg/kg strongly suppressed the growth of human MX-1 breast cancer cells in nude mice. 1 has various functional groups that increase the cytotoxic potential of quinolone derivatives: a (1R, 2R, 6R)-2-amino-8-azabicyclo[4.3.0.]non-3-en-8-yl moiety at C-7, a cyclopropyl group at the 1-position, fluorine atoms at the 6- and 8-positions, and an amino group at the 5-position of the quinoline carboxylic acid. These data suggest that this series of compounds provide good models for the further design of potent antitumor quinolones.

  18. Trop-2-targeting tetrakis-ranpirnase has potent antitumor activity against triple-negative breast cancer

    PubMed Central

    2014-01-01

    Background Ranpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC). Methods The DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model. Results (Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50 ≤ 1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose. Conclusions A new class of immunoRNases was generated with enhanced potency for

  19. Ecteinascidin-743, a new marine natural product with potent antitumor activity on human ovarian carcinoma xenografts.

    PubMed

    Valoti, G; Nicoletti, M I; Pellegrino, A; Jimeno, J; Hendriks, H; D'Incalci, M; Faircloth, G; Giavazzi, R

    1998-08-01

    The antitumor activity of ecteinascidin (ET)-743, a novel marine natural product, was evaluated against a panel of human ovarian carcinoma xenografts characterized by different malignant behaviors and drug responsiveness in nude mice. These tumor models included three xenografts transplanted s.c. (HOC18, HOC22-S, and MNB-PTX-1) into nude mice, representing different levels of sensitivity to cisplatinum (DDP), which was used as reference drug for ovarian carcinoma, and two other xenografts (HOC22 and HOC8), which are highly malignant in the peritoneal cavity of nude mice, representing the growth pattern of this neoplasm. At the maximum tolerated dose of 0.2 mg/kg using an intermittent schedule of one i.v. injection every 4 days, ET-743 was highly active against HOC22-S (sensitive to DDP), inducing long-lasting, complete regressions, and against HOC18 (marginally sensitive to DDP), inducing partial tumor regressions. Moreover, significant growth delay was observed in mice bearing late-stage HOC18 tumor (400-mg tumor weight; nonresponsive to DDP). ET-743, however, was not active against MNB-PTX-1, a tumor that is highly resistant to chemotherapy, including DDP. In the i.p. ovarian carcinoma xenograft model, ET-743 at the maximum tolerated dose induced complete tumor remissions in all mice bearing HOC22 tumor, with 25% histopathologically confirmed cures, and produced marginal tumor growth delay against HOC8. These results indicate that ET-743 is a potent drug against ovarian carcinoma xenografts, being equally as active or more efficacious than DDP in the same tumor line. Our findings with human ovarian carcinoma xenografts justify clinical assessment of this drug with this tumor target.

  20. Synthesis and biological evaluation of diarylthiazole derivatives as antimitotic and antivascular agents with potent antitumor activity.

    PubMed

    Wang, Fang; Yang, Zhuang; Liu, Yibin; Ma, Liang; Wu, Yuzhe; He, Lin; Shao, Mingfeng; Yu, Kun; Wu, Wenshuang; Pu, Yuzhi; Nie, Chunlai; Chen, Lijuan

    2015-07-01

    By switching position of the N and S atom in the thiazole ring which were similar to the previously reported agent 5-(4-ethoxyphenyl)-4-(3',4',5'-trimethoxyphenyl)thiazol-2-amine, a series of 4,5-diarylthiazole derivatives were synthesized using Friedel-Crafts reaction based on chemical modification of Combrestatatin A-4 (CA-4). Their antiproliferative activities were evaluated and identified as new microtubule destabilizing agents. Structure-activity relationship study indicated that compound 8a with 3,4,5-trimethoxyphenyl group at the C-4 position and 4-ethoxyphenyl group at the C-5 position of 2-amino substituted thiazole was of the most potent inhibitory activity in this series. 8a was found to exhibit the IC50 values of 8.4-26.4nM in five human cancer cell lines, with comparable inhibition effects to CA-4. Moreover, 8a showed potency as a tubulin polymerization inhibitor, with colchicine site binding ability and comparable extent of inhibition against the growth of P-glycoprotein over-expressing multidrug resistant cell lines. Mechanism studies revealed that 8a could block the progression of cell cycle in the G2/M phase and result in cellular apoptosis in cancer cells. As a new tubulin destabilizing agent, 8a was also found high antivascular activity as it concentration-dependently reduced the cell migration and disrupted capillary like tube formation of HUVEC cells. Furthermore, 8a significantly suppressed the tumor growth in HCT116 and SK-OV-3 xenograft models with tumor growth inhibitory rate of 55.12% and 72.7%, respectively. Our studies highlighted that 8a was a promising microtubule targeting antitumor agent.

  1. Synthesis and structure-activity relationships of potent antitumor active quinoline and naphthyridine derivatives.

    PubMed

    Srivastava, Sanjay K; Jha, Amrita; Agarwal, Shiv K; Mukherjee, Rama; Burman, Anand C

    2007-11-01

    The disease of cancer has been ranked second after cardiovascular diseases and plant-derived molecules have played an important role for the treatment of cancer. Nine cytotoxic plant-derived molecules such as vinblastine, vincristine, navelbine, etoposide, teniposide, taxol, taxotere, topotecan and irinotecan have been approved as anticancer drugs. Recently, epothilones are being emerging as future potential anti-tumor agents. However, targeted cancer therapy has now been rapidly expanding and small organic molecules are being exploited for this purpose. Amongst target specific small organic molecules, quinazoline was found as one of the most successful chemical class in cancer chemotherapy as three drugs namely Gefitinib, Erlotinib and Canertinib belong to this series. Now, quinazoline related chemical classes such as quinolines and naphthyridines are being exploited in cancer chemotherapy and a number of molecules such as compounds EKB-569 (52), HKI-272 (78) and SNS-595 (127a) are in different phases of clinical trials. This review presents the synthesis of quinolines and naphthyridines derivatives, screened for anticancer activity since year 2000. The synthesis of most potent derivatives in each prototype has been delineated. A brief structure activity relationship for each prototype has also been discussed. It has been observed that aniline group at C-4, aminoacrylamide substituents at C-6, cyano group at C-3 and alkoxy groups at C-7 in the quinoline ring play an important role for optimal activity. While aminopyrrolidine functionality at C-7, 2'-thiazolyl at N-1 and carboxy group at C-3 in 1,8-naphthyridine ring are essential for eliciting the cytotoxicity. This review would help the medicinal chemist to design and synthesize molecules for targeted cancer chemotherapy.

  2. Narciclasine - an Amaryllidaceae Alkaloid with Potent Antitumor and Anti-Inflammatory Properties.

    PubMed

    Fürst, Robert

    2016-11-01

    The isocarbostyril alkaloid narciclasine, also known as lycoricidinol, was discovered in Narcissus species (Amaryllidaceae) in 1967. A few years later, the 60S subunit of ribosomes, and thus protein biosynthesis, were shown to be directly targeted by narciclasine. Due to its selective and highly potent cytotoxic action on cancer cells, narciclasine was intensively investigated as an antitumor compound both in vitro and in vivo. However, narciclasine did not show a strong pharmacological activity in animal tumor models. During the last decade, new fascinating actions, mechanisms, and targets of narciclasine have emerged. This review intends to present a brief but comprehensive overview of these novel insights. Beneficial therapeutical actions have been reported particularly in brain tumor models. The translation elongation factor eEF1A, which does not only participate in protein biosynthesis but also in the regulation of the actin cytoskeleton, was discovered as new direct target. Moreover, narciclasine was found to trigger actin stress fiber formation via the activation of the small GTPase RhoA. Progress has also been made regarding the pharmacokinetic characterization of the alkaloid. The synthesis of a great number of narciclasine derivatives led to a substantial understanding of its pharmacophore and of the structure-activity relationships. However, an optimized compound did not result from these efforts. Most importantly, a new field of indication has emerged: Narciclasine was proven to exert profound anti-inflammatory actions in vivo. Taken together, there has been a strong advance in the preclinical knowledge about the alkaloid. Nevertheless, narciclasine has not been tested in human clinical trials up to now. Georg Thieme Verlag KG Stuttgart · New York.

  3. Poly (I:C) enhances the anti-tumor activity of canine parvovirus NS1 protein by inducing a potent anti-tumor immune response.

    PubMed

    Gupta, Shishir Kumar; Yadav, Pavan Kumar; Tiwari, A K; Gandham, Ravi Kumar; Sahoo, A P

    2016-09-01

    The canine parvovirus NS1 (CPV2.NS1) protein selectively induces apoptosis in the malignant cells. However, for an effective in vivo tumor treatment strategy, an oncolytic agent also needs to induce a potent anti-tumor immune response. In the present study, we used poly (I:C), a TLR3 ligand, as an adjuvant along with CPV2.NS1 to find out if the combination can enhance the oncolytic activity by inducing a potent anti-tumor immune response. The 4T1 mammary carcinoma cells were used to induce mammary tumor in Balb/c mice. The results suggested that poly (I:C), when given along with CPV2.NS1, not only significantly reduced the tumor growth but also augmented the immune response against tumor antigen(s) as indicated by the increase in blood CD4+ and CD8+ counts and infiltration of immune cells in the tumor tissue. Further, blood serum analysis of the cytokines revealed that Th1 cytokines (IFN-γ and IL-2) were significantly upregulated in the treatment group indicating activation of cell-mediated immune response. The present study reports the efficacy of CPV2.NS1 along with poly (I:C) not only in inhibiting the mammary tumor growth but also in generating an active anti-tumor immune response without any visible toxicity. The results of our study may help in developing CPV2.NS1 and poly (I: C) combination as a cancer therapeutic regime to treat various malignancies.

  4. Novel spiropyrazolone antitumor scaffold with potent activity: Design, synthesis and structure-activity relationship.

    PubMed

    Wu, Shanchao; Li, Yu; Xu, Guixia; Chen, Shuqiang; Zhang, Yongqiang; Liu, Na; Dong, Guoqiang; Miao, Chaoyu; Su, Hua; Zhang, Wannian; Sheng, Chunquan

    2016-06-10

    Phenotypic screening of high quality compound library is an effective strategy to discover novel bioactive molecules. Previously, we developed the divergent organocatalytic cascade approach to efficiently construct a focused library with scaffold diversity and successfully identified a novel spiropyrazolone antitumor scaffold. Herein, a series of spiropyrazolone derivatives were designed, synthesized and assayed. Most of them showed good in vitro antitumor activity with a broad spectrum. Preliminary structure-activity relationship for the substitutions and the stereo configuration were obtained. Compound 5k showed good antitumor activity and could effectively induce cancer cell apoptosis, which represents a good starting point for the development of novel antitumor agents. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  5. Design and synthesis of 2-(3-alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones as potent antitumor agents.

    PubMed

    Huang, Shih-Ming; Cheng, Yung-Yi; Chen, Ming-Hua; Huang, Chi-Hung; Huang, Li-Jiau; Hsu, Mei-Hua; Kuo, Sheng-Chu; Lee, Kuo-Hsiung

    2013-02-01

    2-(3-Alkylaminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-ones 1-3 were synthesized and screened for anti-proliferative activity against three human cancer cell lines, as well as the normal cell line Detroit 551. All of the synthesized target compounds 1-3 demonstrated potent cytotoxic activity against the cancer cell lines, but weak inhibitory activity toward the normal cell line. 2-(3-Methyl aminophenyl)-6-(pyrrolidin-1-yl)quinolin-4-one (1), one of the potent compounds in vitro, was also tested in an in vivo Hep3B xenograft nude mice model, and its significant anticancer activity was reconfirmed. Therefore, compound 1 merits further investigation as an antitumor clinical trial candidate and potential anticancer agent.

  6. Oncolytic Immunotherapy: Dying the Right Way is a Key to Eliciting Potent Antitumor Immunity

    PubMed Central

    Guo, Zong Sheng; Liu, Zuqiang; Bartlett, David L.

    2014-01-01

    Oncolytic viruses (OVs) are novel immunotherapeutic agents whose anticancer effects come from both oncolysis and elicited antitumor immunity. OVs induce mostly immunogenic cancer cell death (ICD), including immunogenic apoptosis, necrosis/necroptosis, pyroptosis, and autophagic cell death, leading to exposure of calreticulin and heat-shock proteins to the cell surface, and/or released ATP, high-mobility group box 1, uric acid, and other damage-associated molecular patterns as well as pathogen-associated molecular patterns as danger signals, along with tumor-associated antigens, to activate dendritic cells and elicit adaptive antitumor immunity. Dying the right way may greatly potentiate adaptive antitumor immunity. The mode of cancer cell death may be modulated by individual OVs and cancer cells as they often encode and express genes that inhibit/promote apoptosis, necroptosis, or autophagic cell death. We can genetically engineer OVs with death-pathway-modulating genes and thus skew the infected cancer cells toward certain death pathways for the enhanced immunogenicity. Strategies combining with some standard therapeutic regimens may also change the immunological consequence of cancer cell death. In this review, we discuss recent advances in our understanding of danger signals, modes of cancer cell death induced by OVs, the induced danger signals and functions in eliciting subsequent antitumor immunity. We also discuss potential combination strategies to target cells into specific modes of ICD and enhance cancer immunogenicity, including blockade of immune checkpoints, in order to break immune tolerance, improve antitumor immunity, and thus the overall therapeutic efficacy. PMID:24782985

  7. Scaffold Diversity Inspired by the Natural Product Evodiamine: Discovery of Highly Potent and Multitargeting Antitumor Agents.

    PubMed

    Wang, Shengzheng; Fang, Kun; Dong, Guoqiang; Chen, Shuqiang; Liu, Na; Miao, Zhenyuan; Yao, Jianzhong; Li, Jian; Zhang, Wannian; Sheng, Chunquan

    2015-08-27

    A critical question in natural product-based drug discovery is how to translate the product into drug-like molecules with optimal pharmacological properties. The generation of natural product-inspired scaffold diversity is an effective but challenging strategy to investigate the broader chemical space and identify promising drug leads. Extending our efforts to the natural product evodiamine, a diverse library containing 11 evodiamine-inspired novel scaffolds and their derivatives were designed and synthesized. Most of them showed good to excellent antitumor activity against various human cancer cell lines. In particular, 3-chloro-10-hydroxyl thio-evodiamine (66c) showed excellent in vitro and in vivo antitumor efficacy with good tolerability and low toxicity. Antitumor mechanism and target profiling studies indicate that compound 66c is the first-in-class triple topoisomerase I/topoisomerase II/tubulin inhibitor. Overall, this study provided an effective strategy for natural product-based drug discovery.

  8. Cell-specific expression of artificial microRNAs targeting essential genes exhibit potent antitumor effect on hepatocellular carcinoma cells.

    PubMed

    Mao, Chenyu; Liu, Hao; Chen, Ping; Ye, Jingjia; Teng, Lisong; Jia, Zhenyu; Cao, Jiang

    2015-03-20

    To achieve specific and potent antitumor effect of hepatocyte carcinoma cells, replication defective adenoviral vectors, namely rAd/AFP-amiRG, rAd/AFP-amiRE and rAd/AFP-amiRP, were constructed which were armed with artificial microRNAs (amiRs) targeting essential functional genes glyceraldehyde-3-phosphate dehydrogenase, eukaryotic translation initiation factor 4E and DNA polymerase α respectively under the control of a recombinant promoter comprised of human α-fetoprotein enhancer and basal promoter. The AFP enhancer/promoter showed specific high transcription activity in AFP-positive HCC cells Hep3B, HepG2 and SMMC7721, while low in AFP-negative cell Bcap37. All artificial microRNAs exhibited efficient knockdown of target genes. Decreased ATP production and protein synthesis was observed in rAd/AFP-amiRG and rAd/AFP-amiRE treated HCC cells. All three recombinant adenoviruses showed efficient blockage of cell cycle progression and significant suppression of HCC cells in vitro. In nude mice model bearing Hep3B xenograft, administration of rAd/AFP-amiRG showed potent antitumor effect. The strategy of tumor-specific knockdown of genes essential for cell survival and proliferation may suggest a novel promising approach for HCC gene therapy.

  9. Discovery of the First N-Hydroxycinnamamide-Based Histone Deacetylase 1/3 Dual Inhibitors with Potent Oral Antitumor Activity

    PubMed Central

    2015-01-01

    In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity. PMID:24694055

  10. Discovery of the first N-hydroxycinnamamide-based histone deacetylase 1/3 dual inhibitors with potent oral antitumor activity.

    PubMed

    Li, Xiaoyang; Inks, Elizabeth S; Li, Xiaoguang; Hou, Jinning; Chou, C James; Zhang, Jian; Jiang, Yuqi; Zhang, Yingjie; Xu, Wenfang

    2014-04-24

    In our previous study, we designed and synthesized a novel series of N-hydroxycinnamamide-based HDAC inhibitors (HDACIs), among which the representative compound 14a exhibited promising HDACs inhibition and antitumor activity. In this current study, we report the development of a more potent class of N-hydroxycinnamamide-based HDACIs, using 14a as lead, among which, compound 11r gave IC50 values of 11.8, 498.1, 3.9, 2000.8, 5700.4, 308.2, and 900.4 nM for the inhibition of HDAC1, HDAC2, HDAC3, HDAC8, HDAC4, HDAC6, and HDAC11, exhibiting dual HDAC1/3 selectivity. Compounds 11e, 11r, 11w, and 11y showed excellent growth inhibition in multiple tumor cell lines. In vivo antitumor assay in U937 xenograft model identified compound 11r as a potent, orally active HDACI. To the best of our knowledge, this work constitutes the first report of oral active N-hydroxycinnamamide-based HDACIs with dual HDAC1/3 selectivity.

  11. Targeting Gene-Viro-Therapy with AFP driving Apoptin gene shows potent antitumor effect in hepatocarcinoma

    PubMed Central

    2012-01-01

    Background Gene therapy and viral therapy are used for cancer therapy for many years, but the results are less than satisfactory. Our aim was to construct a new recombinant adenovirus which is more efficient to kill hepatocarcinoma cells but more safe to normal cells. Methods By using the Cancer Targeting Gene-Viro-Therapy strategy, Apoptin, a promising cancer therapeutic gene was inserted into the double-regulated oncolytic adenovirus AD55 in which E1A gene was driven by alpha fetoprotein promoter along with a 55 kDa deletion in E1B gene to form AD55-Apoptin. The anti-tumor effects and safety were examined by western blotting, virus yield assay, real time polymerase chain reaction, 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, Hoechst33342 staining, Fluorescence-activated cell sorting, xenograft tumor model, Immunohistochemical assay, liver function analysis and Terminal deoxynucleotidyl transferase mediated dUTP Nick End Labeling assay. Results The recombinant virus AD55-Apoptin has more significant antitumor effect for hepatocelluar carcinoma cell lines (in vitro) than that of AD55 and even ONYX-015 but no or little impair on normal cell lines. Furthermore, it also shows an obvious in vivo antitumor effect on the Huh-7 liver carcinoma xenograft in nude mice with bigger beginning tumor volume till about 425 mm3 but has no any damage on the function of liver. The induction of apoptosis is involved in AD55-Apoptin induced antitumor effects. Conclusion The AD55-Apoptin can be a potential anti-hepatoma agent with remarkable antitumor efficacy as well as higher safety in cancer targeting gene-viro-therapy system. PMID:22321574

  12. The antimicrobial peptide pardaxin exerts potent anti-tumor activity against canine perianal gland adenoma

    PubMed Central

    Pan, Chieh-Yu; Lin, Chao-Nan; Chiou, Ming-Tang; Yu, Chao Yuan; Chen, Jyh-Yih; Chien, Chi-Hsien

    2015-01-01

    Pardaxin is an antimicrobial peptide of 33 amino acids, originally isolated from marine fish. We previously demonstrated that pardaxin has anti-tumor activity against murine fibrosarcoma, both in vitro and in vivo. In this study, we examined the anti-tumor activity, toxicity profile, and maximally-tolerated dose of pardaxin treatment in dogs with different types of refractory tumor. Local injection of pardaxin resulted in a significant reduction of perianal gland adenoma growth between 28 and 38 days post-treatment. Surgical resection of canine histiocytomas revealed large areas of ulceration, suggesting that pardaxin acts like a lytic peptide. Pardaxin treatment was not associated with significant variations in blood biochemical parameters or secretion of immune-related proteins. Our findings indicate that pardaxin has strong therapeutic potential for treating perianal gland adenomas in dogs. These data justify the veterinary application of pardaxin, and also provide invaluable information for veterinary medicine and future human clinical trials. PMID:25544775

  13. Isopentenyl pyrophosphate-activated CD56+ {gamma}{delta} T lymphocytes display potent antitumor activity toward human squamous cell carcinoma.

    PubMed

    Alexander, Alan A Z; Maniar, Amudhan; Cummings, Jean-Saville; Hebbeler, Andrew M; Schulze, Dan H; Gastman, Brian R; Pauza, C David; Strome, Scott E; Chapoval, Andrei I

    2008-07-01

    The expression of CD56, a natural killer cell-associated molecule, on alphabeta T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of gammadelta T cells. However, antitumor effector functions of CD56(+) gammadelta T cells are poorly characterized. To investigate the potential effector role of CD56(+) gammadelta T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2-expanded gammadelta T cells from peripheral blood mononuclear cells of healthy donors. Thirty to 70% of expanded gammadelta T cells express CD56 on their surface. Interestingly, although both CD56(+) and CD56(-) gammadelta T cells express comparable levels of receptors involved in the regulation of gammadelta T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56(+) gammadelta T lymphocytes are capable of killing squamous cell carcinoma and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules because CD56(+) gammadelta T lymphocytes expressed higher levels of CD107a compared with CD56(-) controls following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanamycin A and a combination of anti-gammadelta T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56(+) gammadelta T cells involves the perforin-granzyme pathway and is mainly gammadelta T-cell receptor/NKG2D dependent. Importantly, CD56-expressing gammadelta T lymphocytes are resistant to Fas ligand and chemically induced apoptosis. Our data indicate that CD56(+) gammadelta T cells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.

  14. Targeted delivery of tumor antigens to activated dendritic cells via CD11c molecules induces potent antitumor immunity in mice.

    PubMed

    Wei, Huafeng; Wang, Suhui; Zhang, Dapeng; Hou, Sheng; Qian, Weizhu; Li, Bohua; Guo, Huaizu; Kou, Geng; He, Jinqiu; Wang, Hao; Guo, Yajun

    2009-07-15

    CD11c is an antigen receptor predominantly expressed on dendritic cells (DC), to which antigen targeting has been shown to induce robust antigen-specific immune responses. To facilitate targeted delivery of tumor antigens to DCs, we generated fusion proteins consisting of the extracellular domain of human HER or its rat homologue neu, fused to the single-chain fragment variable specific for CD11c (scFv(CD11c)-HER2/neu). Induction of cellular and humoral immune responses and antitumoral activity of the fusion proteins admixed with DC-activating CpG oligonucleotides (scFv(CD11c)-HER2/neu(CpG)) were tested in transplantable HER2/neu-expressing murine tumor models and in transgenic BALB-neuT mice developing spontaneous neu-driven mammary carcinomas. Vaccination of BALB/c mice with scFv(CD11c)-HER2(CpG) protected mice from subsequent challenge with HER2-positive, but not HER2-negative, murine breast tumor cells, accompanied by induction of strong HER2-specific T-cell and antibody responses. In a therapeutic setting, injection of scFv(CD11c)-HER2(CpG) caused rejection of established HER2-positive tumors. Importantly, antitumoral activity of such a fusion protein vaccine could be reproduced in immunotolerant BALB-neuT mice, where scFv(CD11c)-neu(CpG) vaccination significantly protected against a subsequent challenge with neu-expressing murine breast tumor cells and markedly delayed the onset of spontaneous mammary carcinomas. CD11c-targeted protein vaccines for in vivo delivery of tumor antigens to DCs induce potent immune responses and antitumoral activities and provide a rationale for further development of this approach for cancer immunotherapy.

  15. The HSP90 inhibitor 17-AAG exhibits potent antitumor activity for pheochromocytoma in a xenograft model.

    PubMed

    Xu, Yunze; Zhu, Qi; Chen, Dongning; Shen, Zhoujun; Wang, Weiqing; Ning, Guang; Zhu, Yu

    2015-07-01

    This study aims to investigate the effect of heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) in the malignant pheochromocytoma using a xenograft mouse model. Treatment with 17-AAG induced a marked reduction in the volume and weight of PC12 pheochromocytoma cell tumor xenografts in mice. Furthermore, 17-AAG also significantly inhibited the expression of HSP90 and its client proteins. Our results validated HSP90 as an important target in pheochromocytoma and provided rationale for the testing of HSP90 inhibitors as a promising therapeutic agent in the antitumor therapy of pheochromocytoma.

  16. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma.

    PubMed

    Casucci, Monica; Nicolis di Robilant, Benedetta; Falcone, Laura; Camisa, Barbara; Norelli, Margherita; Genovese, Pietro; Gentner, Bernhard; Gullotta, Fabiana; Ponzoni, Maurilio; Bernardi, Massimo; Marcatti, Magda; Saudemont, Aurore; Bordignon, Claudio; Savoldo, Barbara; Ciceri, Fabio; Naldini, Luigi; Dotti, Gianpietro; Bonini, Chiara; Bondanza, Attilio

    2013-11-14

    Genetically targeted T cells promise to solve the feasibility and efficacy hurdles of adoptive T-cell therapy for cancer. Selecting a target expressed in multiple-tumor types and that is required for tumor growth would widen disease indications and prevent immune escape caused by the emergence of antigen-loss variants. The adhesive receptor CD44 is broadly expressed in hematologic and epithelial tumors, where it contributes to the cancer stem/initiating phenotype. In this study, silencing of its isoform variant 6 (CD44v6) prevented engraftment of human acute myeloid leukemia (AML) and multiple myeloma (MM) cells in immunocompromised mice. Accordingly, T cells targeted to CD44v6 by means of a chimeric antigen receptor containing a CD28 signaling domain mediated potent antitumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes. Importantly, in vitro activation with CD3/CD28 beads and interleukin (IL)-7/IL-15 was required for antitumor efficacy in vivo. Finally, coexpressing a suicide gene enabled fast and efficient pharmacologic ablation of CD44v6-targeted T cells and complete rescue from hyperacute xenogeneic graft-versus-host disease modeling early and generalized toxicity. These results warrant the clinical investigation of suicidal CD44v6-targeted T cells in AML and MM.

  17. A Novel Immunomodulatory Hemocyanin from the Limpet Fissurella latimarginata Promotes Potent Anti-Tumor Activity in Melanoma

    PubMed Central

    Arancibia, Sergio; Espinoza, Cecilia; Salazar, Fabián; Del Campo, Miguel; Tampe, Ricardo; Zhong, Ta-Ying; De Ioannes, Pablo; Moltedo, Bruno; Ferreira, Jorge; Lavelle, Ed C.; Manubens, Augusto; De Ioannes, Alfredo E.; Becker, María Inés

    2014-01-01

    Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN-γ production and higher numbers of tumor-infiltrating CD4+ lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-α) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID

  18. A Novel Time-Dependent CENP-E Inhibitor with Potent Antitumor Activity

    PubMed Central

    Ohashi, Akihiro; Ohori, Momoko; Iwai, Kenichi; Nambu, Tadahiro; Miyamoto, Maki; Kawamoto, Tomohiro; Okaniwa, Masanori

    2015-01-01

    Centromere-associated protein E (CENP-E) regulates both chromosome congression and the spindle assembly checkpoint (SAC) during mitosis. The loss of CENP-E function causes chromosome misalignment, leading to SAC activation and apoptosis during prolonged mitotic arrest. Here, we describe the biological and antiproliferative activities of a novel small-molecule inhibitor of CENP-E, Compound-A (Cmpd-A). Cmpd-A inhibits the ATPase activity of the CENP-E motor domain, acting as a time-dependent inhibitor with an ATP-competitive-like behavior. Cmpd-A causes chromosome misalignment on the metaphase plate, leading to prolonged mitotic arrest. Treatment with Cmpd-A induces antiproliferation in multiple cancer cell lines. Furthermore, Cmpd-A exhibits antitumor activity in a nude mouse xenograft model, and this antitumor activity is accompanied by the elevation of phosphohistone H3 levels in tumors. These findings demonstrate the potency of the CENP-E inhibitor Cmpd-A and its potential as an anticancer therapeutic agent. PMID:26649895

  19. Elimination of IL-10-inducing T-helper epitopes from an IGFBP-2 vaccine ensures potent antitumor activity.

    PubMed

    Cecil, Denise L; Holt, Gregory E; Park, Kyong Hwa; Gad, Ekram; Rastetter, Lauren; Childs, Jennifer; Higgins, Doreen; Disis, Mary L

    2014-05-15

    Immunization against self-tumor antigens can induce T-regulatory cells, which inhibit proliferation of type I CD4(+) T-helper (TH1) and CD8(+) cytotoxic T cells. Type I T cells are required for potent antitumor immunity. We questioned whether immunosuppressive epitopes could be identified and deleted from a cancer vaccine targeting insulin-like growth factor-binding protein (IGFBP-2) and enhance vaccine efficacy. Screening breast cancer patient lymphocytes with IFN-γ and interleukin (IL)-10 ELISPOT, we found epitopes in the N-terminus of IGFBP-2 that elicited predominantly TH1 whereas the C-terminus stimulated TH2 and mixed TH1/TH2 responses. Epitope-specific TH2 demonstrated a higher functional avidity for antigen than epitopes, which induced IFN-γ (P = 0.014). We immunized TgMMTV-neu mice with DNA constructs encoding IGFBP-2 N-and C-termini. T cell lines expanded from the C-terminus vaccinated animals secreted significantly more type II cytokines than those vaccinated with the N-terminus and could not control tumor growth when infused into tumor-bearing animals. In contrast, N-terminus epitope-specific T cells secreted TH1 cytokines and significantly inhibited tumor growth, as compared with naïve T cells, when adoptively transferred (P = 0.005). To determine whether removal of TH2-inducing epitopes had any effect on the vaccinated antitumor response, we immunized mice with the N-terminus, C-terminus, and a mix of equivalent concentrations of both vaccines. The N-terminus vaccine significantly inhibited tumor growth (P < 0.001) as compared with the C-terminus vaccine, which had no antitumor effect. Mixing the C-terminus with the N-terminus vaccine abrogated the antitumor response of the N-terminus vaccine alone. The clinical efficacy of cancer vaccines targeting self-tumor antigens may be greatly improved by identification and removal of immunosuppressive epitopes.

  20. Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity.

    PubMed

    Liu, Kevin K-C; Zhu, JinJiang; Smith, Graham L; Yin, Min-Jean; Bailey, Simon; Chen, Jeffrey H; Hu, Qiyue; Huang, Qinhua; Li, Chunze; Li, Qing J; Marx, Matthew A; Paderes, Genevieve; Richardson, Paul F; Sach, Neal W; Walls, Marlena; Wells, Peter A; Baxi, Sangita; Zou, Aihua

    2011-11-10

    Highly selective PI3K inhibitors with subnanomolar PI3Kα potency and greater than 7000-fold selectivity against mTOR kinase were discovered through structure-based drug design (SBDD). These tetra-substituted thiophenes were also demonstrated to have good in vitro cellular potency and good in vivo oral antitumor activity in a mouse PI3K driven NCI-H1975 xenograft tumor model. Compounds with the desired human PK predictions and good in vitro ADMET properties were also identified. In this communication, we describe the rationale behind the installation of a critical triazole moiety to maintain the intricate H-bonding network within the PI3K receptor leading to both better potency and selectivity. Furthermore, optimization of the C-4 phenyl group was exploited to maximize the compounds mTOR selectivity.

  1. Potent antitumor activity of a urokinase-activated engineered anthrax toxin

    NASA Astrophysics Data System (ADS)

    Liu, Shihui; Aaronson, Hannah; Mitola, David J.; Leppla, Stephen H.; Bugge, Thomas H.

    2003-01-01

    The acquisition of cell-surface urokinase plasminogen activator activity is a hallmark of malignancy. We generated an engineered anthrax toxin that is activated by cell-surface urokinase in vivo and displays limited toxicity to normal tissue but broad and potent tumoricidal activity. Native anthrax toxin protective antigen, when administered with a chimeric anthrax toxin lethal factor, Pseudomonas exotoxin fusion protein, was extremely toxic to mice, causing rapid and fatal organ damage. Replacing the furin activation sequence in anthrax toxin protective antigen with an artificial peptide sequence efficiently activated by urokinase greatly attenuated toxicity to mice. In addition, the mutation conferred cell-surface urokinase-dependent toxin activation in vivo, as determined by using a panel of plasminogen, plasminogen activator, plasminogen activator receptor, and plasminogen activator inhibitor-deficient mice. Surprisingly, toxin activation critically depended on both urokinase plasminogen activator receptor and plasminogen in vivo, showing that both proteins are essential cofactors for the generation of cell-surface urokinase. The engineered toxin displayed potent tumor cell cytotoxicity to a spectrum of transplanted tumors of diverse origin and could eradicate established solid tumors. This tumoricidal activity depended strictly on tumor cell-surface plasminogen activation. The data show that a simple change of protease activation specificity converts anthrax toxin from a highly lethal to a potent tumoricidal agent.

  2. Organometallic osmium arene complexes with potent cancer cell cytotoxicity.

    PubMed

    Fu, Ying; Habtemariam, Abraha; Pizarro, Ana M; van Rijt, Sabine H; Healey, David J; Cooper, Patricia A; Shnyder, Steven D; Clarkson, Guy J; Sadler, Peter J

    2010-11-25

    Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells. They exhibit low toxicity and negligible deleterious effects in a colon cancer xenograft model, giving rise to the possibility of a broad therapeutic window. The most active complexes are stable and inert toward aquation. Their cytotoxic activity appears to involve redox mechanisms.

  3. New benzothiazole/thiazole-containing hydroxamic acids as potent histone deacetylase inhibitors and antitumor agents.

    PubMed

    Tung, Truong Thanh; Oanh, Dao Thi Kim; Dung, Phan Thi Phuong; Hue, Van Thi My; Park, Sang Ho; Han, Byung Woo; Kim, Youngsoo; Hong, Jin-Tae; Han, Sang-Bae; Nam, Nguyen-Hai

    2013-12-01

    Results from clinical studies have demonstrated that inhibitors of histone deacetylase (HDAC) enzymes possess promise for the treatment of several types of cancer. Zolinza(®) (widely known as SAHA) has been approved by the FDA for the treatment of T-cell lymphoma. As a continuity of our ongoing research to find novel small molecules to target these important enzymes, we synthesized a series of benzothiazole-containing analogues of SAHA and found several compounds with very potent anticancer cytotoxicity. In this study, three more compounds of this type, including N(1)-(6-chlorobenzo[d]thiazol-2-yl)-N(8)-hydroxyoctanediamide (3a), N(1)-[6-(trifluoromethyl)benzo[d]thiazol-2-yl]-N(8)-hydroxyoctanediamide (3b) and N(1)-(thiazol-2-yl)-N(8)-hydroxyoctanediamide (6) were synthesized and evaluated for HDAC inhibition and cytotoxic activities. All three compounds showed very potent HDAC inhibitory effects. Docking revealed that both two compounds 3a, 3b showed higher affinities towards HDAC(8) compared to SAHA. In vitro, compound 3a exhibited cytotoxicity equipotent to SAHA against five human cancer cell lines. In term of in vivo activity, compound 3a demonstrated equivalent efficacy to SAHA in mouse xenograft model.

  4. Prostate Cancer-Specific and Potent Antitumor Effect of a DD3-Controlled Oncolytic Virus Harboring the PTEN Gene

    PubMed Central

    Ding, Miao; Cao, Xin; Xu, Hai-neng; Fan, Jun-kai; Huang, Hong-ling; Yang, Dong-qin; Li, Yu-hua; Wang, Jian; Li, Runsheng; Liu, Xin-Yuan

    2012-01-01

    Prostate cancer is a major health problem for men in Western societies. Here we report a Prostate Cancer-Specific Targeting Gene-Viro-Therapy (CTGVT-PCa), in which PTEN was inserted into a DD3-controlled oncolytic viral vector (OV) to form Ad.DD3.E1A.E1B(Δ55)-(PTEN) or, briefly, Ad.DD3.D55-PTEN. The woodchuck post-transcriptional element (WPRE) was also introduced at the downstream of the E1A coding sequence, resulting in much higher expression of the E1A gene. DD3 is one of the most prostate cancer-specific genes and has been used as a clinical bio-diagnostic marker. PTEN is frequently inactivated in primary prostate cancers, which is crucial for prostate cancer progression. Therefore, the Ad.DD3.D55-PTEN has prostate cancer specific and potent antitumor effect. The tumor growth rate was almost completely inhibited with the final tumor volume after Ad.DD3.D55-PTEN treatment less than the initial volume at the beginning of Ad.DD3.D55-PTEN treatment, which shows the powerful antitumor effect of Ad.DD3.D55-PTEN on prostate cancer tumor growth. The CTGVT-PCa construct reported here killed all of the prostate cancer cell lines tested, such as DU145, 22RV1 and CL1, but had a reduced or no killing effect on all the non-prostate cancer cell lines tested. The mechanism of action of Ad.DD3.D55-PTEN was due to the induction of apoptosis, as detected by TUNEL assays and flow cytometry. The apoptosis was mediated by mitochondria-dependent and -independent pathways, as determined by caspase assays and mitochondrial membrane potential. PMID:22509396

  5. COH-203, a novel microtubule inhibitor, exhibits potent anti-tumor activity via p53-dependent senescence in hepatocellular carcinoma

    SciTech Connect

    Qi, Huan; Zuo, Dai-Ying; Bai, Zhao-Shi; Xu, Jing-Wen; Li, Zeng-Qiang; Shen, Qi-Rong; Wang, Zhi-Wei; Zhang, Wei-Ge; Wu, Ying-Liang

    2014-12-12

    Highlights: • COH-203 exhibits anti-hepatoma effects in vitro and in vivo with low toxicity. • COH-203 inhibits tubulin polymerization. • COH-203 induces mitotic arrest followed by mitotic slippage in BEL-7402 cells. • COH-203 induces p53-dependent senescence in BEL-7402 cells. - Abstract: 5-(3-Hydroxy-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-3H-1, 2-dithiol-3-one (COH-203) is a novel synthesized analogue of combretastatin A-4 that can be classified as a microtubule inhibitor. In this study, we evaluated the anti-hepatoma effect of COH-203 in vitro and in vivo and explored the underlying molecular mechanisms. COH-203 was shown to be more effective in inhibiting the proliferation of liver cancer cells compared with normal liver cells. COH-203 also displayed potent anti-tumor activity in a hepatocellular carcinoma xenograft model without significant toxicity. Mechanistic studies demonstrated that treatment with COH-203 induced mitotic arrest by inhibiting tubulin polymerization in BEL-7402 liver cancer cells. Long-term COH-203 treatment in BEL-7402 cells led to mitotic slippage followed by senescence via the p14{sup Arf}–p53–p21 and p16{sup INK4α}–Rb pathways. Furthermore, suppression of p53 via pifithrin-α (p53 inhibitor) and p53-siRNA attenuated COH-203-induced senescence in BEL-7402 cells, suggesting that COH-203 induced senescence p53-dependently. In conclusion, we report for the first time that COH-203, one compound in the combretastatin family, promotes anti-proliferative activity through the induction of p-53 dependent senescence. Our findings will provide a molecular rationale for the development of COH-203 as a promising anti-tumor agent.

  6. Targeting PI3K/mTOR signaling exerts potent antitumor activity in pheochromocytoma in vivo.

    PubMed

    Lee, Misu; Minaskan, Ninelia; Wiedemann, Tobias; Irmler, Martin; Beckers, Johannes; Yousefi, Behrooz H; Kaissis, Georgios; Braren, Rickmer; Laitinen, Iina; Pellegata, Natalia S

    2017-01-01

    Pheochromocytomas (PCCs) are mostly benign tumors, amenable to complete surgical resection. However, 10-17% of cases can become malignant, and once metastasized, there is no curative treatment for this disease. Given the need to identify the effective therapeutic approaches for PCC, we evaluated the antitumor potential of the dual-PI3K/mTOR inhibitor BEZ235 against these tumors. We employed an in vivo model of endogenous PCCs (MENX mutant rats), which closely recapitulate the human tumors. Mutant rats with PCCs were treated with 2 doses of BEZ235 (20 and 30 mg/kg), or with placebo, for 2 weeks. Treatment with BEZ235 induced cytostatic and cytotoxic effects on rat PCCs, which could be appreciated by both staining the tumors ex vivo with appropriate markers and non-invasively by functional imaging (diffusion-weighted magnetic resonance imaging) in vivo Transcriptomic analyses of tumors from rats treated with BEZ235 or placebo-identified potential mediators of therapy response were performed. Slc6a2, encoding the norepinephrine transporter (NET), was downregulated in a dose-dependent manner by BEZ235 in rat PCCs. Moreover, BEZ235 reduced Slc6a2/NET expression in PCC cell lines (MPC) also. Studies of a BEZ235-resistant derivative of the MPC cell line confirmed that the reduction of NET expression associates with the response to the drug. Reduction of NET expression after BEZ235 treatment in vivo could be monitored by positron emission tomography (PET) using a tracer targeting NET. Altogether, here we demonstrate the efficacy of BEZ235 against PCC in vivo, and show that functional imaging can be employed to monitor the response of PCC to PI3K/mTOR inhibition therapy.

  7. A novel agent exerts antitumor activity in breast cancer cells by targeting mitochondrial complex II

    PubMed Central

    Cui, Guozhen; Chan, Judy Yuet-Wa; Wang, Li; Li, Chuwen; Shan, Luchen; Xu, Changjiang; Zhang, Qingwen; Wang, Yuqiang; Di, Lijun; Lee, Simon Ming-Yuen

    2016-01-01

    The mitochondrial respiratory chain, including mitochondrial complex II, has emerged as a potential target for cancer therapy. In the present study, a novel conjugate of danshensu (DSS) and tetramethylpyrazine (TMP), DT-010, was synthesized. Our results showed that DT-010 is more potent than its parental compounds separately or in combination, in inhibiting the proliferation of MCF-7 and MDA-MB-231 cells by inducing cytotoxicity and promoting cell cycle arrest. It also inhibited the growth of 4T1 breast cancer cells in vivo. DT-010 suppressed the fundamental parameters of mitochondrial function in MCF-7 cells, including basal respiration, ATP turnover, maximal respiration. Treatment with DT-010 in MCF-7 and MDA-MB-231 cells resulted in the loss of mitochondrial membrane potential and decreased ATP production. DT-010 also promoted ROS generation, while treatment with ROS scavenger, NAC (N-acetyl-L-cysteine), reversed DT-010-induced cytotoxicity. Further study showed that DT-010 suppressed succinate-induced mitochondrial respiration and impaired mitochondrial complex II enzyme activity indicating that DT-010 may inhibit mitochondrial complex II. Overall, our results suggested that the antitumor activity of DT-010 is associated with inhibition of mitochondrial complex II, which triggers ROS generation and mitochondrial dysfunction in breast cancer cells. PMID:27081033

  8. An NQO1 Substrate with Potent Antitumor Activity That Selectively Kills by PARP1-Induced Programmed Necrosis

    PubMed Central

    Huang, Xiumei; Dong, Ying; Bey, Erik A.; Kilgore, Jessica A.; Bair, Joseph S.; Li, Long-Shan; Patel, Malina; Parkinson, Elizabeth I.; Wang, Yiguang; Williams, Noelle S.; Gao, Jinming; Hergenrother, Paul J.; Boothman, David A.

    2016-01-01

    Agents, such as β-lapachone, that target the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce programmed necrosis in solid tumors have shown great promise, but more potent tumor-selective compounds are needed. Here, we report that deoxynyboquinone kills a wide spectrum of cancer cells in an NQO1-dependent manner with greater potency than β-lapachone. Deoxynyboquinone lethality relies on NQO1-dependent futile redox cycling that consumes oxygen and generates extensive reactive oxygen species (ROS). Elevated ROS levels cause extensive DNA lesions, PARP1 hyperactivation, and severe NAD+/ATP depletion that stimulate Ca2+–dependent programmed necrosis, unique to this new class of NQO1 "bioactivated" drugs. Short-term exposure of NQO1+ cells to deoxynyboquinone was sufficient to trigger cell death, although genetically matched NQO1− cells were unaffected. Moreover, siRNA-mediated NQO1 or PARP1 knockdown spared NQO1+ cells from short-term lethality. Pretreatment of cells with BAPTA-AM (a cytosolic Ca2+ chelator) or catalase (enzymatic H2O2 scavenger) was sufficient to rescue deoxynyboquinone-induced lethality, as noted with β-lapachone. Investigations in vivo showed equivalent antitumor efficacy of deoxynyboquinone to β-lapachone, but at a 6-fold greater potency. PARP1 hyperactivation and dramatic ATP loss were noted in the tumor, but not in the associated normal lung tissue. Our findings offer preclinical proof-of-concept for deoxynyboquinone as a potent chemotherapeutic agent for treatment of a wide spectrum of therapeutically challenging solid tumors, such as pancreatic and lung cancers. PMID:22532167

  9. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma.

    PubMed

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-02-02

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma.

  10. Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma

    PubMed Central

    Zhu, Yongxia; Ye, Tinghong; Yu, Xi; Lei, Qian; Yang, Fangfang; Xia, Yong; Song, Xuejiao; Liu, Li; Deng, Hongxia; Gao, Tiantao; Peng, Cuiting; Zuo, Weiqiong; Xiong, Ying; Zhang, Lidan; Wang, Ningyu; Zhao, Lifeng; Xie, Yongmei; Yu, Luoting; Wei, Yuquan

    2016-01-01

    Melanoma is a highly malignant neoplasm of melanocytes with considerable metastatic potential and drug resistance, explaining the need for new candidates that inhibit tumor growth and metastasis. The signal transducer and activator of the transcription 3 (Stat3) signaling pathway plays an important role in melanoma and has been validated as promising anticancer target for melanoma therapy. In this study, nifuroxazide, an antidiarrheal agent identified as an inhibitor of Stat3, was evaluated for its anti-melanoma activity in vitro and in vivo. It had potent anti-proliferative activity against various melanoma cell lines and could induce G2/M phase arrest and cell apoptosis. Moreover, nifuroxazide markedly impaired melanoma cell migration and invasion by down-regulating phosphorylated-Src, phosphorylated-FAK, and expression of matrix metalloproteinase (MMP) -2, MMP-9 and vimentin. It also significantly inhibited tumor growth without obvious side effects in the A375-bearing mice model by inducing apoptosis and reducing cell proliferation and metastasis. Notably, nifuroxazide significantly inhibited pulmonary metastases, which might be associated with the decrease of myeloid-derived suppressor cells (MDSCs). These findings suggested that nifuroxazide might be a potential agent for inhibiting the growth and metastasis of melanoma. PMID:26830149

  11. Potent anti-tumor effects of EGFR-targeted hybrid peptide on mice bearing liver metastases.

    PubMed

    Gaowa, Arong; Horibe, Tomohisa; Kohno, Masayuki; Harada, Hiroshi; Hiraoka, Masahiro; Kawakami, Koji

    2016-01-01

    In this study, we investigated the therapeutic efficacy of EGFR2R-lytic hybrid peptide for the treatment of liver metastasis from colon carcinoma. The cytotoxic activity of the hybrid peptide against luciferase-expressing human colon cancer (HCT-116-luc) cells was determined by the WST-8 assay. The experimental mouse model of liver metastases was generated by splenic injection of HCT-116-luc cells. The hybrid peptide was intravenously injected into mice the day after cell implantation at a dose of 5 mg/kg and this was repeated on alternate days for a total of 7 doses. Saline-treated mice were used as controls. Tumor growth and therapeutic responses were monitored by an IVIS imaging system. It was shown that the hybrid peptide exhibited potent cytotoxic activity against HCT-116-luc cells and the liver metastases were significantly reduced after intravenous injections of hybrid peptide compared with controls. Furthermore, Kaplan–Meier analysis showed that hybrid peptide-treated mice had significantly longer survival than controls. In addition, bright-field and ex vivo imaging of liver tissue revealed that mice treated with the hybrid peptide had significantly fewer tumors compared with controls. These results demonstrated that the EGFR2R-lytic hybrid peptide is a potential treatment option for patients with colorectal cancer metastases in the liver.

  12. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells

    PubMed Central

    2013-01-01

    Background Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. Methods MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs’ antitumor activity. Immunohistochemical analyses were carried out to study the Abs’ inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. Results MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of

  13. Enantioselective synthesis of pactamycin, a complex antitumor antibiotic.

    PubMed

    Malinowski, Justin T; Sharpe, Robert J; Johnson, Jeffrey S

    2013-04-12

    Medicinal application of many complex natural products is precluded by the impracticality of their chemical synthesis. Pactamycin, the most structurally intricate aminocyclopentitol antibiotic, displays potent antiproliferative properties across multiple phylogenetic domains, but it is highly cytotoxic. A limited number of analogs produced by genetic engineering technologies show reduced cytotoxicity against mammalian cells, renewing promise for therapeutic applications. For decades, an efficient synthesis of pactamycin amenable to analog derivatizations has eluded researchers. Here, we present a short asymmetric total synthesis of pactamycin. An enantioselective Mannich reaction and symmetry-breaking reduction sequence was designed to enable assembly of the entire carbon core skeleton in under five steps and control critical three-dimensional (stereochemical) functional group relationships. This modular route totals 15 steps and is immediately amenable for structural analog synthesis.

  14. Design and synthesis of a tetrahydroisoquinoline-based hydroxamate derivative (ZYJ-34v), an oral active histone deacetylase inhibitor with potent antitumor activity.

    PubMed

    Zhang, Yingjie; Liu, Chunxi; Chou, C James; Wang, Xuejian; Jia, Yuping; Xu, Wenfang

    2013-08-01

    In our previous study, we developed a novel series of tetrahydroisoquinoline-based hydroxamic acid derivatives as histone deacetylase inhibitors (Bioorg Med Chem, 2010, 18, 1761-1772; J Med Chem, 2011, 54, 2823-2838), among which, compound ZYJ-34c (1) was identified and validated as the most potent one with marked in vitro and in vivo antitumor potency (J Med Chem, 2011, 54, 5532-5539.). Herein, further modification in 1 afforded another oral active analog ZYJ-34v (2) with simplified structure and lower molecular weight. Biological evaluation of compound 2 showed efficacious inhibition against histone deacetylase 1, 2, 3, and 6, which was confirmed by Western blot analysis results. Most importantly, compound 2 exhibited similar even more potent in vitro and in vivo antitumor activities relative to the approved histone deacetylase inhibitor SAHA.

  15. The novel oral Hsp90 inhibitor NVP-HSP990 exhibits potent and broad-spectrum antitumor activities in vitro and in vivo.

    PubMed

    Menezes, Daniel L; Taverna, Pietro; Jensen, Michael R; Abrams, Tinya; Stuart, Darrin; Yu, Guoying Karen; Duhl, David; Machajewski, Timothy; Sellers, William R; Pryer, Nancy K; Gao, Zhenhai

    2012-03-01

    A novel oral Hsp90 inhibitor, NVP-HSP990, has been developed and characterized in vitro and in vivo. In vitro, NVP-HSP990 exhibits single digit nanomolar IC(50) values on three of the Hsp90 isoforms (Hsp90α, Hsp90β, and GRP94) and 320 nanomolar IC(50) value on the fourth (TRAP-1), with selectivity against unrelated enzymes, receptors, and kinases. In c-Met amplified GTL-16 gastric tumor cells, NVP-HSP990 dissociated the Hsp90-p23 complex, depleted client protein c-Met, and induced Hsp70. NVP-HSP990 potently inhibited the growth of human cell lines and primary patient samples from a variety of tumor types. In vivo, NVP-HSP990 exhibits drug-like pharmaceutical and pharmacologic properties with high oral bioavailability. In the GTL-16 xenograft model, a single oral administration of 15 mg/kg of NVP-HSP990 induced sustained downregulation of c-Met and upregulation of Hsp70. In repeat dosing studies, NVP-HSP990 treatment resulted in tumor growth inhibition of GTL-16 and other human tumor xenograft models driven by well-defined oncogenic Hsp90 client proteins. On the basis of its pharmacologic profile and broad-spectrum antitumor activities, clinical trials have been initiated to evaluate NVP-HSP990 in advanced solid tumors.

  16. Murine Dendritic Cells Pulsed with Whole Tumor Lysates Mediate Potent Antitumor Immune Responses in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Fields, R. C.; Shimizu, K.; Mule, J. J.

    1998-08-01

    The highly efficient nature of dendritic cells (DC) as antigen-presenting cells raises the possibility of uncovering in tumor-bearing hosts very low levels of T cell reactivity to poorly immunogenic tumors that are virtually undetectable by other means. Here, we demonstrate the in vitro and in vivo capacities of murine bone marrow-derived, cytokine-driven DC to elicit potent and specific anti-tumor responses when pulsed with whole tumor lysates. Stimulation of naive spleen-derived T cells by tumor lysate-pulsed DC generated tumor-specific proliferative cytokine release and cytolytic reactivities in vitro. In addition, in two separate strains of mice with histologically distinct tumors, s.c. injections of DC pulsed with whole tumor lysates effectively primed these animals to reject subsequent lethal challenges with viable parental tumor cells and, important to note, also mediated significant reductions in the number of metastases established in the lungs. Tumor rejection depended on host-derived CD8+ T cells and, to a lesser extent, CD4+ T cells. Spleens from mice that had rejected their tumors contained specific precursor cytotoxic T lymphocytes. The use of whole tumor lysates as a source of tumor-associated antigen(s) for pulsing of DC circumvents several limitations encountered with other methods as well as provides certain distinct advantages, which are discussed. These data serve as rationale for our recent initiation of a phase I clinical trial of immunization with autologous tumor lysate-pulsed DC in adult and pediatric cancer patients.

  17. Aspartate aminotransferase is potently inhibited by copper complexes: Exploring copper complex-binding proteome.

    PubMed

    Jia, Yuqi; Lu, Liping; Yuan, Caixia; Feng, Sisi; Zhu, Miaoli

    2017-05-01

    Recent researches indicated that a copper complex-binding proteome that potently interacted with copper complexes and then influenced cellular metabolism might exist in organism. In order to explore the copper complex-binding proteome, a copper chelating ion-immobilized affinity chromatography (Cu-IMAC) column and mass spectrometry were used to separate and identify putative Cu-binding proteins in primary rat hepatocytes. A total of 97 putative Cu-binding proteins were isolated and identified. Five higher abundance proteins, aspartate aminotransferase (AST), malate dehydrogenase (MDH), catalase (CAT), calreticulin (CRT) and albumin (Alb) were further purified using a SP-, and (or) Q-Sepharose Fast Flow column. The interaction between the purified proteins and selected 11 copper complexes and CuCl2 was investigated. The enzymes inhibition tests demonstrated that AST was potently inhibited by copper complexes while MDH and CAT were weakly inhibited. Schiff-based copper complexes 6 and 7 potently inhibited AST with the IC50 value of 3.6 and 7.2μM, respectively and exhibited better selectivity over MDH and CAT. Fluorescence titration results showed the two complexes tightly bound to AST with binding constant of 3.89×10(6) and 3.73×10(6)M(-1), respectively and a stoichiometry ratio of 1:1. Copper complex 6 was able to enter into HepG2 cells and further inhibit intracellular AST activity. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. KRN951, a highly potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, has antitumor activities and affects functional vascular properties.

    PubMed

    Nakamura, Kazuhide; Taguchi, Eri; Miura, Toru; Yamamoto, Atsushi; Takahashi, Kazumi; Bichat, Francis; Guilbaud, Nicolas; Hasegawa, Kazumasa; Kubo, Kazuo; Fujiwara, Yasunari; Suzuki, Rika; Kubo, Kinya; Shibuya, Masabumi; Isae, Toshiyuki

    2006-09-15

    Vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis by stimulating the proangiogenic signaling of endothelial cells via activation of VEGF receptor (VEGFR) tyrosine kinases. Therefore, VEGFRs are an attractive therapeutic target for cancer treatment. In the present study, we show that a quinoline-urea derivative, KRN951, is a novel tyrosine kinase inhibitor for VEGFRs with antitumor angiogenesis and antigrowth activities. KRN951 potently inhibited VEGF-induced VEGFR-2 phosphorylation in endothelial cells at in vitro subnanomolar IC50 values (IC50 = 0.16 nmol/L). It also inhibited ligand-induced phosphorylation of platelet-derived growth factor receptor-beta (PDGFR-beta) and c-Kit (IC50 = 1.72 and 1.63 nmol/L, respectively). KRN951 blocked VEGF-dependent, but not VEGF-independent, activation of mitogen-activated protein kinases and proliferation of endothelial cells. In addition, it inhibited VEGF-mediated migration of human umbilical vein endothelial cells. Following p.o. administration to athymic rats, KRN951 decreased the microvessel density within tumor xenografts and attenuated VEGFR-2 phosphorylation levels in tumor endothelium. It also displayed antitumor activity against a wide variety of human tumor xenografts, including lung, breast, colon, ovarian, pancreas, and prostate cancer. Furthermore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) analysis revealed that a significant reduction in tumor vascular hyperpermeability was closely associated with the antitumor activity of KRN951. These findings suggest that KRN951 is a highly potent, p.o. active antiangiogenesis and antitumor agent and that DCE-MRI would be useful in detecting early responses to KRN951 in a clinical setting. KRN951 is currently in phase I clinical development for the treatment of patients with advanced cancer.

  19. Original Multivalent Gold (III) and Dual Gold(III)-Copper(II) Conjugated Phosphorus Dendrimers as Potent Antitumoral and Antimicrobial Agents.

    PubMed

    Mignani, Serge M; El Brahmi, Nabil; El Kazzouli, Saïd; Laurent, Regis; Ladeira, Sonia; Caminade, Anne-Marie; Pedziwiatr-Werbicka, Elzbieta; Szewcyk, Eligia M; Bryszewska, Maria; Bousmina, Mosto M; Cresteil, Thierry; Majoral, Jean Pierre

    2017-09-29

    Original metallo phosphorus dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus dendrimers bearing imino-pyridino end groups with Au(III) or both with Au(III) and Cu(II) The complexation of the dendrimer with Au(III), leading to 1G3-[Au48] [AuCl4]48, strongly increased the anti-proliferative activities against both KB and HL-60 tumoral cell lines, showing IC50's in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of dendrimers, all the dendrimers prepared displayed similar potency (nanomolar range) to 1G3-[Au48] [AuCl4]48 against KB and HL60. In marked contrast synergistic effect on the antimicrobial activity of some of these phosphorus dendrimers are observed when both Au (III) and Cu(II) are present on the dendritic structure.

  20. Copper(II) complexes with saccharinate and glutamate as antitumor agents. Cyto- and genotoxicity in human osteosarcoma cells.

    PubMed

    Cadavid-Vargas, J F; León, I E; Etcheverry, S B; Santi, E; Torre, M H; Di Virgilio, A L

    2016-05-13

    We report herein the antitumor actions of three copper(II) complexes on MG-63 human osteosarcoma cells. The three complexes: Cu-sac, Cu-gln and Cu-sac-gln (sac= saccharinate, gln= glutamine) caused a decline in cell viability. The half-maximal inhibitory concentration in MG-63 cells for Cu-sac-gln is 170 µM, showing the strongest antiproliferative effect. Moreover, only Cu-sac-gln caused a decrease of the mitochondrial activity from 100 μM. Our results indicate that the copper(II) complexes studied here produce DNA damage and suggest that the rise of reactive oxygen species (ROS) is the central mechanism action. Genotoxicity studied by the Cytokinesis-block micronucleus (MN) assay and the Single cell gel electrophoresis (comet assay) could be observed in MG-63 cells treated with Cu-sac-gln from 100 and 50 μM, respectively. Cu-sac and Cu-gln also induced DNA damage; however their effect was definitively weaker. The generation of reactive oxygen species increased from 50 μM of Cu-sac-gln and Cu-sac and only from 250 μM of Cu-gln, as well as a reduction of the GSH/GSSG ratio from 50 μM. When cells were treated with several concentrations of the complexes in addition to a combination of 50 μM of vitamin C plus 50 μM of vitamin E, a total recovery in cell survival was obtained for Cu-gln in the whole range of tested concentrations while only a partial viability recovery was obtained from 250 μM of Cu-sac and Cu-sac-gln. Overall, our results point to a differential cyto- and genotoxicity of the three copper(II) complexes and demonstrate that the complexation with both ligands confers the most potent antitumor action in human osteosarcoma cells.

  1. Direct tumor recognition by a human CD4+ T-cell subset potently mediates tumor growth inhibition and orchestrates anti-tumor immune responses

    PubMed Central

    Matsuzaki, Junko; Tsuji, Takemasa; Luescher, Immanuel F.; Shiku, Hiroshi; Mineno, Junichi; Okamoto, Sachiko; Old, Lloyd J.; Shrikant, Protul; Gnjatic, Sacha; Odunsi, Kunle

    2015-01-01

    Tumor antigen-specific CD4+ T cells generally orchestrate and regulate immune cells to provide immune surveillance against malignancy. However, activation of antigen-specific CD4+ T cells is restricted at local tumor sites where antigen-presenting cells (APCs) are frequently dysfunctional, which can cause rapid exhaustion of anti-tumor immune responses. Herein, we characterize anti-tumor effects of a unique human CD4+ helper T-cell subset that directly recognizes the cytoplasmic tumor antigen, NY-ESO-1, presented by MHC class II on cancer cells. Upon direct recognition of cancer cells, tumor-recognizing CD4+ T cells (TR-CD4) potently induced IFN-γ-dependent growth arrest in cancer cells. In addition, direct recognition of cancer cells triggers TR-CD4 to provide help to NY-ESO-1-specific CD8+ T cells by enhancing cytotoxic activity, and improving viability and proliferation in the absence of APCs. Notably, the TR-CD4 either alone or in collaboration with CD8+ T cells significantly inhibited tumor growth in vivo in a xenograft model. Finally, retroviral gene-engineering with T cell receptor (TCR) derived from TR-CD4 produced large numbers of functional TR-CD4. These observations provide mechanistic insights into the role of TR-CD4 in tumor immunity, and suggest that approaches to utilize TR-CD4 will augment anti-tumor immune responses for durable therapeutic efficacy in cancer patients. PMID:26447332

  2. Vaccination with Irradiated Tumor Cells Engineered to Secrete Murine Granulocyte-Macrophage Colony-Stimulating Factor Stimulates Potent, Specific, and Long-Lasting Anti-Tumor Immunity

    NASA Astrophysics Data System (ADS)

    Dranoff, Glenn; Jaffee, Elizabeth; Lazenby, Audrey; Golumbek, Paul; Levitsky, Hyam; Brose, Katja; Jackson, Valerie; Hamada, Hirofumi; Pardoll, Drew; Mulligan, Richard C.

    1993-04-01

    To compare the ability of different cytokines and other molecules to enhance the immunogenicity of tumor cells, we generated 10 retroviruses encoding potential immunomodulators and studied the vaccination properties of murine tumor cells transduced by the viruses. Using a B16 melanoma model, in which irradiated tumor cells alone do not stimulate significant anti-tumor immunity, we found that irradiated tumor cells expressing murine granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulated potent, long-lasting, and specific anti-tumor immunity, requiring both CD4^+ and CD8^+ cells. Irradiated cells expressing interleukins 4 and 6 also stimulated detectable, but weaker, activity. In contrast to the B16 system, we found that in a number of other tumor models, the levels of anti-tumor immunity reported previously in cytokine gene transfer studies involving live, transduced cells could be achieved through the use of irradiated cells alone. Nevertheless, manipulation of the vaccine or challenge doses made it possible to demonstrate the activity of murine GM-CSF in those systems as well. Overall, our results have important implications for the clinical use of genetically modified tumor cells as therapeutic cancer vaccines.

  3. In Vitro and In Vivo Studies of Non-Platinum-Based Halogenated Compounds as Potent Antitumor Agents for Natural Targeted Chemotherapy of Cancers

    PubMed Central

    Lu, Qing-Bin; Zhang, Qin-Rong; Ou, Ning; Wang, Chun-Rong; Warrington, Jenny

    2015-01-01

    Based on a molecular-mechanism-based anticancer drug discovery program enabled by an innovative femtomedicine approach, we have found a previously unknown class of non-platinum-based halogenated molecules (called FMD compounds) as potent antitumor agents for effective treatment of cancers. Here, we present in vitro and in vivo studies of the compounds for targeted chemotherapy of cervical, breast, ovarian, and lung cancers. Our results show that these FMD agents led to DNA damage, cell cycle arrest in the S phase, and apoptosis in cancer cells. We also observed that such a FMD compound caused an increase of reduced glutathione (GSH, an endogenous antioxidant) levels in human normal cells, while it largely depleted GSH in cancer cells. We correspondingly found that these FMD agents exhibited no or little toxicity toward normal cells/tissues, while causing significant cytotoxicity against cancer cells, as well as suppression and delay in tumor growth in mouse xenograft models of cervical, ovarian, breast and lung cancers. These compounds are therefore a previously undiscovered class of potent antitumor agents that can be translated into clinical trials for natural targeted chemotherapy of multiple cancers. PMID:26351651

  4. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs.

    PubMed

    Lu, Lei; Xu, Xiaobing; Zhang, Bin; Zhang, Rongsheng; Ji, Hongzan; Wang, Xuan

    2014-02-07

    cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models. Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.

  5. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs

    PubMed Central

    2014-01-01

    -γ production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models. Conclusions Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic. PMID:24502656

  6. Synergistic anti-tumor therapy by a comb-like multifunctional antibody nanoarray with exceptionally potent activity

    NASA Astrophysics Data System (ADS)

    Li, Huafei; Sun, Yun; Chen, Di; Zhao, He; Zhao, Mengxin; Zhu, Xiandi; Ke, Changhong; Zhang, Ge; Jiang, Cheng; Zhang, Li; Zhang, Fulei; Wei, Huafeng; Li, Wei

    2015-10-01

    Simultaneously blocking multiple mediators offers new hope for the treatment of complex diseases. However, the curative potential of current combination therapy by chronological administration of separate monoclonal antibodies (mAbs) or multi-specific mAbs is still moderate due to inconvenient manipulation, low cooperative effectors, poor pharmacokinetics and insufficient tumor accumulation. Here, we describe a facile strategy that arms distinct mAbs with cooperative effectors onto a long chain to form a multicomponent comb-like nano mAb. Unlike dissociative parental mAbs, the multifunctional mAb nanoarray (PL-RB) constructed from type I/II anti-CD20 mAbs shows good pharmacokinetics. This PL-RB simultaneously targets distinct epitopes on a single antigen (Ag) and neighboring Ags on different lymphocytes. This unique intra- and intercellular Ag cross-linking endows the multifunctional mAb nanoarray with potent apoptosis activity. The exceptional apoptosis, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) that are synchronously evoked by the nano PL-RB are further synergistically promoted via enhanced permeability and retention (EPR), which resulted in high intratumor accumulation and excellent anti-lymphoma efficiency.

  7. DNA binding, antitumor activities, and hydroxyl radical scavenging properties of novel oxovanadium (IV) complexes with substituted isoniazid.

    PubMed

    Liao, Xiangwen; Lu, Jiazheng; Ying, Peng; Zhao, Ping; Bai, Yinliang; Li, Wengjie; Liu, Mingpei

    2013-12-01

    Four novel oxovanadium(IV) complexes—[VO(PAHN)(phen)] (1; PAHN is 4-pyridinecarboxylic acid, 2-[(2-hydroxy)-1-naphthalenylene] hydrazide, phen is 1,10-phenanthroline), [VO(PAHN)(bpy)] (2; bpy is 2,2′-bipyridine), [VO(PAH)(phen)] (3; PAH is 4-pyridinecarboxylic acid, 2-[(2-hydroxy)-1-phenyl]methylene hydrazide), and [VO(PAH)(bpy)] (4)—have been synthesized and characterized by elemental analysis, UV–vis spectroscopy, electrospray ionization mass spectrometry, IR spectroscopy, 1H-NMR spectroscopy, and 13C-NMR spectroscopy. Their interactions with calf thymus DNA were investigated. The results suggest that these complexes bind to DNA in an intercalative mode. All four complexes exhibited highly cytotoxic activity against tumor cells (SH-SY5Y, MCF-7, and SK-N-SH), with 50 % inhibitory concentrations of the same order of magnitude as for cisplatin or of lower order of magnitude. Complex 1 exhibited the highest interaction ability and was found to be the most potent antitumor agent among the four complexes. It can cause G2/M phase arrest of the cell cycle, induces significant apoptosis in SK-N-SH cells, and displays typical morphological apoptotic characteristics. In addition, their hydroxyl radical scavenging properties have been tested, and complex 1 was the best inhibitor.

  8. EBI-907, a novel BRAFV600E inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile

    PubMed Central

    Zhang, Jiayin; Lu, Biao; Liu, Dong; Shen, Ru; Yan, Yinfa; Yang, Liuqing; Zhang, Minsheng; Zhang, Lei; Cao, Guoqing; Cao, Hu; Fu, Beibei; Gong, Aishen; Sun, Qiming; Wan, Hong; Zhang, Lianshan; Tao, Weikang; Cao, Jingsong

    2016-01-01

    abstract The oncogenic mutation of BRAFV600E has been found in approximately 8% of all human cancers, including more than 60% of melanoma and 10% of colorectal cancers. The clinical proof of concept in treating BRAFV600E-driving melanoma patients with the BRAF inhibitors has been well established. We have sought to identify and develop novel BRAFV600E inhibitors with more favorable profiles. Our chemistry effort has led to the discovery of EBI-907 as a novel BRAFV600E inhibitor with potent anti-tumor activity in vitro and in vivo. In a LanthaScreen BRAFV600E kinase assay, EBI-907 showed an IC50 of 4.8 nM, which is >10 -fold more potent than Vemurafenib (IC50 = 58.5 nM). In addition, EBI-907 showed a broader kinase selectivity profile, with potent activity against a number of important oncogenic kinases including FGFR1-3, RET, c-Kit, and PDGFRb. Concomitant with such properties, EBI-907 exhibits potent and selective cytotoxicity against a broader range of BRAFV600E-dependent cell lines including certain colorectal cancer cell lines with innate resistance to Vemurafenib. In BRAFV600E-dependent human Colo-205 and A375 tumor xenograft mouse models, EBI-907 caused a marked tumor regression in a dose-dependent manner, with superior efficacy to Vemurafenib. Our results also showed that combination with EGFR or MEK inhibitor enhanced the potency of EBI-907 in cell lines with innate or acquired resistance to BRAF inhibition alone. Our findings present EBI-907 as a potent and promising BRAF inhibitor, which might be useful in broader indications. PMID:26810733

  9. Synthesis, cytotoxicity and antitumor activity of platinum(II) complexes of cyclopentanecarboxylic acid hydrazide.

    PubMed

    Kushev, D; Gorneva, G; Taxirov, S; Spassovska, N; Grancharov, K

    1999-11-01

    New platinum(II) complexes of cyclopentanecarboxylic acid hydrazide (cpcah) were prepared, characterized by elemental analysis, IR and 1H NMR spectra, and evaluated for in vitro cytotoxicity in Friend leukemia (FL) and A2780 ovarian tumor cells, induction of apoptosis in FL cells, as well as for in vivo antitumor activity toward murine L1210 leukemia and Lewis lung carcinoma. The spectral analyses indicated a cis-square planar structure of the complexes with hydrazide ligand coordinated via the NH2 group. The compounds exerted significantly lower in vitro and in vivo toxicities as compared with those of cisplatin (cis-diamminedichloroplatinum(II), DDP). On the other hand, the complex [Pt(NH3)(cpcah)Cl2] exhibited antitumor activity against L1210 leukemia in mice comparable to that of cisplatin, resulting at a dose of 42 mg/kg (administered 3 times) in a T/C (mean survival time) of 280%. This compound displayed an in vitro macromolecular synthesis inhibition pattern similar to that of DDP. At concentrations close to the cytostatic ones (10-20 microM) this complex, as well as DDP, was able to induce apoptosis in FL cells as shown by neutral comet assay and morphological analysis. We concluded that there is a correlation between the ability of platinum complexes to induce apoptosis and their antitumor activity.

  10. Vaccination with Irradiated Autologous Melanoma Cells Engineered to Secrete Human Granulocyte--Macrophage Colony-Stimulating Factor Generates Potent Antitumor Immunity in Patients with Metastatic Melanoma

    NASA Astrophysics Data System (ADS)

    Soiffer, Robert; Lynch, Thomas; Mihm, Martin; Jung, Ken; Rhuda, Catherine; Schmollinger, Jan C.; Hodi, F. Stephen; Liebster, Laura; Lam, Prudence; Mentzer, Steven; Singer, Samuel; Tanabe, Kenneth K.; Benedict Cosimi, A.; Duda, Rosemary; Sober, Arthur; Bhan, Atul; Daley, John; Neuberg, Donna; Parry, Gordon; Rokovich, Joseph; Richards, Laurie; Drayer, Jan; Berns, Anton; Clift, Shirley; Cohen, Lawrence K.; Mulligan, Richard C.; Dranoff, Glenn

    1998-10-01

    We conducted a Phase I clinical trial investigating the biologic activity of vaccination with irradiated autologous melanoma cells engineered to secrete human granulocyte--macrophage colony-stimulating factor in patients with metastatic melanoma. Immunization sites were intensely infiltrated with T lymphocytes, dendritic cells, macrophages, and eosinophils in all 21 evaluable patients. Although metastatic lesions resected before vaccination were minimally infiltrated with cells of the immune system in all patients, metastatic lesions resected after vaccination were densely infiltrated with T lymphocytes and plasma cells and showed extensive tumor destruction (at least 80%), fibrosis, and edema in 11 of 16 patients examined. Antimelanoma cytotoxic T cell and antibody responses were associated with tumor destruction. These results demonstrate that vaccination with irradiated autologous melanoma cells engineered to secrete granulocyte--macrophage colony-stimulating factor stimulates potent antitumor immunity in humans with metastatic melanoma.

  11. Isopentenyl pyrophosphate activated CD56+ γδ T lymphocytes display potent anti-tumor activity towards human squamous cell carcinoma

    PubMed Central

    Alexander, Alan A.Z.; Maniar, Amudhan; Cummings, Jean-Saville; Hebbeler, Andrew M.; Schulze, Dan H.; Gastman, Brian R.; Pauza, C. David; Strome, Scott E.; Chapoval, Andrei I.

    2008-01-01

    Purpose The expression of CD56, a natural killer (NK) cell-associated molecule, on αβ T lymphocytes correlates with their increased anti-tumor effector function. CD56 is also expressed on a subset of γδ T cells. However, anti-tumor effector functions of CD56+ γδ T cells are poorly characterized. Experimental design To investigate the potential effector role of CD56+ γδ T cells in tumor killing, we employed isopentenyl pyrophosphate (IPP) and IL-2 expanded γδ T cells from PBMC of healthy donors. Results Thirty to 70% of IPP+IL-2 expanded γδ T cells express CD56 on their surface. Interestingly, while both CD56+ and CD56− γδ T cells express comparable levels of receptors involved in the regulation of γδ T cell cytotoxicity (e.g. NKG2D and CD94) only CD56+ γδ T lymphocytes are capable of killing squamous cell carcinoma (SCC) and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules, since CD56+ γδ T lymphocytes expressed higher levels of CD107a compared to CD56− controls, following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanomycin A and a combination of anti-γδTCR + anti-NKG2D mAb, suggesting that the lytic activity of CD56+ γδ T cells involves the perforin-granzyme pathway and is mainly γδTCR/NKGD2 dependent. Importantly, CD56 expressing γδ T lymphocytes are resistant to Fas ligand and chemically induced apoptosis. Conclusions Our data indicate that CD56+ γδ T cells are potent anti-tumor effectors capable of killing SCC and may play an important therapeutic role in patients with head and neck cancer and other malignancies. PMID:18594005

  12. SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer prodrug that cross-links DNA and exerts highly potent antitumor activity.

    PubMed

    Hartley, John A; Hamaguchi, Anzu; Coffils, Marissa; Martin, Christopher R H; Suggitt, Marie; Chen, Zhizhi; Gregson, Stephen J; Masterson, Luke A; Tiberghien, Arnaud C; Hartley, Janet M; Pepper, Christopher; Lin, Thet Thet; Fegan, Christopher; Thurston, David E; Howard, Philip W

    2010-09-01

    The pyrrolobenzodiazepines (PBD) are naturally occurring antitumor antibiotics, and a PBD dimer (SJG-136, SG2000) is in phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble prodrug of SG2202 in which two bisulfite groups inactivate the PBD N10-C11 imines. Once the bisulfites are eliminated, the imine moieties can bind covalently in the DNA minor groove, forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumor cell lines is GI(50) 20 pmol/L. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was primarily dependent on ERCC1 and homologous recombination repair. In primary B-cell chronic lymphocytic leukemia samples, the mean LD(50) was significantly lower than in normal age-matched B and T lymphocytes. Antitumor activity was shown in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic, and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced-stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development.

  13. SG2285, a novel C2-aryl-substituted pyrrolobenzodiazepine dimer pro-drug that cross-links DNA and exerts highly potent antitumor activity

    PubMed Central

    Hartley, John A.; Hamaguchi, Anzu; Coffils, Marissa; Martin, Christopher R.H.; Suggitt, Marie; Chen, Zhizhi; Gregson, Stephen J.; Masterson, Luke A.; Tiberghien, Arnaud C.; Hartley, Janet M.; Pepper, Christopher; Lin, Thet Thet; Fegan, Christopher; Thurston, David E.; Howard, Philip W.

    2010-01-01

    The pyrrolobenzodiazepines (PBDs) are naturally occurring antitumor antibiotics and a PBD dimer (SJG-136, SG2000) is in Phase II trials. Many potent PBDs contain a C2-endo-exo unsaturated motif associated with the pyrrolo C-ring. The novel compound SG2202 is a PBD dimer containing this motif. SG2285 is a water-soluble pro-drug of SG2202 in which two bisulphite groups inactivate the PBD N10-C11 imines. Once the bisulphites are eliminated, the imine moieties can bind covalently in the DNA minor groove forming an interstrand cross-link. The mean in vitro cytotoxic potency of SG2285 against human tumour cell lines is GI50 20 pM. SG2285 is highly efficient at producing DNA interstrand cross-links in cells, but they form more slowly than those produced by SG2202. Cellular sensitivity to SG2285 was dependent primarily on ERCC1 and homologous recombination repair. In primary B-CLL samples the mean LD50 was significantly lower than in normal age-matched B- and T-lymphocytes. Antitumor activity was demonstrated in several human tumor xenograft models, including ovarian, non-small cell lung, prostate, pancreatic and melanoma, with cures obtained in the latter model with a single dose. Further, in an advanced stage colon model, SG2285 administered either as a single dose, or in two repeat dose schedules, was superior to irinotecan. Our findings define SG2285 as a highly active cytotoxic compound with antitumor properties desirable for further development. PMID:20660714

  14. The discovery of potent antitumor agent C11-deoxypsymberin/irciniastatin A: total synthesis and biology of advanced psymberin analogs.

    PubMed

    Huang, Xianhai; Shao, Ning; Huryk, Robert; Palani, Anandan; Aslanian, Robert; Seidel-Dugan, Cynthia

    2009-02-19

    Structure-activity relationship (SAR) studies by modification of the unsaturated side chain of potent anticancer marine natural product psymberin/irciniastatin A (1) suggest that substitution at C4 and C5 is important for the cytotoxicity of psymberin, but the terminal double bond is not essential for activity. An aryl group is a good replacement for the olefin. The total synthesis of structurally simplified C11-deoxypsymberin (29) was completed, and its activity is consistently more potent than the natural product which provides a unique opportunity for further SAR studies in the psymberin and pederin family. Preliminary mechanism studies suggest the mode of action of psymberin is through cell apoptosis.

  15. Therapeutic vaccination based on side population cells transduced by the granulocyte-macrophage colony-stimulating factor gene elicits potent antitumor immunity.

    PubMed

    Sakamoto, C; Kohara, H; Inoue, H; Narusawa, M; Ogawa, Y; Hirose-Yotsuya, L; Miyamoto, S; Matsumura, Y; Yamada, K; Takahashi, A; Tani, K

    2017-04-01

    Among cancer immunotherapies, granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor cell vaccine (GVAX) therapies appear promising and have been shown to be safe and effective in multiple clinical trials. However, the antitumor efficacies of GVAX therapy alone are in some cases limited. Here we showed that GVAX therapy targeting cancer stem cells (CSCs) substantially suppressed tumor development in syngeneic immunocompetent mice recapitulating normal immune systems. CSCs were isolated as side population (SP) cells from 4T1 murine breast carcinoma cell line and transduced with GM-CSF gene delivered by non-transmissible Sendai virus (4T1-SP/GM). Impaired tumorigenicity of subcutaneously injected 4T1-SP/GM depended on CD8(+) T cells in concert with CD4(+) T cells and natural killer cells. Mice therapeutically vaccinated with irradiated 4T1-SP/GM cells had markedly suppressed tumor development of subcutaneously transplanted 4T1-SP cells compared with those treated with irradiated cells of non-transduced 4T1-SP cells or non-SP (4T1-NSP/GM) cells. Tumor suppression was accompanied by the robust accumulation of mature dendritic cells at vaccination sites and T-helper type 1-skewed systemic cellular immunity. Our results suggested that CSC cell-based GVAX immunotherapy might be clinically useful for inducing potent tumor-specific antitumor immunity.

  16. Pazopanib, a novel multi-kinase inhibitor, shows potent antitumor activity in colon cancer through PUMA-mediated apoptosis.

    PubMed

    Zhang, Lingling; Wang, Huanan; Li, Wei; Zhong, Juchang; Yu, Rongcheng; Huang, Xinfeng; Wang, Honghui; Tan, Zhikai; Wang, Jiangang; Zhang, Yingjie

    2017-01-10

    Colon cancer is still the third most common cancer which has a high mortality but low five-year survival rate. Novel tyrosine kinase inhibitors (TKI) such as pazopanib become effective antineoplastic agents that show promising clinical activity in a variety of carcinoma, including colon cancer. However, the precise underlying mechanism against tumor is unclear. Here, we demonstrated that pazopanib promoted colon cancer cell apoptosis through inducing PUMA expression. Pazopanib induced p53-independent PUMA activation by inhibiting PI3K/Akt signaling pathway, thereby activating Foxo3a, which subsequently bound to the promoter of PUMA to activate its transcription. After induction, PUMA activated Bax and triggered the intrinsic mitochondrial apoptosis pathway. Furthermore, administration of pazopanib highly suppressed tumor growth in a xenograft model. PUMA deletion in cells and tumors led to resistance of pazopanib, indicating PUMA-mediated pro-apoptotic and anti-tumor effects in vitro and in vivo. Combing pazopanib with some conventional or novel drugs, produced heightened and synergistic antitumor effects that were associated with potentiated PUMA induction via different pathways. Taken together, these results establish a critical role of PUMA in mediating the anticancer effects of pazopanib in colon cancer cells and provide the rationale for clinical evaluation.

  17. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    PubMed Central

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-01-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers. PMID:27256519

  18. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation

    NASA Astrophysics Data System (ADS)

    Zhu, Jun; Zhang, Yan; Zhang, Aili; He, Kun; Liu, Ping; Xu, Lisa X.

    2016-06-01

    Achieving control of metastatic disease is a long-sought goal in cancer therapy. Treatments that encourage a patient’s own immune system are bringing new hopes in reaching such a goal. In clinic, local hyperthermia and cryoablation have been explored to induce anti-tumor immune responses against tumors. We have also developed a novel therapeutic modality of cryo-thermal treatment by alternating liquid nitrogen (LN2) cooling and radio frequency (RF) heating, and better therapeutic effect was achieved in treating metastatic cancer in animal model. In this study, we investigated the mechanism of systemic immune response elicited by cryo-thermal therapy. In the 4T1 murine mammary carcinoma model, we found that local cryo-thermal therapy resulted in a considerable reduction of distant lung metastases, and improved long-term survival. Moreover, results of tumor re-challenge experiments indicated generation of a strong tumor-specific immune memory after the local treatment of primary tumors. Our further study indicated that cryo-thermal therapy caused an elevated extracellular release of Hsp70. Subsequently, Hsp70 induced differentiation of MDSCs into mature DCs, contributing to the relief of MDSCs-mediated immunosuppression and ultimately the activation of strong anti-tumor immune response. Our findings reveal new insight into the mechanism of robust therapeutic effects of cryo-thermal therapy against metastatic cancers.

  19. The CDK9 Inhibitor Dinaciclib Exerts Potent Apoptotic and Antitumor Effects in Preclinical Models of MLL-Rearranged Acute Myeloid Leukemia.

    PubMed

    Baker, Adele; Gregory, Gareth P; Verbrugge, Inge; Kats, Lev; Hilton, Joshua J; Vidacs, Eva; Lee, Erwin M; Lock, Richard B; Zuber, Johannes; Shortt, Jake; Johnstone, Ricky W

    2016-03-01

    Translocations of the mixed lineage leukemia (MLL) gene occur in 60% to 80% of all infant acute leukemias and are markers of poor prognosis. MLL-AF9 and other MLL fusion proteins aberrantly recruit epigenetic regulatory proteins, including histone deacetylases (HDAC), histone methyltransferases, bromodomain-containing proteins, and transcription elongation factors to mediate chromatin remodeling and regulate tumorigenic gene expression programs. We conducted a small-molecule inhibitor screen to test the ability of candidate pharmacologic agents targeting epigenetic and transcriptional regulatory proteins to induce apoptosis in leukemic cells derived from genetically engineered mouse models of MLL-AF9-driven acute myeloid leukemia (AML). We found that the CDK inhibitor dinaciclib and HDAC inhibitor panobinostat were the most potent inducers of apoptosis in short-term in vitro assays. Treatment of MLL-rearranged leukemic cells with dinaciclib resulted in rapidly decreased expression of the prosurvival protein Mcl-1, and accordingly, overexpression of Mcl-1 protected AML cells from dinaciclib-induced apoptosis. Administration of dinaciclib to mice bearing MLL-AF9-driven human and mouse leukemias elicited potent antitumor responses and significantly prolonged survival. Collectively, these studies highlight a new therapeutic approach to potentially overcome the resistance of MLL-rearranged AML to conventional chemotherapies and prompt further clinical evaluation of CDK inhibitors in AML patients harboring MLL fusion proteins.

  20. Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity.

    PubMed

    Su, Tsann-Long; Lin, Yi-Wen; Chou, Ting-Chao; Zhang, Xiuguo; Bacherikov, Valeriy A; Chen, Ching-Huang; Liu, Leroy F; Tsai, Tsong-Jen

    2006-06-15

    A series of 9-anilinoacridine and acridine derivatives bearing an alkylating N-mustard residue at C4 of the acridine chromophore were synthesized. The N-mustard pharmacophore was linked to the C4 of the acridine ring with an O-ethyl (O-C(2)), O-propyl (O-C(3)), or O-butyl (O-C(4)) spacer. It revealed that all newly synthesized compounds were very potent cytotoxic agents against human leukemia and various solid tumors in vitro. These agents did not exhibit cross-resistance against vinblastine-resistant (CCRF-CEM/VBL) or taxol-resistant (CCRF-CEM/taxol) cells. It also showed that these agents were DNA cross-linking agents rather than topoisomerase II inhibitors. Of these agents, compounds 27a and 27c were shown to have potent antitumor activity in nude mice bearing the human breast carcinoma MX-1 xenograft. The therapeutic efficacies of these two agents are comparable to that of taxol.

  1. Design and synthesis of 2-(3-benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one analogues as potent antitumor agents that inhibit tubulin assembly.

    PubMed

    Chang, Yu-Hsun; Hsu, Mei-Hua; Wang, Sheng-Hung; Huang, Li-Jiau; Qian, Keduo; Morris-Natschke, Susan L; Hamel, Ernest; Kuo, Sheng-Chu; Lee, Kuo-Hsiung

    2009-08-13

    As part of our continuing investigation of azo-flavonoid derivatives as potential anticancer drug candidates, a series of 2-aryl-6,7-methylenedioxyquinolin-4-one analogues was designed and synthesized. The design combined structural features of 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one (CHM-1), a previously discovered compound with potent in vivo antitumor activity, and 2-arylquinolin-4-ones, identified by CoMFA models. The newly synthesized analogues were evaluated for cytotoxicity against seven human cancer cell lines, and structure-activity relationship (SAR) correlations were established. Analogues 1, 37, and 39 showed potent cytotoxicity against different cancer cell lines. Compound 1 demonstrated selective cytotoxicity against Hep 3B (hepatoma) cells. Compound 37 was cytotoxic against HL-60 (leukemia), HCT-116 (colon cancer), Hep 3B (hepatoma), and SK-MEL-5 (melanoma) cells. Compound 39 exhibited broad cytotoxicity against all seven cancer cell lines, with IC50 values between 0.07 and 0.19 microM. Results from mechanism of action studies revealed that these new quinolone derivatives function as antitubulin agents.

  2. DNA interactions of new antitumor aminophosphine platinum(II) complexes.

    PubMed

    Neplechová, K; Kaspárková, J; Vrána, O; Nováková, O; Habtemariam, A; Watchman, B; Sadler, P J; Brabec, V

    1999-07-01

    Mechanistic studies are presented of a novel class of aminophosphine platinum(II) complexes as potential anticancer agents. These new agents, which have demonstrated activity against murine and human tumor cells including those resistant to cisplatin are cis-[PtCl2(Me2N(CH2)3PPh2-P)2] (Com1) and cis-[PtCl(C6H11NH(CH2)2PPh2-N,P)(C6H11NH(CH2) 2PPh2-P)] (Com2). We studied modifications of natural and synthetic DNAs in cell-free media by Com1 and Com2 by various biomedical and biophysical methods and compared the results with those obtained when DNA was modified by cisplatin. The results indicated that Com1 and Com2 coordinated to DNA faster than cisplatin. Bifunctional Com1 formed DNA adducts coordinating to single adenine or guanine residues or by forming cross-links between these residues. In comparison with cisplatin, Com1 formed the adducts more frequently at adenine residues and also formed fewer bidentate lesions. The monofunctional Com2 only formed DNA monodentate adducts at guanine residues. In addition, Com1 terminated DNA synthesis in vitro more efficiently than cisplatin whereas Com2 blocked DNA synthesis only slightly. DNA unwinding studies, measurements of circular dichroism spectra, immunochemical analysis, and studies of the B-Z transition in DNA revealed conformational alterations induced by the adducts of Com1, which were distinctly different from those induced by cisplatin. Com2 had little influence on DNA conformation. It is suggested that the activity profile of aminophosphine platinum(II) complexes, which is different from that of cisplatin and related analogs, might be associated with the specific DNA binding properties of this new class of platinum(II) compounds.

  3. Antitumor activities and interaction with DNA of oxaliplatin-type platinum complexes with linear or branched alkoxyacetates as leaving groups.

    PubMed

    Yin, Runting; Gou, Shaohua; Liu, Xia; Lou, Liguang

    2011-08-01

    Five oxaliplatin-typed platinum complexes containing trans-1R, 2R-diaminocyclohexane chelating platinum cores, characteristic of linear or branched alkoxycarboxylates as leaving groups, were biologically evaluated. These compounds showed higher antitumor activity, lower toxicity in vivo than cisplatin or oxaliplatin. And the results revealed that the antitumor activity and interaction with DNA of these compounds were highly related to the nature of leaving groups. Among these complexes, 5a, cis-(trans-1R, 2R-diaminocyclohexane) bis (2-tert-butoxyacetate) platinum(II), showed the highest antitumor activity and the lowest toxicity.

  4. Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents

    PubMed Central

    Gomha, Sobhi M.; Edrees, Mastoura M.; Altalbawy, Farag M. A.

    2016-01-01

    A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a–i were synthesized via reaction of 5,5′-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a–i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC50 equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 μM, respectively. PMID:27618013

  5. Novel Histone Deacetylase Inhibitors with Enhanced Enzymatic Inhibition Effects and Potent in vitro and in vivo Anti-tumor Activities

    PubMed Central

    Zhang, Lei; Zhang, Yingjie; Chou, C. James; Inks, Elizabeth S.; Wang, Xuejian; Li, Xiaoguang; Hou, Jinning; Xu, Wenfang

    2014-01-01

    In the present work, a series of small molecules were designed and synthesized based on structural optimization. Significant improvement in the enzymatic inhibition activity of the synthesized compounds was discovered. Moreover, tested compounds have moderate preference for class I HDACs over HDAC6 proved by enzymatic selectivity assay. The in vitro anti-proliferation assay reveals that representative compounds can selectively inhibit the growth of the non-solid lymphomatous cells and leukemic cells such as U937, K562 and HL60 cell lines. In the in vivo anti-tumor assay, molecule D17 showed better performance than SAHA in inhibition of U937 tumor growth. The western blot analysis revealed that representative molecules can block the function of both class I HDACs and HDAC6. More importantly, our western blot results revealed that the levels of some oncogenic proteins (p-Akt in the PI3K/AKT/mTOR signal pathway, c-Raf and p-Erk in the MAPK signal pathway) were dramatically down-regulated by our compounds in U937 cell line rather than MDA-MB-231 cells. This cellular mechanism difference might be an important reason why U937 cell line was more sensitive to our HDACs inhibitors than MDA-MB-231 cell line. PMID:24227760

  6. Stat3 inhibitor Stattic exhibits potent antitumor activity and induces chemo- and radio-sensitivity in nasopharyngeal carcinoma.

    PubMed

    Pan, Yunbao; Zhou, Fuling; Zhang, Ronghua; Claret, Francois X

    2013-01-01

    Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated malignancy most common in East Asia, Africa and Alaska. Radiotherapy and cisplatin-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to cisplatin and radiotherapy. Signal transducer and activator of transcription 3 (Stat3) has been implicated in the development and progression of various solid tumors. In this study, we assessed the activation and expression of Stat3 in NPC cells. We found that Stat3 was activated and could be blocked by the small molecule inhibitor Stattic. The inhibition of Stat3 in NPC cells by Stattic decreased the expression of cyclin D1 in a dose- and time-dependent manner. Thus, Stattic was used to target Stat3 in NPC cell lines. We found that Stattic could inhibit cell viability and proliferation in NPC cells and significantly induced apoptosis. Additionally, Stat3 transfection attenuated, whereas Stat3 knockdown enhanced, the effects of Stattic upon cell viability inhibition and apoptosis induction. Furthermore, Stattic sensitized NPC cells to cisplatin and ionizing radiation (IR) by preventing cell proliferation and inducing apoptosis. Taken together, Stattic inhibit Stat3 and display antitumor effect in NPC, and enhanced chemosensitivity and radiosensitivity in NPC. Therefore, our findings provide the base for more rational approaches to treat NPC in the clinic.

  7. Azido- and chlorido-cobalt complex as carrier-prototypes for antitumoral prodrugs.

    PubMed

    Pires, Bianca M; Giacomin, Letícia C; Castro, Frederico A V; Cavalcanti, Amanda dos S; Pereira, Marcos D; Bortoluzzi, Adailton J; Faria, Roberto B; Scarpellini, Marciela

    2016-04-01

    Cobalt(III) complexes are well-suited systems for cytotoxic drug release under hypoxic conditions. Here, we investigate the effect of cytotoxic azide release by cobalt-containing carrier-prototypes for antitumoral prodrugs. In addition, we study the species formed after reduction of Co(3+) → Co(2+) in the proposed models for these prodrugs. Three new complexes, [Co(III)(L)(N3)2]BF4(1), [{Co(II)(L)(N3)}2](ClO4)2(2), and [Co(II)(L)Cl]PF6(3), L=[(bis(1-methylimidazol-2-yl)methyl)(2-(pyridyl-2-yl)ethyl)amine], were synthesized and studied by several spectroscopic, spectrometric, electrochemical, and crystallographic methods. Reactivity and spectroscopic data reveal that complex 1 is able to release N3(-) either after reduction with ascorbic acid, or by ambient light irradiation, in aqueous phosphate buffer (pH6.2, 7.0 and 7.4) and acetonitrile solutions. The antitumoral activities of compounds 1-3 were tested in normoxia on MCF-7 (human breast adenocarcinoma), PC-3 (human prostate) and A-549 (human lung adenocarcinoma epithelial) cell lines, after 24h of exposure. Either complexes or NaN3 presented IC50 values higher than 200 μM, showing lower cytotoxicity than the clinical standard antitumoral complex cisplatin, under the same conditions. Complexes 1-3 were also evaluated in hypoxia on A-549 and results indicate high IC50 data (>200 μM) after 24h of exposure. However, an increase of cancer cell susceptibility to 1 and 2 was observed at 300 μM. Regarding complex 3, no cytotoxic activity was observed in the same conditions. The data presented here indicate that the tridentate ligand L is able to stabilize both oxidation states of cobalt (+3 and +2). In addition, the cobalt(III) complex generates the low cytotoxic cobalt(II) species after reduction, which supports their use as as carrier prototypes for antitumoral prodrugs. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Recombinant immune complexes as versatile and potent vaccines.

    PubMed

    Mason, Hugh S

    2016-04-02

    Immune complexes (IC) used as vaccines have the potential to enhance both antibody and cell-mediated immune responses over those obtained with antigen alone. However, difficulty of manufacture represents a significant hurdle to the widespread use of IC as vaccines. Recombinant IC (RIC) and their expression in plants enable manufacturing by the coordinate expression of immunoglobulin and antigen as a fusion protein. The use of a modular RIC system facilitates insertion of antigen genes and provides a broadly applicable platform that can be adapted for a wide variety of antigens.

  9. Single-domain antibody-based and linker-free bispecific antibodies targeting FcγRIII induce potent antitumor activity without recruiting regulatory T cells.

    PubMed

    Rozan, Caroline; Cornillon, Amélie; Pétiard, Corinne; Chartier, Martine; Behar, Ghislaine; Boix, Charlotte; Kerfelec, Brigitte; Robert, Bruno; Pèlegrin, André; Chames, Patrick; Teillaud, Jean-Luc; Baty, Daniel

    2013-08-01

    Antibody-dependent cell-mediated cytotoxicity, one of the most prominent modes of action of antitumor antibodies, suffers from important limitations due to the need for optimal interactions with Fcγ receptors. In this work, we report the design of a new bispecific antibody format, compact and linker-free, based on the use of llama single-domain antibodies that are capable of circumventing most of these limitations. This bispecific antibody format was created by fusing single-domain antibodies directed against the carcinoembryonic antigen and the activating FcγRIIIa receptor to human Cκ and CH1 immunoglobulin G1 domains, acting as a natural dimerization motif. In vitro and in vivo characterization of these Fab-like bispecific molecules revealed favorable features for further development as a therapeutic molecule. They are easy to produce in Escherichia coli, very stable, and elicit potent lysis of tumor cells by human natural killer cells at picomolar concentrations. Unlike conventional antibodies, they do not engage inhibitory FcγRIIb receptor, do not compete with serum immunoglobulins G for receptor binding, and their cytotoxic activity is independent of Fc glycosylation and FcγRIIIa polymorphism. As opposed to anti-CD3 bispecific antitumor antibodies, they do not engage regulatory T cells as these latter cells do not express FcγRIII. Studies in nonobese diabetic/severe combined immunodeficient gamma mice xenografted with carcinoembryonic antigen-positive tumor cells showed that Fab-like bispecific molecules in the presence of human peripheral blood mononuclear cells significantly slow down tumor growth. This new compact, linker-free bispecific antibody format offers a promising approach for optimizing antibody-based therapies.

  10. Discovery of hybrid dual N-acylhydrazone and diaryl urea derivatives as potent antitumor agents: design, synthesis and cytotoxicity evaluation.

    PubMed

    Zhai, Xin; Huang, Qiang; Jiang, Nan; Wu, Di; Zhou, Hongyu; Gong, Ping

    2013-03-04

    Based on the hybrid pharmacophore design concept, a novel series of dual diaryl urea and N-acylhydrazone derivatives were synthesized and evaluated for their in vitro cytotoxicity by the standard MTT assay. The pharmacological results indicated that most compounds exhibited moderate to excellent activity. Moreover, compound 2g showed the most potent cytotoxicity against HL-60, A549 and MDA-MB-231 cell lines, with IC50 values of 0.22, 0.34 and 0.41 μM, respectively, which was 3.8 to 22.5 times more active than the reference compounds sorafenib and PAC-1. The promising compound 2g thus emerges as a lead for further structural modifications.

  11. DNA Binding and Antitumor Activity of α-Diimineplatinum(II) and Palladium(II) Dithiocarbamate Complexes

    PubMed Central

    Mansouri-Torshizi, Hassan; Saeidifar, Maryam; Khosravi, Fatemeh; Divsalar, Adeleh; Saboury, Ali Akbar; Hassani, Fatemeh

    2011-01-01

    The two water-soluble designed platinum(II) complex, [Pt(Oct-dtc)(bpy)]NO3 (Oct-dtc = Octyldithiocarbamate and bpy = 2,2′ -bipyridine) and palladium(II) complex, [Pd(Oct-dtc)(bpy)]NO3, have been synthesized and characterized by elemental analyses, molar conductivity measurements, IR, 1H NMR, and electronic spectra studies. Studies of antitumor activity of these complexes against human cell tumor lines (K562) have been carried out. They show Ic50 values lower than that of cisplatin. The complexes have been investigated for their interaction with calf thymus DNA (CT-DNA) by utilizing the electronic absorption spectroscopy, fluorescence spectra, and ethidium bromide displacement and gel filtration techniques. Both of these water-soluble complexes bound cooperatively and intercalatively to the CT-DNA at very low concentrations. Several binding and thermodynamic parameters are also described. PMID:22110410

  12. IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.

    PubMed

    Ab, Olga; Whiteman, Kathleen R; Bartle, Laura M; Sun, Xiuxia; Singh, Rajeeva; Tavares, Daniel; LaBelle, Alyssa; Payne, Gillian; Lutz, Robert J; Pinkas, Jan; Goldmacher, Victor S; Chittenden, Thomas; Lambert, John M

    2015-07-01

    A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody-drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N(2')-deacetyl-N(2')-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models. The level of expression of FRα on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors.

  13. Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.

    PubMed

    Guzmán, Esther A; Xu, Qunli; Pitts, Tara P; Mitsuhashi, Kaoru Ogawa; Baker, Cheryl; Linley, Patricia A; Oestreicher, Judy; Tendyke, Karen; Winder, Priscilla L; Suh, Edward M; Wright, Amy E

    2016-11-01

    Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity toward the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The antitumor activities of leiodermatolide, as well as the proven utility of antimitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research. © 2016 UICC.

  14. Generation of a novel Antibody-Drug Conjugate targeting endosialin: potent and durable antitumor response in sarcoma.

    PubMed

    Capone, Emily; Piccolo, Enza; Fichera, Imma; Ciufici, Paolo; Barcaroli, Daniela; Sala, Arturo; De Laurenzi, Vincenzo; Iacobelli, Valentina; Iacobelli, Stefano; Sala, Gianluca

    2017-09-01

    The endosialin/CD248/TEM1 receptor is expressed on the cell surface of tumor-associated stroma cells as well as in sarcoma and neuroblastoma cells. This receptor is emerging as an attractive molecule in diagnostics and therapeutics because of its expression across the stroma of many human tumors, the low to absent expression in normal tissues and accessibility from the vascular circulation. In this study, we present evidence of the preclinical efficacy of a novel Antibody-Drug Conjugate (ENDOS/ADC). It consists of a humanized endosialin monoclonal antibody, named hMP-E-8.3, conjugated to a potent duocarmycin derivative. In endosialin expressing cancer cell lines, this ENDOS/ADC showed a powerful, specific and target-dependent killing activity. High expression levels of endosialin in cells correlated with efficient internalization and cytotoxic effects in vitro. Efficacy studies demonstrated that ENDOS/ADC treatment led to a long-lasting tumor growth inhibition of a cell line-based model of human osteosarcoma. Taken together, our results demonstrate that endosialin is an attractive target in sarcoma and suggest that ENDOS/ADC has the potential to be developed into a bio-therapeutic agent for these malignancies.

  15. Synthesis, Characterization and Biological Evaluation of Some Quinoxaline Derivatives: A Promising and Potent New Class of Antitumor and Antimicrobial Agents.

    PubMed

    Al-Marhabi, Aisha R; Abbas, Hebat-Allah S; Ammar, Yousry A

    2015-11-03

    In continuation of our endeavor towards the development of potent and effective anticancer and antimicrobial agents; the present work deals with the synthesis of some novel tetrazolo[1,5-a]quinoxalines, N-pyrazoloquinoxalines, the corresponding Schiff bases, 1,2,4-triazinoquinoxalines and 1,2,4-triazoloquinoxalines. These compounds were synthesized via the reaction of the key intermediate hydrazinoquinoxalines with various reagents and evaluated for anticancer and antimicrobial activity. The results indicated that tetrazolo[1,5-a]quinoxaline derivatives showed the best result, with the highest inhibitory effects towards the three tested tumor cell lines, which were higher than that of the reference doxorubicin and these compounds were non-cytotoxic to normal cells (IC50 values > 100 μg/mL). Also, most of synthesized compounds exhibited the highest degrees of inhibition against the tested strains of Gram positive and negative bacteria, so tetrazolo[1,5-a]quinoxaline derivatives show dual activity as anticancer and antimicrobial agents.

  16. Bovine lactoferrin binds oleic acid to form an anti-tumor complex similar to HAMLET.

    PubMed

    Fang, Bing; Zhang, Ming; Tian, Mai; Jiang, Lu; Guo, Hui Yuan; Ren, Fa Zheng

    2014-04-04

    α-Lactalbumin (α-LA) can bind oleic acid (OA) to form HAMLET-like complexes, which exhibited highly selective anti-tumor activity in vitro and in vivo. Considering the structural similarity to α-LA, we conjectured that lactoferrin (LF) could also bind OA to obtain a complex with anti-tumor activity. In this study, LF-OA was prepared and its activity and structural changes were compared with α-LA-OA. The anti-tumor activity was evaluated by methylene blue assay, while the apoptosis mechanism was analyzed using flow cytometry and Western blot. Structural changes of LF-OA were measured by fluorescence spectroscopy and circular dichroism. The interactions of OA with LF and α-LA were evaluated by isothermal titration calorimetry (ITC). LF-OA was obtained by heat-treatment at pH8.0 with LD50 of 4.88, 4.95 and 4.62μM for HepG2, HT29, and MCF-7 cells, respectively, all of which were 10 times higher than those of α-LA-OA. Similar to HAMLET, LF-OA induced apoptosis in tumor cells through both death receptor- and mitochondrial-mediated pathways. Exposure of tryptophan residues and the hydrophobic regions as well as the loss of tertiary structure were observed in LF-OA. Besides these similarities, LF showed different secondary structure changes when compared with α-LA, with a decrease of α-helix and β-turn and an increase of β-sheet and random coil. ITC results showed that there was a higher binding number of OA to LF than to α-LA, while both of the proteins interacted with OA through van der Waals forces and hydrogen bonds. This study provides a theoretical basis for further exploration of protein-OA complexes. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Design, synthesis and biological evaluation of novel thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety as potent antitumor agents.

    PubMed

    Liu, Zijian; Wang, Yu; Lin, Huafang; Zuo, Dazhuang; Wang, Lihui; Zhao, Yanfang; Gong, Ping

    2014-10-06

    Two series of thieno[3,2-d]pyrimidine derivatives containing diaryl urea moiety were designed, synthesized and evaluated for their biological activity. The preliminary investigation showed that most compounds displayed good to excellent potency against four tested cancer cell lines as compared with GDC-0941 and sorafenib. In particular, the most promising compound 29a showed the most potent antitumor activities with IC50 values of 0.081 μM, 0.058 μM, 0.18 μM, and 0.23 μM against H460, HT-29, MKN-45 and MDA-MB-231 cell lines, respectively. The SAR analyses indicated that compounds with mono-halogen groups at 4-position on the terminal phenyl ring were more active than those with double-halogen groups or methyl groups. In addition, the introduction of chlorine atoms into 6,7-position of thieno[3,2-d]pyrimidine moiety led to a slight decline, but more selective activity against H460 and HT-29 cell lines.

  18. Antitumor agents 292. Design, synthesis and pharmacological study of S- and O-substituted 7-mercapto- or hydroxy-coumarins and chromones as potent cytotoxic agents.

    PubMed

    Chen, Ying; Liu, Hong-Rui; Liu, Hong-Shan; Cheng, Ming; Xia, Peng; Qian, Keduo; Wu, Pei-Chi; Lai, Chin-Yu; Xia, Yi; Yang, Zheng-Yu; Morris-Natschke, Susan L; Lee, Kuo-Hsiung

    2012-03-01

    Thirty-five S- and O-substituted 7-mercaptocoumarin (9-23) and 7-hydroxy- or 7-mercapto-chromone (24-43) analogs were designed, synthesized and evaluated in vitro against four human tumor cell lines [KB (nasopharyngeal), KB-vin (vincristine-resistant subline), A549 (lung) and DU145 (prostate)] with paclitaxel as the positive control. Many of the synthesized compounds exhibited potent cytotoxic activity. Among them, compounds 10 and 18 showed broad spectrum activity with GI(50) values ranging from 0.92 to 2.11 μM and 2.06-14.07 μM, respectively. However, 33, a 3-brominated compound, displayed significant and selective inhibition against MDR KB-vin with a GI(50) of 5.84 μM. Regardless of the size of the 7-alkoxy group, 2-α-bromoethyl-8-bromomethyl compounds (40-43) exhibited increased cytotoxicity compared with 2-ethyl-8-bromomethyl compounds (36-39). Moreover, in a preliminary pharmacological study, 10 not only remarkably increased cellular apoptosis in a concentration-dependent manner, but also clearly induced A549 cell cycle arrest at the G2/M phase. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism(s).

  19. Molecular-targeted antitumor agents: the Saururus cernuus dineolignans manassantin B and 4-O-demethylmanassantin B are potent inhibitors of hypoxia-activated HIF-1.

    PubMed

    Hodges, Tyler W; Hossain, Chowdhury Faiz; Kim, Yong-Pil; Zhou, Yu-Dong; Nagle, Dale G

    2004-05-01

    The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of tumor cell adaptation and survival under hypoxic conditions. Selective HIF-1 inhibitors represent an important new class of potential molecular-targeted antitumor therapeutic agents. Extracts of plants and marine organisms were evaluated using a T47D human breast tumor cell-based reporter assay for HIF-1 inhibitors. Bioassay-guided fractionation of the lipid extract of Saururus cernuus resulted in the isolation of manassantin B (1) and a new compound, 4-O-demethylmanassantin B (2). The structure of 2 was determined spectroscopically. The absolute configurations of manassantin-type dineolignans have not been previously reported. Therefore, the absolute configurations of the chiral centers in each side chain were deduced from spectroscopic analysis of the Mosher MTPA ester derivatives of 1. Both 1 and 2 are among the most potent small molecule HIF-1 inhibitors discovered, to date, with IC(50) values of 3 and 30 nM, respectively. Compounds 1 and 2 selectively inhibited hypoxia-activated HIF-1 in contrast to iron chelator-activated HIF-1. Compounds 1 and 2 also inhibited hypoxic induction of the angiogenic factor VEGF. Further study revealed that 1 selectively blocked the induction of HIF-1alpha protein, the oxygen regulated HIF-1 subunit that determines HIF-1 activity.

  20. Vanadium and cancer treatment: antitumoral mechanisms of three oxidovanadium(IV) complexes on a human osteosarcoma cell line.

    PubMed

    León, I E; Butenko, N; Di Virgilio, A L; Muglia, C I; Baran, E J; Cavaco, I; Etcheverry, S B

    2014-05-01

    We report herein the antitumor actions of three oxidovanadium(IV) complexes on MG-63 human osteosarcoma cell line. The three complexes: VO(oda), VO(oda)bipy and VO(oda)phen (oda=oxodiacetate), caused a concentration dependent inhibition of cell viability. The antiproliferative action of VO(oda)phen could be observed in the whole range of concentrations (at 2.5 μM), while VO(oda)bipy and VO(oda) showed a decrease of cell viability only at higher concentrations (at 50 and 75 μM, respectively) (p<0.01). Moreover, VO(oda)phen caused a decrease of lysosomal and mitochondrial activities at 2.5 μM, while VO(oda) and VO(oda)bipy affected neutral red uptake and mitochondrial metabolism at 50 μM (p<0.01). On the other hand, no DNA damage studied by the Comet assay could be observed in MG-63 cells treated with VO(oda) at 2.5-10 μM. Nevertheless, VO(oda)phen and VO(oda)bipy induced DNA damage at 2.5 and 10 μM, respectively (p<0.01). The generation of reactive oxygen species increased at 10 μM of VO(oda)phen and only at 100 μM of VO(oda) and VO(oda)bipy (p<0.01). Besides, VO(oda)phen and VO(oda)bipy triggered apoptosis as determined by externalization of the phosphatidylserine. The determination of DNA cleavage by agarose gel electrophoresis showed that the ability of VO(oda)(bipy) is similar to that of VO(oda), while VO(oda)(phen) showed the highest nuclease activity in this series. Overall, our results showed a good relationship between the bioactivity of the complexes and their structures since VO(oda)phen presented the most potent antitumor action in human osteosarcoma cells followed by VO(oda)bipy and then by VO(oda) according to the number of intercalating heterocyclic moieties.

  1. Endonuclease cleavage of blocked replication forks: An indirect pathway of DNA damage from antitumor drug-topoisomerase complexes

    NASA Astrophysics Data System (ADS)

    Hong, George; Kreuzer, Kenneth N.

    2003-04-01

    The cytotoxicity of several important antitumor drugs depends on formation of the covalent topoisomerase-DNA cleavage complex. However, cellular processes such as DNA replication are necessary to convert the cleavage complex into a cytotoxic lesion, but the molecular mechanism of this conversion and the precise nature of the cytotoxic lesion are unknown. Using a bacteriophage T4 model system, we have previously shown that antitumor drug-induced cleavage complexes block replication forks in vivo. In this report, we show that these blocked forks can be cleaved by T4 endonuclease VII to create overt DNA breaks. The accumulation of blocked forks increased in endonuclease VII-deficient infections, suggesting that endonuclease cleavage contributes to fork processing in vivo. Furthermore, purified endonuclease VII cleaved the blocked forks in vitro close to the branch points. These results suggest that an indirect pathway of branched-DNA cleavage contributes to the cytotoxicity of antitumor drugs that target DNA topoisomerases.

  2. Metal-N-heterocyclic carbene complexes as anti-tumor agents.

    PubMed

    Hu, Chunqi; Li, Xin; Wang, Wei; Zhang, Ruoyu; Deng, Liping

    2014-04-01

    It has been a long story of the development of anticancer metallopharmaceuticals since the identification of cisplatin. Advances in metallodrugs discovery during the past 40 years have made it an ever-growing area of research in medicinal inorganic chemistry. Meanwhile, the emerging of N-heterocyclic carbene (NHC) chemistry has stimulated the newly burgeoning interests in the biomedical applications of metal-NHC complexes. This review will detail what have been achieved hitherto in the research of metal-NHC complexes as potential anti-tumor agents coupled with gold, silver, copper, platinum and palladium. Their mechanism of action will also be discussed. All the results obtained indicate that this promising approach is worthy of more focuses and further studies.

  3. Antitumor drug nogalamycin binds DNA in both grooves simultaneously: molecular structure of nogalamycin-DNA complex.

    PubMed

    Liaw, Y C; Gao, Y G; Robinson, H; van der Marel, G A; van Boom, J H; Wang, A H

    1989-12-26

    The three-dimensional molecular structures of the complexes between an interesting antitumor drug, nogalamycin, and two DNA hexamers, d[CGT(pS)ACG] and d[m5CGT(pS)Am5CG], were determined at high resolution by X-ray diffraction analyses. Two nogalamycins bind to the DNA double helix in a 2:1 ratio with the aglycon chromophore intercalated between the CpG steps at both ends of the helix. The nogalose and aminoglucose sugars lie in the minor and major grooves, respectively, of the distorted B-DNA double helix. The binding of nogalamycin to DNA requires that the base pairs in DNA open up transiently to allow the bulky sugars to go through. Specific hydrogen bonds are found in the complex between the drug and guanine bases. We suggest that nogalamycin may prefer GC sequences embedded in a stretch of AT sequences.

  4. An optimized peptide vaccine strategy capable of inducing multivalent CD8+ T cell responses with potent antitumor effects

    PubMed Central

    Cho, Hyun-Il; Jung, Soo-Hyun; Sohn, Hyun-Jung; Celis, Esteban; Kim, Tai-Gyu

    2015-01-01

    Therapeutic cancer vaccines are an attractive alternative to conventional therapies for treating malignant tumors, and successful tumor eradication depends primarily on obtaining high numbers of long-lasting tumor-reactive CD8+ T cells. Dendritic cell (DC)-based vaccines constitute a promising approach for treating cancer, but in most instances low immune responses and suboptimal therapeutic effects are achieved indicating that further optimization is required. We describe here a novel vaccination strategy with peptide-loaded DCs followed by a mixture of synthetic peptides, polyinosine-polycytidylic acid (poly-IC) and anti-CD40 antibodies (TriVax) for improving the immunogenicity and therapeutic efficacy of DC-based vaccines in a melanoma mouse model. TriVax immunization 7–12 d after priming with antigen-loaded DCs generated large numbers of long-lasting multiple antigen-specific CD8+ T cells capable of recognizing tumor cells. These responses were far superior to those generated by homologous immunizations with either TriVax or DCs. CD8+ T cells but not CD4+ T cells or NK cells mediated the therapeutic efficacy of this heterologous prime-boost strategy. Moreover, combinations of this vaccination regimen with programmed cell death-1 (PD-1) blockade or IL2 anti-IL2 antibody complexes led to complete disease eradication and survival enhancement in melanoma-bearing mice. The overall results suggest that similar strategies would be applicable for the design of effective therapeutic vaccination for treating viral diseases and various cancers, which may circumvent current limitations of cell-based cancer vaccines. PMID:26451316

  5. Antitumor activity of phenylene bridged binuclear bis(imino-quinolyl)palladium(II) and platinum(II) complexes.

    PubMed

    Motswainyana, William M; Onani, Martin O; Madiehe, Abram M; Saibu, Morounke

    2014-04-01

    Antitumor effects of a known bis(imino-quinolyl)palladium(II) complex 1 and its newly synthesized platinum(II) analogue 2 were evaluated against human breast (MCF-7) and human colon (HT-29) cancer cell lines. The complexes gave cytotoxicity profiles that were better than the reference drug cisplatin. The highest cytotoxic activities were pronounced in complex 2 across the two examined cancer cell lines. Both compounds represent potential active drugs based on bimetallic complexes.

  6. Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents

    PubMed Central

    Sestak, Vit; Stariat, Jan; Cermanova, Jolana; Potuckova, Eliska; Chladek, Jaroslav; Roh, Jaroslav; Bures, Jan; Jansova, Hana; Prusa, Petr; Sterba, Martin; Micuda, Stanislav; Simunek, Tomas; Kalinowski, Danuta S.; Richardson, Des R.; Kovarikova, Petra

    2015-01-01

    Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment. PMID:26623727

  7. Novel and potent anti-tumor and anti-metastatic di-2-pyridylketone thiosemicarbazones demonstrate marked differences in pharmacology between the first and second generation lead agents.

    PubMed

    Sestak, Vit; Stariat, Jan; Cermanova, Jolana; Potuckova, Eliska; Chladek, Jaroslav; Roh, Jaroslav; Bures, Jan; Jansova, Hana; Prusa, Petr; Sterba, Martin; Micuda, Stanislav; Simunek, Tomas; Kalinowski, Danuta S; Richardson, Des R; Kovarikova, Petra

    2015-12-15

    Di(2-pyridyl)ketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) and di(2-pyridyl)ketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) are novel, highly potent and selective anti-tumor and anti-metastatic drugs. Despite their structural similarity, these agents differ in their efficacy and toxicity in-vivo. Considering this, a comparison of their pharmacokinetic and pharmaco/toxico-dynamic properties was conducted to reveal if these factors are involved in their differential activity. Both compounds were administered to Wistar rats intravenously (2 mg/kg) and their metabolism and disposition were studied using UHPLC-MS/MS. The cytotoxicity of both thiosemicarbazones and their metabolites was also examined using MCF-7, HL-60 and HCT116 tumor cells and 3T3 fibroblasts and H9c2 cardiac myoblasts. Their intracellular iron-binding ability was characterized by the Calcein-AM assay and their iron mobilization efficacy was evaluated. In contrast to DpC, Dp44mT undergoes rapid demethylation in-vivo, which may be related to its markedly faster elimination (T1/2 = 1.7 h for Dp44mT vs. 10.7 h for DpC) and lower exposure. Incubation of these compounds with cancer cells or cardiac myoblasts did not result in any significant metabolism in-vitro. The metabolism of Dp44mT in-vivo resulted in decreased anti-cancer activity and toxicity. In conclusion, marked differences in the pharmacology of Dp44mT and DpC were observed and highlight the favorable pharmacokinetics of DpC for cancer treatment.

  8. Anti-CCR7 therapy exerts a potent anti-tumor activity in a xenograft model of human mantle cell lymphoma

    PubMed Central

    2013-01-01

    Background The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model. Methods NOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively. Results The anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated. Conclusions The anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies. PMID:24305507

  9. Complex of C60 Fullerene with Doxorubicin as a Promising Agent in Antitumor Therapy

    NASA Astrophysics Data System (ADS)

    Prylutska, Svitlana V.; Skivka, Larysa M.; Didenko, Gennadiy V.; Prylutskyy, Yuriy I.; Evstigneev, Maxim P.; Potebnya, Grygoriy P.; Panchuk, Rostyslav R.; Stoika, Rostyslav S.; Ritter, Uwe; Scharff, Peter

    2015-12-01

    The main aim of this work was to evaluate the effect of doxorubicin in complex with C60 fullerene (C60 + Dox) on the growth and metastasis of Lewis lung carcinoma in mice and to perform a primary screening of the potential mechanisms of C60 + Dox complex action. We found that volume of tumor from mice treated with the C60 + Dox complex was 1.4 times less than that in control untreated animals. The number of metastatic foci in lungs of animals treated with C60 + Dox complex was two times less than that in control untreated animals. Western blot analysis of tumor lysates revealed a significant decrease in the level of heat-shock protein 70 in animals treated with C60 + Dox complex. Moreover, the treatment of tumor-bearing mice was accompanied by the increase of cytotoxic activity of immune cells. Thus, the potential mechanisms of antitumor effect of C60 + Dox complex include both its direct action on tumor cells by inducing cell death and increasing of stress sensitivity and an immunomodulating effect. The obtained results provide a scientific basis for further application of C60 + Dox nanocomplexes as treatment agents in cancer chemotherapy.

  10. Antitumor cell-complex vaccines employing genetically modified tumor cells and fibroblasts.

    PubMed

    Miguel, Antonio; Herrero, María José; Sendra, Luis; Botella, Rafael; Diaz, Ana; Algás, Rosa; Aliño, Salvador F

    2014-02-19

    The present study evaluates the immune response mediated by vaccination with cell complexes composed of irradiated B16 tumor cells and mouse fibroblasts genetically modified to produce GM-CSF. The animals were vaccinated with free B16 cells or cell complexes. We employed two gene plasmid constructions: one high producer (pMok) and a low producer (p2F). Tumor transplant was performed by injection of B16 tumor cells. Plasma levels of total IgG and its subtypes were measured by ELISA. Tumor volumes were measured and survival curves were obtained. The study resulted in a cell complex vaccine able to stimulate the immune system to produce specific anti-tumor membrane proteins (TMP) IgG. In the groups vaccinated with cells transfected with the low producer plasmid, IgG production was higher when we used free B16 cell rather than cell complexes. Nonspecific autoimmune response caused by cell complex was not greater than that induced by the tumor cells alone. Groups vaccinated with B16 transfected with low producer plasmid reached a tumor growth delay of 92% (p ≤ 0.01). When vaccinated with cell complex, the best group was that transfected with high producer plasmid, reaching a tumor growth inhibition of 56% (p ≤ 0.05). Significant survival (40%) was only observed in the groups vaccinated with free transfected B16 cells.

  11. Antitumor Cell-Complex Vaccines Employing Genetically Modified Tumor Cells and Fibroblasts

    PubMed Central

    Miguel, Antonio; Herrero, María José; Sendra, Luis; Botella, Rafael; Diaz, Ana; Algás, Rosa; Aliño, Salvador F.

    2014-01-01

    The present study evaluates the immune response mediated by vaccination with cell complexes composed of irradiated B16 tumor cells and mouse fibroblasts genetically modified to produce GM-CSF. The animals were vaccinated with free B16 cells or cell complexes. We employed two gene plasmid constructions: one high producer (pMok) and a low producer (p2F). Tumor transplant was performed by injection of B16 tumor cells. Plasma levels of total IgG and its subtypes were measured by ELISA. Tumor volumes were measured and survival curves were obtained. The study resulted in a cell complex vaccine able to stimulate the immune system to produce specific anti-tumor membrane proteins (TMP) IgG. In the groups vaccinated with cells transfected with the low producer plasmid, IgG production was higher when we used free B16 cell rather than cell complexes. Nonspecific autoimmune response caused by cell complex was not greater than that induced by the tumor cells alone. Groups vaccinated with B16 transfected with low producer plasmid reached a tumor growth delay of 92% (p ≤ 0.01). When vaccinated with cell complex, the best group was that transfected with high producer plasmid, reaching a tumor growth inhibition of 56% (p ≤ 0.05). Significant survival (40%) was only observed in the groups vaccinated with free transfected B16 cells. PMID:24556729

  12. 2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity.

    PubMed

    Mi, Qian; Ma, Yuru; Gao, Xiangqian; Liu, Ran; Liu, Pengxing; Mi, Yi; Fu, Xuegang; Gao, Qingzhi

    2016-11-01

    Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1's substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.

  13. Synthesis, characterization, antioxidative and antitumor activities of solid quercetin rare earth(III) complexes.

    PubMed

    Zhou, J; Wang, L F; Wang, J Y; Tang, N

    2001-01-01

    Eight rare earth metal(II) complexes with quercetin ML3 x 6H2O [L=quercetin (3-OH group deprotonated); M = La, Nd, Eu, Gd, Tb, Dy, Tm and Y] have been synthesized and characterized by elemental analysis, complexometric titration, thermal analysis, conductivity, IR, UV, 1HNMR and fluorescence spectra techniques as well as cyclic voltammetry. The quercetin:metal stoichiometry and the equilibrium stability constant for metal binding to quercetin have been determined. The antioxidative and antitumor activities of quercetin x 2H2O and the complexes were tested by both the MTT and SRB methods. The results show that the suppression ratio of the complexes against the tested tumour cells are superior to quercetin x 2H2O. The property of LaL3 x 6H2O reacting with calf thymus DNA was studied by fluorescence methods. The La-complex binding to DNA has been determined by fluorescence titration in 0.05 M Tris-HCl, 0.5 M NaCl buffer (pH 7.0). The results indicate that the interaction of the complex with DNA is very evident.

  14. Formation of complexes of antimicrobial agent norfloxacin with antitumor antibiotics of anthracycline series

    NASA Astrophysics Data System (ADS)

    Evstigneev, M. P.; Rybakova, K. A.; Davies, D. B.

    2007-05-01

    The formation of complexes in solutions of the norfloxacin antimicrobial agent (NOR) with daunomycin (DAU) and nogalamycin (NOG), antitumor anthracycline antibiotics, was studied using 1H NMR spectroscopy. Based on the concentration and temperature dependences of the chemical shifts of the protons of interacting molecules, the equilibrium constants and thermodynamic parameters (enthalpy and entropy) of heteroassociation of the antibiotics were calculated. It was shown that NOR interacts with DAU (NOG) in aqueous solutions forming stacked heterocomplexes with parallel orientation of the molecular chromophores. The conclusion was drawn that such interactions should be taken into account when anthracyclines and quinolones are jointly administered during combined chemotherapy, since they can contribute to the medico-biological synergistic effect of these antibiotics.

  15. [Toxicity and antitumoral activity of two new complex compounds of rhenium].

    PubMed

    Natorkhin, M I; Stukov, A N; Filov, V A

    2002-01-01

    Toxicity and antitumor action of two new complex compounds of rhenium (K2 [ReCl6] and [ReCl(4).2C6H4N2]) were investigated. LD50 of K2 [ReCl6], i.v., was 136 +/- 37 mg/kg; i.p.,--272 +/- 74 mg/kg. LD50 of [ReCl(4).2C6H4N2], i.v., was 543 +/- 148 mg/kg; i.p., 600 mg/kg was tolerable. Single maximum tolerable dose of 200 mg/kg K2 [ReCl6], i.p., did not influence the growth of ascitic tumor of Ehrlich, nor did daily intravenous dose of 50 mg/kg inhibit solid tumor of Ehrlich. No inhibition by [ReCl(4).2C6H4N2] was registered when 25 or 50 mg/kg were administered.

  16. Gold(I) Complexes of 9-Deazahypoxanthine as Selective Antitumor and Anti-Inflammatory Agents

    PubMed Central

    Vančo, Ján; Gáliková, Jana; Hošek, Jan; Dvořák, Zdeněk; Paráková, Lenka; Trávníček, Zdeněk

    2014-01-01

    The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1–5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1–5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1–5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1–5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds. PMID:25333949

  17. Biochemical action of new complexes of ruthenium with quinolones as potential antitumor agents.

    PubMed

    Gruia, Maria Iuliana; Negoita, Valentina; Vasilescu, Monica; Panait, Marieta; Gruia, Ion; Velescu, Bruno Stefan; Uivarosi, Valentina

    2015-06-01

    The aim of the present study paper was to identify the role of reactive oxygen species (ROS) in apoptosis signaling mechanisms. We used for this purpose two ruthenium complex compounds based on that overproduce these reactive species by their metabolism thus manifesting their antitumor activity too. In vivo studies were performed in Walker 256 carcinoma-bearing Wistar rats treated with two ruthenium (III) (Ru(III)) complexes with -fluoroquinolones norfloxacin and ofloxacin. The treatment started 7 days after tumor grafting. We assayed the dynamics of apoptosis by flow-cytometry and the biochemical oxidative status parameters. The biological samples used were serum and whole-tumor tissues; the results were compared to the untreated control group. The results showed an increase of apoptosis from 14.79% to 59.72% 14.79% to 59.72% in tumor cells treated with the most active combination, ruthenium complex with norfloxacin. We also noted an increase of the oxidative status and ROS production during treatment. The newly-synthesized complexes are less toxic and their activity is based on the induction of oxidative stress. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. High antitumor activity of 5,7-dihalo-8-quinolinolato cerium complexes.

    PubMed

    Chen, Zhen-Feng; Wei, Jian-Hua; Liu, Yan-Cheng; Liu, Mei; Gu, Yun-Qiong; Huang, Ke-Bin; Wang, Meng; Liang, Hong

    2013-10-01

    Three cerium complexes: [Ce(ClQ)4] (1) (H-ClQ=5,7-dichloro-8-hydroxylquinoline), [Ce(ClIQ)4]·CH2Cl2·0.5H2O (2) (H-ClIQ=5-chloro-7-iodo-8-hydroxylquinoline) and [Ce2(BrQ)4(H-BrQ)(H2O)3Cl2]·1.5H2O (3) (H-BrQ=5,7-dibromo-8-hydroxylquinoline) were synthesized. The structures of 1 and 2 are mononuclear whereas 3 has a binuclear structure. Compared with the H-ClQ, H-ClIQ and H-BrQ, complexes 1-3 exhibited significantly higher cytotoxicity (IC50=0.09-5.23 μM) to SK-OV-3 and BEL-7404, 1 and 2 exhibited higher cytotoxicity to NCI-H460. Most the complexes and ligands exhibited higher cytotoxicity than cisplatin. Complexes 1-3 are much more sensitive to SK-OV-3 than to human normal liver cell HL-7702. Their antitumor activities were achieved through cell apoptosis and arrest at G0/G1-phase. Studies on the binding properties of 1-3 to DNA indicate that intercalation is the most probable binding mode.

  19. Anti-tumor and immunomodulatory activity of iron hepta-tungsten phosphate oxygen clusters complex.

    PubMed

    Zhang, Bisong; Qiu, Jianping; Wu, Changsheng; Li, Yunxia; Liu, Zhenxiang

    2015-12-01

    Polyoxometalates (POMs) have attracted a considerable attention due to their unique structural characteristics, physicochemical properties and biological activities. In this study, iron hepta-tungsten phosphate oxygen clusters complex Na12H[Fe(HPW7O28)2]·44H2O (IHTPO) was synthesized and evaluated for in vitro cytotoxic activities on human hepatoma HepG2, leukemia K562, lung carcinoma A549, and large cell lung cancer NCI-H460 cells, therapeutic efficacies on mice transplantable tumor, and immunomodulatory potentials on the immune response in tumor-bearing mice. IHTPO exhibited lower in vitro cytotoxic activities against four human tumor cell lines, with the IC50 values being higher than 62.5μM (ca. 300μg/ml). IHTPO, however, significantly inhibited the growth of S180 sarcoma transplanted in mice. It was further showed that IHTPO could not only significantly promote splenocytes proliferation, NK cell and CTL activity from splenocytes, but remarkably enhance serum antigen-specific IgG, IgG2a and IgG2b antibody levels in S180-bearing mice. IHTPO also significantly promoted Th1 cytokines IFN-γ and IL-2 production, and up-regulated the mRNA expression levels of IFN-γ, IL-2 and Th1 transcription factors T-bet and STAT-4 in splenocytes from the S180-bearing mice. These results suggested that IHTPO significantly inhibited the growth of mice transplantable tumor, and that its in vivo antitumor activity might be achieved by improving Th1 protective cell-mediated immunity. IHTPO could act as antitumor agent with immunomodulatory activity.

  20. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex can inhibit Ehrlich solid tumor growth in mice: A potential new antitumor drug.

    PubMed

    Saad, Entsar A; Hassanien, Mohamed M; El-Lban, Faten W

    2017-03-11

    The chief chemotherapeutic drug, cisplatin had common bad effects such as nephrotoxicity, ototoxicity and bone marrow depression. This led us to develop a new potential anticancer drug based on nickel metal ion that may be less toxic. Nickel(II) diacetyl monoxime-2-pyridyl hydrazone complex cytoprotective effect, superoxide dismutase (SOD)-like activity and anticancer activities were studied. In vitro, the complex showed SOD-like activity of 86.62%. It was capable to kill 90.2% of Ehrlich ascites carcinoma (EAC) cells and to protect 92.48% of human RBCs. In vivo, the complex lowered the tumor burden markedly in a concentration-dependent manner. Noticeably, solid tumor growth was suppressed; tumor volume and weight were reduced and mice life span was lengthened. The hematological indices were improved, catalase activity was re-elevated and malondialdehyde (MDA) level was reversed towards normal. Nucleic acids, cholesterol, triglycerides, liver enzymes, urea and creatinine contents were reduced to near normal ranges. Glutathione (GSH), SOD, albumin and total protein levels were increased. In conclusion, our results revealed that the complex has the ability to suppress Ehrlich solid tumor growth in mice with minimal side effects. This may possibly via its redox activity. Surprisingly, nickel complex antitumor activities were more potent than those of cisplatin. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Novel antitumor adamantane-azole gold(I) complexes as potential inhibitors of thioredoxin reductase.

    PubMed

    Garcia, Adriana; Machado, Rafael Carvalhaes; Grazul, Richard Michael; Lopes, Miriam Teresa Paz; Corrêa, Charlane Cimini; Dos Santos, Hélio F; de Almeida, Mauro Vieira; Silva, Heveline

    2016-04-01

    Gold complexes that could act as antitumor agents have attracted great attention. Heterocyclic compounds and their metal complexes display a broad spectrum of pharmacological properties. The present study reports the preparation and characterization of four novel gold(I) complexes containing tertiary phosphine and new ligands 5-adamantyl-1,3-thiazolidine-2-thione, 3-methyladamantane-1,3,4-oxadiazole-2-thione. Spectroscopic data suggest that gold is coordinated to the exocyclic sulfur atom in all cases, as confirmed by X-ray crystallographic data obtained for complex (1) and supported by quantum-mechanical calculations. The cytotoxicity of the compounds has been evaluated in comparison to cisplatin and auranofin in three different tumor cell lines, colon cancer (CT26WT), metastatic skin melanoma (B16F10), mammary adenocarcinoma (4T1) and kidney normal cell (BHK-21). The gold complexes were more active than their respective free ligands and able to inhibit the thioredoxin reductase (TrxR) enzyme, even in the presence of albumin. Molecular modeling studies were carried out to understand the interaction between the compounds and the TrxR enzyme, considered as a potential target for new compounds in cancer treatment. The docking results show that the adamantane ring is essential to stabilize the ligand-enzyme complex prior the formation of covalent bond with gold center. The structure of the new gold compounds was established on the basis of spectroscopic data, DFT calculations and X-ray diffraction. TrxR inhibition was evaluated and the results correlated with the assays in tumor cells, suggesting the TrxR as possible target for these compounds.

  2. Design, synthesis and biological evaluation of a novel series of glycosylated platinum(iv) complexes as antitumor agents.

    PubMed

    Wang, Qingpeng; Huang, Zhonglv; Ma, Jing; Lu, Xiaolin; Zhang, Li; Wang, Xin; George Wang, Peng

    2016-06-21

    A new series of glycosylated Pt(iv) complexes were designed, synthesized and evaluated for antitumor activities in vitro and in vivo. The incorporation of glycosyl groups to the Pt(iv) system has much influence on the antitumor abilities. Four lead compounds with activities comparable or even superior to cisplatin and oxaliplatin are screened out. These Pt(iv) complexes could be reduced to release Pt(ii) complexes and cause the death of tumour cells. The apoptosis-inducing properties of these compounds are similar to cisplatin. The accumulation of the glycosylated Pt(iv) complexes in cells and DNA is higher than cisplatin and oxaliplatin. The in vivo assay demonstrates that the tested compounds inhibit the growth of HepG2 tumors with low toxicity.

  3. Synthesis, Characterization, and in Vitro Antitumor Activity of Ruthenium(II) Polypyridyl Complexes Tethering EGFR-Inhibiting 4-Anilinoquinazolines.

    PubMed

    Du, Jun; Kang, Yan; Zhao, Yao; Zheng, Wei; Zhang, Yang; Lin, Yu; Wang, Zhaoying; Wang, Yuanyuan; Luo, Qun; Wu, Kui; Wang, Fuyi

    2016-05-02

    Ruthenium-based anticancer complexes are promising antitumor agents for their low system toxicity and versatile chemical structures. Epidermal growth factor receptor (EGFR) has been found to be overexpressed in a broad range of tumor cells and is regarded as a drug target in developing novel antitumor drugs. In this work, five ruthenium(II) polypyridyl complexes containing EGFR-inhibiting 4-anilinoquinazoline pharmacophores were synthesized and characterized. These complexes showed both high EGFR-inhibiting activity and strong DNA minor groove-binding activity. In vitro antiproliferation screening demonstrated that the prepared ruthenium complexes are highly cytotoxic against a series of cancer cell lines, in particular non-small-cell lung A549 and human epidermoid carcinoma A431. Fluorescence-activated cell sorting analysis and fluorescence microscopy revealed that the most active complex, K4, induced much more late-stage cell apoptosis and necrosis than gefitinib, the first EGFR-targeting antitumor drug in clinical use. These results indicate that the ruthenium(II) polypyridyl complexes bearing EGFR-inhibiting 4-anilinoquinazolines possess highly active dual-targeting anticancer activity and are promising in developing new anticancer agents.

  4. Structure of the human autophagy initiating kinase ULK1 in complex with potent inhibitors.

    PubMed

    Lazarus, Michael B; Novotny, Chris J; Shokat, Kevan M

    2015-01-16

    Autophagy is a conserved cellular process that involves the degradation of cellular components for energy maintenance and cytoplasmic quality control that has recently gained interest as a novel target for a variety of human diseases, including cancer. A prime candidate to determine the potential therapeutic benefit of targeting autophagy is the kinase ULK1, whose activation initiates autophagy. Here, we report the first structures of ULK1, in complex with multiple potent inhibitors. These structures show features unique to the enzyme and will provide a path for the rational design of selective compounds as cellular probes and potential therapeutics.

  5. Synthesis of antitumor azolato-bridged dinuclear platinum(ii) complexes with in vivo antitumor efficacy and unique in vitro cytotoxicity profiles.

    PubMed

    Komeda, Seiji; Takayama, Hiroshi; Suzuki, Toshihiro; Odani, Akira; Yamori, Takao; Chikuma, Masahiko

    2013-05-01

    We synthesised four tetrazolato-bridged dinuclear Pt(ii) complexes, [{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)](n+), where R is CH3 (1), C6H5 (2), CH2COOC2H5 (3), or CH2COO(-) (4) and n = 2 (1-3) or 1 (4). Their structures were characterised by (1)H, (13)C, and (195)Pt NMR spectroscopy, mass spectrometry, and elemental analysis, and the crystal structure of 1 was determined by X-ray crystallography. The cytotoxicities of the complexes to human non-small-cell lung cancer (NSCLC) cell lines sensitive and resistant to cisplatin were assayed. Complex 1 was more cytotoxic than cisplatin in both PC-9 and PC-14 NSCLC cell lines, and cross-resistance to 1 in the cisplatin-resistant cells was largely circumvented. Complex 3 was moderately cytotoxic, whereas 2 and 4 were only marginally cytotoxic. We also determined the growth inhibitory activities of 1 and 3, as well as prototype azolato-bridged complexes [{cis-Pt(NH3)2}2(μ-OH)(μ-pyrazolato)](2+) (AMPZ), [{cis-Pt(NH3)2}2(μ-OH)(μ-1,2,3-triazolato-N1,N2)](2+) (AMTA), [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N1,N2)](2+) (5-H-X), and [{cis-Pt(NH3)2}2(μ-OH)(μ-tetrazolato-N2,N3)](2+) (5-H-Y), against a panel of 39 human cancer cell lines (JFCR39). The average 50% growth inhibition concentrations of the complexes against the JFCR39 cell lines ranged from 0.933 to 23.4 μM. The cytotoxicity fingerprints of the complexes based on the JFCR39 cytotoxicity data were similar to one another but completely different from the fingerprints of clinical platinum-based anticancer drugs. Complex 3 exhibited marked antitumor efficiency when tested in vivo on xenografts of PANC-1 pancreatic cancer in nude mice. The high potency of 3 confirmed that the tetrazolato-bridged structure exhibits high in vivo antitumor efficacy.

  6. New transition metal ion complexes with benzimidazole-5-carboxylic acid hydrazides with antitumor activity.

    PubMed

    Galal, Shadia A; Hegab, Khaled H; Kassab, Ahmed S; Rodriguez, Mireya L; Kerwin, Sean M; el-Khamry, Abdel-Mo'men A; el-Diwani, Hoda I

    2009-04-01

    Metal complexes of 2-methyl-1H-benzimidazole-5-carboxylic acid hydrazide (4a; L(1)) and its Schiff base 2-methyl-N-(propan-2-ylidene)-1H-benzimidazole-5-carbohydrazide (5a; L(2)) with transition metal ions e.g., copper, silver, nickel, iron and manganese were prepared. The complexes formed were 1:1 or 1:2 M:L complexes and have the structural formulae [Cu(L(1))Cl(H(2)O)]Cl x 3 H(2)O (6), [Ag(L(1))NO(3)(H(2)O)] (7), [Ni(L(1))Cl(2)(H(2)O)(2)] x H(2)O (8), [Fe(L(1))Cl(3)(H(2)O)] x 3 H(2)O (9) and [Mn(L(1))(2)Cl(H(2)O)]Cl x 3 H(2)O (10) for ligand L(1), and [Cu(L(2))Cl(2)(H(2)O)(2)] x H(2)O (11), [Ag(L(2))(2)]NO(3) x H(2)O (12), [Ni(L(2))(2)Cl(2)] x 5 H(2)O (13), [Fe(L(2))(2)Cl(2)]Cl x 2 H(2)O (14) and [Mn(L(2))Cl(2)(H(2)O)(2)] x H(2)O (15) for ligand L(2). The antitumor activity of the synthesized compounds has been studied. The silver complex 7 was found to display cytotoxicity (IC(50)=2 microM) against both human lung cancer cell line A549 and human breast cancer cell line MCF-7.

  7. Antitumor activity of a Trans-thiosemicarbazone schiff base palladium (II) complex on human gastric adenocarcinoma cells.

    PubMed

    Zhang, Bingchang; Luo, Haiqing; Xu, Qinjuan; Lin, Lirong; Zhang, Bing

    2017-02-21

    The development of transition-metal-based antitumor drug candidates increases the metallopharmaceuticals study dramatically. Two trans-thiosemicarbazone-based, Schiff base palladium (Pd) (II) complexes, DMABTSPd (TSPd) and DMABPTSPd (PTSPd), were prepared and characterized as described in our previous study. Here, we investigated whether the two complexes have antitumor effect on human gastric adenocarcinoma cell lines, BGC-823 and SGC-7901, compared with normal human gastric mucosal epithelial cell line, Ges-1. The results show that the Pd complex with the bare amino group (DMABTSPd(TSPd)) can inhibit cell viabilities and induce apoptosis in human gastric carcinoma cells, rather than the Pd complex without the bare amino group (DMABPTSPd (PTSPd)). This occurs via a mitochondrial-related pathway by down-regulating the level of Bcl-2 expression and up-regulating the level of Bid expression. Meanwhile, DMABTSPd (TSPd) suppressed tumor growth via a mitochondrial-related pathway in a nude mouse tumor xenograft model derived from BGC-823 cells. These findings demonstrate that DMABTSPd (TSPd) is worthy of further structural optimization and representing a promising Pd complex for the development of a new antitumor therapeutic agent.

  8. Copper (II) complexes possessing alkyl-substituted polypyridyl ligands: Structural characterization and in vitro antitumor activity.

    PubMed

    Angel, Noah R; Khatib, Raneen M; Jenkins, Julia; Smith, Michelle; Rubalcava, Justin M; Le, Brian Khoa; Lussier, Daniel; Chen, Zhuo Georgia; Tham, Fook S; Wilson, Emma H; Eichler, Jack F

    2017-01-01

    In an effort to find alternatives to the antitumor drug cisplatin, a series of copper (II) complexes possessing alkyl-substituted polypyridyl ligands have been synthesized. Eight new complexes are reported herein: μ-dichloro-bis{2,9-di-sec-butyl-1,10-phenanthrolinechlorocopper(II)} {[((di-sec-butyl)phen)ClCu(μ-Cl)2CuCl((di-sec-butyl)phen)]}(1), 2-sec-butyl-1,10-phenanthrolinedichlorocopper(II) {([mono-sec-butyl)phen) CuCl2} (2), 2,9-di-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[(di-n-butyl)phen) CuCl2}(3), 2-n-butyl-1,10-phenanthrolinedichlorocopper(II) {[(mono-n-butyl)phen) CuCl2} (4), 2,9-di-methyl-1,10-phenanthrolineaquadichlorocopper(II) {[(di-methyl)phen) Cu(H2O)Cl2}(5), μ-dichloro-bis{6-sec-butyl-2,2'-bipyridinedichlorocopper(II)} {((mono-sec-butyl)bipy) ClCu(μ-Cl)2CuCl((mono-sec-butyl)bipy)} (6), 6,6'-di-methyl-2,2'-bipyridinedichlorocopper(II) {(6,6'-di-methyl)bipy) CuCl2} (7), and 4,4'-dimethyl-2,2'-bipyridinedichlorocopper(II) {(4,4'-di-methyl)bipy) CuCl2} (8). These complexes have been characterized via elemental analysis, UV-vis spectroscopy, and mass spectrometry. Single crystal X-ray diffraction experiments revealed the complexes synthesized with the (di-sec-butyl)phen ligand (1) and (mono-sec-butyl)bipy ligand (6) crystallized as dimers in which two copper(II) centers are bridged by two chloride ligands. Conversely, complexes 2, 7, and 8 were isolated as monomeric species possessing distorted tetrahedral geometries, and the [((di-methyl)phen)Cu(H2O)Cl2] (5) complex was isolated as a distorted square pyramidal monomer possessing a coordinating aqua ligand. Compounds 1-8 were evaluated for their in vitro antitumor efficacy. Compounds 1, 5, and 7 in particular were found to exhibit remarkable activity against human derived lung cancer cells, yet this class of copper(II) compounds had minimal cytotoxic effect on non-cancerous cells. In vitro control experiments indicate the activity of the copper(II) complexes most likely does not arise from the

  9. Studies on the mechanism of action of antitumor bis(aminophenolate) ruthenium(III) complexes.

    PubMed

    Dömötör, Orsolya; de Almeida, Rodrigo F M; Côrte-Real, Leonor; Matos, Cristina P; Marques, Fernanda; Matos, António; Real, Carla; Kiss, Tamás; Enyedy, Éva Anna; Helena Garcia, M; Tomaz, Ana Isabel

    2017-03-01

    Two recently published Ru(III) complexes bearing (N2O2) tetradentate bis(aminophenolate) ligands, formulated as [Ru(III)(salan)(PPh3)Cl] (salan is the tetradentate ligand 6,6'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(3-methoxyphenol) in complex 1, or 2,2'-(1S,2S)-cyclohexane-1,2-diylbis(azanediyl)bis(methylene)bis(4-methoxyphenol) in complex 2; PPh3 is triphenylphosphane) and found very active against ovarian and breast adenocarcinoma human cells were studied to outline their antitumor mode of action. The human cisplatin-sensitive ovarian adenocarcinoma line A2780 was used herein as the cell model. At a 24h challenge (similarly as found before for 72h) both complexes are active, their cytotoxicity being comparable to that of cisplatin in the same conditions. As a possible target in the cell for their action, the interaction of 1 and 2 with DNA was assessed through displacement of well-established DNA fluorescent probes (ethidium bromide, EB, and 4',6-diamidino-2-phenylindole, DAPI) through steady-state and time-resolved fluorescence spectroscopy. The whole emission spectra were analyzed globally for the binary DNA-probe and ternary DNA-probe-Ru(III) complex systems. Both Ru(III) complexes can displace EB and bind to DNA with similar and moderate strong affinity with conditional stability constants of logK'=(5.05±0.01) for 1 and logK'=(4.79±0.01) for 2. The analysis of time-domain fluorescence intensity decays confirmed both qualitatively and quantitatively the model used to describe the binding and competition processes. Cell studies indicated that apoptosis is the major mechanism of cell death for both complexes, with 2 (the more active complex) promoting that process more efficiently than 1. Transmission electron micrographs revealed clear alterations on intracellular organization consistent with the induction of programmed cell death processes.

  10. Mirror-image organometallic osmium arene iminopyridine halido complexes exhibit similar potent anticancer activity.

    PubMed

    Fu, Ying; Soni, Rina; Romero, María J; Pizarro, Ana M; Salassa, Luca; Clarkson, Guy J; Hearn, Jessica M; Habtemariam, Abraha; Wills, Martin; Sadler, Peter J

    2013-11-04

    Four chiral Os(II) arene anticancer complexes have been isolated by fractional crystallization. The two iodido complexes, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 2, (S)-ImpyMe: N-(2-pyridylmethylene)-(S)-1-phenylethylamine) and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)I]PF6 (complex 4, (R)-ImpyMe: N-(2-pyridylmethylene)-(R)-1-phenylethylamine), showed higher anticancer activity (lower IC50 values) towards A2780 human ovarian cancer cells than cisplatin and were more active than the two chlorido derivatives, (S(Os),S(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 1, and (R(Os),R(C))-[Os(η(6)-p-cym)(ImpyMe)Cl]PF6, 3. The two iodido complexes were evaluated in the National Cancer Institute 60-cell-line screen, by using the COMPARE algorithm. This showed that the two potent iodido complexes, 2 (NSC: D-758116/1) and 4 (NSC: D-758118/1), share surprisingly similar cancer cell selectivity patterns with the anti-microtubule drug, vinblastine sulfate. However, no direct effect on tubulin polymerization was found for 2 and 4, an observation that appears to indicate a novel mechanism of action. In addition, complexes 2 and 4 demonstrated potential as transfer-hydrogenation catalysts for imine reduction.

  11. Polyelectrolyte complex containing silver nanoparticles with antitumor property on Caco-2 colon cancer cells.

    PubMed

    Martins, Alessandro F; Follmann, Heveline D M; Monteiro, Johny P; Bonafé, Elton G; Nocchi, Samara; Silva, Cleiser T P; Nakamura, Celso V; Girotto, Emerson M; Rubira, Adley F; Muniz, Edvani C

    2015-08-01

    Polyelectrolyte complex (beads) based on N,N,N-trimethyl chitosan/alginate was successful obtained and silver nanoparticles (AgNPs) were loaded within beads. In vitro cytotoxicity assays using beads/silver nanoparticles (beads/AgNPs) provided results, indicating that this material significantly inhibited the growth of colon cancer cells (Caco-2). In vitro release studies showed that the beads stabilized AgNPs and repressed Ag(0) oxidation under gastric conditions (pH 2.0). On the other hand, at physiological condition (pH 7.4) the beads/AgNPs released 3.3 μg of Ag(+) per each beads milligram. These studies showed that the concentration of Ag(+) released (3.3 μg) was cytotoxic for the Caco-2 cells and was not cytotoxic on healthy VERO cells. This result opens new perspectives for the manufacture of biomaterials based on beads/AgNPs with anti-tumor properties. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents

    PubMed Central

    Dong, Yizhou; Nakagawa-Goto, Kyoko; Lai, Chin-Yu; Kim, Yoon; Morris-Natschke, Susan L.; Lee, Eva Y.-H. P.; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2010-01-01

    In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6–12 and 14–24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED50 1.1–4.3 µg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED50 0.73 µg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED50 1.7 and 0.85 µg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1f11/f11p53f5&6/f5&6Crec mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands. PMID:21147529

  13. Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents.

    PubMed

    Dong, Yizhou; Nakagawa-Goto, Kyoko; Lai, Chin-Yu; Kim, Yoon; Morris-Natschke, Susan L; Lee, Eva Y-H P; Bastow, Kenneth F; Lee, Kuo-Hsiung

    2011-01-01

    In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6-12 and 14-24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED(50) 1.1-4.3 μg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED(50) 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED(50) 1.7 and 0.85 μg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1(f11/f11)p53(f5&6/f5&6)Cre(c) mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands. Copyright © 2010 Elsevier Ltd. All rights reserved.

  14. Potent inhibition of protein tyrosine phosphatases by copper complexes with multi-benzimidazole derivatives.

    PubMed

    Li, Ying; Lu, Liping; Zhu, Miaoli; Wang, Qingming; Yuan, Caixia; Xing, Shu; Fu, Xueqi; Mei, Yuhua

    2011-12-01

    A series of copper complexes with multi-benzimidazole derivatives, including mono- and di-nuclear, were synthesized and characterized by Fourier transform IR spectroscopy, UV-Vis spectroscopy, elemental analysis, electrospray ionization mass spectrometry. The speciation of Cu/NTB in aqueous solution was investigated by potentiometric pH titrations. Their inhibitory effects against human protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2), srchomology phosphatase 1 (SHP-1) and srchomology phosphatase 2 (SHP-2) were evaluated in vitro. The five copper complexes exhibit potent inhibition against PTP1B, TCPTP and PTP-MEG2 with almost same inhibitory effects with IC(50) at submicro molar level and about tenfold weaker inhibition versus SHP-1, but almost no inhibition against SHP-2. Kinetic analysis indicates that they are reversible competitive inhibitors of PTP1B. Fluorescence study on the interaction between PTP1B and complex 2 or 4 suggests that the complexes bind to PTP1B with the formation of a 1:1 complex. The binding constant are about 1.14 × 10(6) and 1.87 × 10(6) M(-1) at 310 K for 2 and 4, respectively.

  15. Development of DS-5573a: A novel afucosylated mAb directed at B7-H3 with potent antitumor activity.

    PubMed

    Nagase-Zembutsu, Akiko; Hirotani, Kenji; Yamato, Michiko; Yamaguchi, Junko; Takata, Takehiko; Yoshida, Makoto; Fukuchi, Keisuke; Yazawa, Mitsuhiro; Takahashi, Shu; Agatsuma, Toshinori

    2016-05-01

    B7-H3 is highly overexpressed in a variety of human clinical tumors, and its expression is significantly associated with poor outcomes. In our study, we aimed to develop new antitumor mAbs by employing cancer cell immunization, and succeeded in generating a mouse anti-human B7-H3 antibody (M30) that shows antitumor activity. M30 was humanized (Hu-M30), and an afucosylated Hu-M30 (DS-5573a) was also generated. To assess the potency of DS-5573a as a therapeutic mAb, we characterized this mAb and evaluated its antitumor activity in vitro and in vivo. Flow cytometry analysis showed that B7-H3 proteins were expressed on various types of cancer cell lines broadly, and DS-5573a binds to IgC1 and IgC2 domains of human B7-H3. Antibody-dependent cellular cytotoxicity activity of DS-5573a was drastically enhanced against medium to high B7-H3-expressing cancer cell lines MDA-MB-231 and NCI-H322. DS-5573a also induced high antibody-dependent cellular cytotoxicity activity against low B7-H3-expressing cancer cell line COLO205, whereas Hu-M30 induced little activity against it. In addition, DS-5573a was found to be a novel anti-B7-H3 antibody which showed antibody-dependent cellular phagocytosis activity. Furthermore, DS-5573a showed dose-dependent and significant antitumor efficacy (0.03-3 mg/kg) in MDA-MB-231-bearing SCID mice (which have functional natural killer cells and macrophages), but little antitumor efficacy in NOG mice (which lack natural killer cells and have reduced macrophage function). These results suggest that antitumor activity of DS-5573a is mediated by effector cells, and this mAb could be a promising antitumor therapy for patients with a wide range of B7-H3-expressing tumors. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  16. Redox cycling of a copper complex with benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone contributes to its enhanced antitumor activity, but no change in the mechanism of action occurs after chelation.

    PubMed

    Yang, Yinli; Li, Cuiping; Fu, Yun; Liu, Youxun; Zhang, Yu; Zhang, Yanfang; Zhou, Pingxin; Yuan, Yanbin; Zhou, Sufeng; Li, Shaoshan; Li, Changzheng

    2016-03-01

    Many anticancer drugs used in the clinical have potent metal chelating ability. The formed metal complex(es) may exhibit improved (or antagonistic) antitumor activity. However, the underlying mechanism has received limited attention. Therefore, investigation of the mechanism involved in the change upon chelation is required to extend our understanding of the effects of various drugs. In the present study, the proliferation inhibition effect of benzaldehyde nitrogen mustard-2-pyridine carboxylic acid hydrazone (BNMPH) and its copper complex on tumor cell lines was investigated. The copper chelate exhibited almost a 10-fold increase in antitumor activity (with IC50 <5 µM). The results showed that both BNMPH and its copper complex induced reactive oxygen species (ROS) generation, and caused upregulation of caspase 8 and Bax as well as the downregulation of Bcl-2, indicating that apoptosis was involved in the cytotoxic effects. DNA fragmentation noted in the comet assay further supported ROS involvement. The present study indicated that BNMPH and its copper complex effectively induced S phase arrest and the cell cycle arrest was associated with the downregulation of cyclin D1. The formation of acidic vesicular organelles (AVOs) and an increase in cleaved LC3-II demonstrated that autophagy occurred in the HepG2 cells treated with the agents. Taken together, BNMPH and its copper complex exhibited proliferation inhibition via apoptosis, cell cycle arrest and autophagy, which was dependent on ROS. The enhanced antitumor activity of the copper complex was due to its redox-cycling ability, but the mechanism was not altered compared to BNMPH. Our findings may significantly contribute to the understanding of the anti-proliferative effect of BNMPH and its copper complex.

  17. Tumor-localized ligation of CD3 and CD28 with systemic regulatory T-cell depletion induces potent innate and adaptive antitumor responses.

    PubMed

    Lee, Chien-Hsin; Chiang, Yi-Hsuan; Chang, Shih-En; Chong, Chin-Liew; Cheng, Bing-Mae; Roffler, Steve R

    2009-04-15

    Tumor-localized activation of immune cells by membrane-tethered anti-CD3 antibodies (CD3L) is under investigation to treat poorly immunogenic tumors. Here we sought to elucidate the mechanism of antitumor immunity elicited by CD3L. CD3L and CD86 were expressed on poorly immunogenic B16 melanoma cells (B16/3L86 cells) and the effect of various lymphocytes, including CD4(+) and CD8(+) T cells, natural killer T (NKT) cells, and regulatory T cells, on antitumor activity was investigated. B16/3L86 cells activated naïve T cells; suppressed tumor growth in subcutaneous, peritoneal, and metastasis models; and protected mice from rechallenge with B16 melanoma cells. However, in vivo antitumor activity against primary B16/3L86 tumors unexpectedly depended on NKT cells rather than CD4(+) or CD8(+) T cells. Treatment of mice with low-dose cyclophosphamide or anti-CD25 antibody to deplete regulatory T cells unmasked latent T-cell antitumor activity; the number of activated CD8(+) T cells in tumors increased and B16/3L86 tumors were completely rejected in a CD8(+) and CD4(+) T-cell-dependent fashion. Furthermore, fibroblasts expressing CD3L and CD86 suppressed the growth of neighboring B16 cancer cells in vivo, and direct intratumoral injection of adenoviral vectors expressing CD3L and CD86 or CD3L and a membrane-tethered anti-CD28 antibody significantly suppressed the growth of subcutaneous tumors. Tumor-located ligation of CD3 and CD28 can activate both innate (NKT cells) and adaptive (CD4(+) and CD8(+) T cells) responses to create a tumor-destructive environment to control tumor growth, but modulation of regulatory T cells is necessary to unmask local adaptive antitumor responses.

  18. Synthesis, crystal structures and antitumor activities of copper(II) complexes with a 2-acetylpyrazine isonicotinoyl hydrazone ligand

    NASA Astrophysics Data System (ADS)

    Xu, Jun; Zhou, Tao; Xu, Zhou-Qing; Gu, Xin-Nan; Wu, Wei-Na; Chen, Hong; Wang, Yuan; Jia, Lei; Zhu, Tao-Feng; Chen, Ru-Hua

    2017-01-01

    Five complexes, [Cu(L)2]·4.5H2O (1), [Cu(HL)2](NO3)2·CH3OH (2) {[Cu2(L)2(NO3)(H2O)2]·(NO3)}n (3), [Cu2(HL)2(SO4)2]·2CH3OH (4) and [Cu4(L)4Cl4]·5H2O (5) based on HL (where HL = 2-acetylpyrazine isonicotinoyl hydrazone) have been synthesized and characterized by X-ray diffraction analyses. The counter anion and organic base during the synthesis procedure influence the structures of the complexes efficiently, which generate five complexes as mono-, bi-, tetra-nuclear and one-dimensional structures. The antitumor activities of the complexes 1-5 (except for complex 3 with the poor solubility) against the Patu8988 human pancreatic cancer, ECA109 human esophagus cancer and SGC7901 human gastric cancer cell lines are screened by MTT assay. The results indicate that the chelation of Cu(II) with the ligand is responsible for the observed high cytotoxicity of the copper(II) complexes and the 1:2 copper species 1 and 2 demonstrate lower antitumor activities than that of the 1:1 copper species 4 and 5. In addition, the in vitro apoptosis inducing activity of the copper(II) complex 5 against SGC7901 cell line is determined. And the results show that the complex can bring about apoptosis of the cancerous cells in vitro.

  19. Antitumor activity of a rhenium (I)-diselenoether complex in experimental models of human breast cancer.

    PubMed

    Collery, Philippe; Mohsen, Ahmed; Kermagoret, Anthony; Corre, Samantha; Bastian, Gérard; Tomas, Alain; Wei, Ming; Santoni, François; Guerra, Nadia; Desmaële, Didier; d'Angelo, Jean

    2015-08-01

    Rhenium (I)-diselenother (Re-diselenoether) is a water soluble metal-based compound, combining one atom of rhenium and two atoms of selenium. This compound has been reported to exhibit marked activities against several solid tumor cell lines. We now disclose an improved synthesis of this complex. The Re-diselenoether showed a potent inhibitory effect on MDA-MB231 cell division in vitro, which lasted when the complex was no longer present in the culture. Re-diselenoether induced a remarkable reduction of the volume of the primitive breast tumors and of the pulmonary metastases without clinical signs of toxicity, in mice-bearing a MDA-MB231 Luc+ tumor, orthotopically transplanted, after a daily oral administration at the dose of 10 mg/kg/d. Interestingly, an antagonism was observed when cisplatin was administered as a single i.p. injection 1 week after the end of the Re-diselenoether administration. In an effort to gain insight of the mechanisms of action of Re-diselenoether complex, interaction with 9-methylguanine as a nucleic acid base model was studied. We have shown that Re-diselenoether gave both mono- and bis-guanine Re adducts, the species assumed to be responsible for the DNA intrastrand lesions.

  20. Potent Adjuvant Activity of Cationic Liposome-DNA Complexes for Genital Herpes Vaccines▿

    PubMed Central

    Bernstein, David I.; Cardin, Rhonda D.; Bravo, Fernando J.; Strasser, Jane E.; Farley, Nicholas; Chalk, Claudia; Lay, Marla; Fairman, Jeff

    2009-01-01

    Development of a herpes simplex virus (HSV) vaccine is a priority because these infections are common. It appears that potent adjuvants will be required to augment the immune response to subunit HSV vaccines. Therefore, we evaluated cationic liposome-DNA complexes (CLDC) as an adjuvant in a mouse model of genital herpes. Using a whole-virus vaccine (HVAC), we showed that the addition of CLDC improved antibody responses compared to vaccine alone. Most important, CLDC increased survival, reduced symptoms, and decreased vaginal virus replication compared to vaccine alone or vaccine administered with monophosphoryl lipid A (MPL) plus trehalose dicorynomycolate (TDM) following intravaginal challenge of mice. When CLDC was added to an HSV gD2 vaccine, it increased the amount of gamma interferon that was produced from splenocytes stimulated with gD2 compared to the amount produced with gD2 alone or with MPL-alum. The addition of CLDC to the gD2 vaccine also improved the outcome following vaginal HSV type 2 challenge compared to vaccine alone and was equivalent to vaccination with an MPL-alum adjuvant. CLDC appears to be a potent adjuvant for HSV vaccines and should be evaluated further. PMID:19279167

  1. The Elastin Receptor Complex: A Unique Matricellular Receptor with High Anti-tumoral Potential

    PubMed Central

    Scandolera, Amandine; Odoul, Ludivine; Salesse, Stéphanie; Guillot, Alexandre; Blaise, Sébastien; Kawecki, Charlotte; Maurice, Pascal; El Btaouri, Hassan; Romier-Crouzet, Béatrice; Martiny, Laurent; Debelle, Laurent; Duca, Laurent

    2016-01-01

    Elastin, one of the longest-lived proteins, confers elasticity to tissues with high mechanical constraints. During aging or pathophysiological conditions such as cancer progression, this insoluble polymer of tropoelastin undergoes an important degradation leading to the release of bioactive elastin-derived peptides (EDPs), named elastokines. EDP exhibit several biological functions able to drive tumor development by regulating cell proliferation, invasion, survival, angiogenesis, and matrix metalloproteinase expression in various tumor and stromal cells. Although, several receptors have been suggested to bind elastokines (αvβ3 and αvβ5 integrins, galectin-3), their main receptor remains the elastin receptor complex (ERC). This heterotrimer comprises a peripheral subunit, named elastin binding protein (EBP), associated to the protective protein/cathepsin A (PPCA). The latter is bound to a membrane-associated protein called Neuraminidase-1 (Neu-1). The pro-tumoral effects of elastokines have been linked to their binding onto EBP. Additionally, Neu-1 sialidase activity is essential for their signal transduction. Consistently, EDP-EBP interaction and Neu-1 activity emerge as original anti-tumoral targets. Interestingly, besides its direct involvement in cancer progression, the ERC also regulates diabetes outcome and thrombosis, an important risk factor for cancer development and a vascular process highly increased in patients suffering from cancer. In this review, we will describe ERC and elastokines involvement in cancer development suggesting that this unique receptor would be a promising therapeutic target. We will also discuss the pharmacological concepts aiming at blocking its pro-tumoral activities. Finally, its emerging role in cancer-associated complications and pathologies such as diabetes and thrombotic events will be also considered. PMID:26973522

  2. Anti-tumor activity of fenretinide complexed with human serum albumin in lung cancer xenograft mouse model.

    PubMed

    Durante, Sandra; Orienti, Isabella; Teti, Gabriella; Salvatore, Viviana; Focaroli, Stefano; Tesei, Anna; Pignatta, Sara; Falconi, Mirella

    2014-07-15

    Sufficient knowledge regarding cellular and molecular basis of lung cancer progression and metastasis would help in the development of novel and effective strategies for the treatment of lung cancer. 4HPR is a synthetic retinoid with potential anti-tumor activity but is still limited because of its poor bioavailability. The use of albumin as a complexing agent for a hydrophobic drug is expected to improve the water solubility and consequently their bioavailability.This study investigated the antitumor activity of a novel complex between albumin and 4-HPR in a mouse model of human lung cancer and focuses on role and mechanism of Cav-1 mainly involved in regulating cancer and ACSVL3 mainly connected with tumor growth. Their expressions were assayed by immunohistochemistry and qRT-PCR, to demonstrate the reduction of the tumor growth following the drug treatment. Our results showed a high antitumor activity of 4HPR-HSA by reduction of the volume of tumor mass and the presence of a high level of apoptotic cell by TUNEL assay. The downregulation of Cav-1 and ACSVL3 suggested a reduction of tumor growth. In conclusion, we demonstrated the great potential of 4HPR-HSA in the treatment of lung cancer. More data about the mechanism of drug delivery the 4HPR-HSA are necessary.

  3. The antitumor activity of a red alga polysaccharide complexes carrying 5-fluorouracil.

    PubMed

    Wang, Xiaomei; Zhang, Zhongshan

    2014-08-01

    Porphyran is a sulfated galactan isolated from red algae Porphyra haitanensis, and have been reported to have many kinds of biological activities such as antitumor activity. In order to provide a water-soluble macromolecule prodrug of 5-Fu showing slow release of 5-Fu and reducing side-effect, we carried out fixation of 5-Fu to porphyran at 6-position. In this study, the antitumor and immunomodulation activities of low MW porphyran carrying 5-Fu on transplanted S180 tumor mice were studied. Weight of immune organ, proliferation ratio of lymphocyte concentration of TNF-α and NO from the transplanted S180 tumor mice were also determined. Results indicated that the conjugate could enhance antitumor activity of 5-Fu and improve immunocompetence damaged by 5-Fu.

  4. Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells.

    PubMed

    García-Vilas, Javier A; Quesada, Ana R; Medina, Miguel A

    2015-01-26

    Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis.

  5. Design, synthesis, and structure-activity relationships of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Chen, Dong; Lu, Kuan; Wang, Lihui; Han, Xiaoqi; Zhao, Yanfang; Gong, Ping

    2014-10-30

    A series of novel benzothiazole derivatives bearing the ortho-hydroxy N-carbamoylhydrazone moiety were designed and synthesized and their cytotoxic activities against five cancer cell lines (NCI-H226, SK-N-SH, HT29, MKN45, and MDA-MB-231) were screened in vitro. Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 15g (procaspase-3 EC50 = 1.42 μM) and 16b (procaspase-3 EC50 = 0.25 μM) exhibited excellent antitumor activity with IC50 values ranging from 0.14 μM to 0.98 μM against all cancer cell lines, which were 1.8-8.7 times more active than the first procaspase activating compound (PAC-1) (procaspase-3 EC50 = 4.08 μM). The structure-activity relationship (SAR) analyses indicated that the introduction of a lipophilic group (a benzyloxy or heteroaryloxy group) at the 4-position of the 2-hydroxy phenyl ring was beneficial to antitumor activity, and the presence of substituents containing nitrogen that are positively charged at physiological pH could also improve antitumor activity. It was also confirmed that the steric effect of the 4-position substituent of the benzyloxy group had a significant influence on cytotoxic activity.

  6. Damnacanthal, a noni anthraquinone, inhibits c-Met and is a potent antitumor compound against Hep G2 human hepatocellular carcinoma cells

    PubMed Central

    García-Vilas, Javier A.; Quesada, Ana R.; Medina, Miguel A.

    2015-01-01

    Damnacanthal, an anthraquinone present in noni plants, targets several tyrosine kinases and has antitumoral effects. This study aims at getting additional insight on the potential of damnacanthal as a natural antitumor compound. The direct effect of damnacanthal on c-Met was tested by in vitro activity assays. Additionally, Western blots of c-Met phosphorylation in human hepatocellular carcinoma Hep G2 cells were performed. The antitumor effects of damnacanthal were tested by using cell growth, soft agar clonogenic, migration and invasion assays. Their mechanisms were studied by Western blot, and cell cycle, apoptosis and zymographic assays. Results show that damnacanthal targets c-Met both in vitro and in cell culture. On the other hand, damnacanthal also decreases the phosphorylation levels of Akt and targets matrix metalloproteinase-2 secretion in Hep G2 cells. These molecular effects are accompanied by inhibition of the growth and clonogenic potential of Hep G2 hepatocellular carcinoma cells, as well as induction of Hep G2 apoptosis. Since c-Met has been identified as a new potential therapeutical target for personalized treatment of hepatocellular carcinoma, damnacanthal and noni extract supplements containing it could be potentially interesting for the treatment and/or chemoprevention of hepatocellular carcinoma through its inhibitory effects on the HGF/c-Met axis. PMID:25620570

  7. Breast milk immune complexes are potent inducers of oral tolerance in neonates and prevent asthma development.

    PubMed

    Mosconi, E; Rekima, A; Seitz-Polski, B; Kanda, A; Fleury, S; Tissandie, E; Monteiro, R; Dombrowicz, D D; Julia, V; Glaichenhaus, N; Verhasselt, V

    2010-09-01

    Allergic asthma is a chronic lung disease resulting from an inappropriate T helper (Th)-2 response to environmental antigens. Early tolerance induction is an attractive approach for primary prevention of asthma. Here, we found that breastfeeding by antigen-sensitized mothers exposed to antigen aerosols during lactation induced a robust and long-lasting antigen-specific protection from asthma. Protection was more profound and persistent than the one induced by antigen-exposed non-sensitized mothers. Milk from antigen-exposed sensitized mothers contained antigen-immunoglobulin (Ig) G immune complexes that were transferred to the newborn through the neonatal Fc receptor resulting in the induction of antigen-specific FoxP3(+) CD25(+) regulatory T cells. The induction of oral tolerance by milk immune complexes did not require the presence of transforming growth factor-beta in milk in contrast to tolerance induced by milk-borne free antigen. Furthermore, neither the presence of IgA in milk nor the expression of the inhibitory FcgammaRIIb in the newborn was required for tolerance induction. This study provides new insights on the mechanisms of tolerance induction in neonates and highlights that IgG immune complexes found in breast milk are potent inducers of oral tolerance. These observations may pave the way for the identification of key factors for primary prevention of immune-mediated diseases such as asthma.

  8. Evaluation of antitumor, immunomodulatory and free radical scavenging effects of a new herbal prescription seaweed complex preparation

    NASA Astrophysics Data System (ADS)

    Liu, Xin; Shao, Changlun; Kong, Wenwen; Fang, Yuchun; Wang, Changyun

    2013-09-01

    Seaweed Complex Preparation (SCP) is a clinical traditional Chinese medicine preparation which is composed of seven traditional Chinese herbs, and it has been used for treatment of lung cancer, liver cancer and digestive cancer. However, little information is available about the pharmacodynamic basis. The antitumor, immunomodulatory and free radical scavenging effects of SCP were evaluated in this study. Transplanted tumor in vivo method was used to determine the antitumor effect. The effects on splenocyte proliferation and phagocytosis of macrophages in tumor-bearing mice were measured by the MTT method and the phagocytizing cock red blood cell (CRBC) method respectively. The scavenging activities of SCP on DPPH and hydroxyl radicals in vitro were investigated. It was found that the medium-dose and high-dose of SCP could significantly inhibit the growth of transplanted hepatic tumor of murine hepatocarcinoma cell line H22, and promote proliferation of splenocytes and phagocytosis of macrophages. SCP possessed noticeable scavenging activities on DPPH and hydroxyl radicals. The antitumor effects of SCP might be achieved by improving immune system and scavenging free radicals, which is in accordance with the viewpoint of traditional Chinese medicine in promoting the body resistance and eliminating pathogenic factors for cancer treatment.

  9. Antitumor effects of a tetradentate amido-carboxylate ligands and corresponding square-planar palladium(II) complexes toward some cancer cells. Crystal structure, DFT modeling and ligand to DNA probe docking simulation.

    PubMed

    Matović, Zoran D; Mrkalić, Emina; Bogdanović, Gordana; Kojić, Vesna; Meetsma, Auke; Jelić, Ratomir

    2013-04-01

    Novel square-planar palladium(II) complexes with O-N-N-O-type ligands H4mda (H4mda=malamido-N,N'-diacetic acid) and H4obp (H4obp=oxamido-N,N'-di-3-propionic acid) were prepared and characterized. The ligands coordinate to the palladium(II) ion via two pairs of deprotonated ligating atoms with square chelation. A four coordinate, square-planar geometry was verified crystallographicaly for the K2[Pd(mda)]·H2O complex. The binary and ternary systems of Pd(II) ion with H4mda or H4obp (L) as primary ligands and guanosine (A) as secondary ligand were studied in aqueous solutions in 0.1 M NaCl ionic medium at 25 °C by potentiometric titrations. In addition, calculations based on density functional methods (DFT) were carried out. A natural bonding orbital analysis indicated that the Pd-N bonds are three-centric in nature and mainly governed by charge transfer via a strong delocalization of the oxygen lone pair with "p" character into the bonding Pd-N orbital. Mononuclear palladium(II) complexes together with amido acid N,O-containing ligands were tested against several tumor cells and reveal significant antitumor activity and lower resistance of tumor cells in vitro than cisplatin. In this paper, interactions of palladium complexes with DNA are discussed in order to provide guidance and determine structure and antitumor activity relationships for continuing studies of these systems. Docking simulation on DNA dodecamer or 29-mer (Lippard solved crystal structures), suggests several favorable interactions with the hydrogen pocket/binding site for the incoming ligands. These results support amidoacids/Pd complexes as novel antitumor drugs and suggest that their potent cell life inhibition may contribute to its anti-cancer efficacy.

  10. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.

    PubMed

    Freeman, Michael M; Seaman, Michael S; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D; Chen, Bing

    2010-12-08

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  11. Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody

    PubMed Central

    Freeman, Michael M.; Seaman, Michael S.; Rits-Volloch, Sophia; Hong, Xinguo; Kao, Chia-Ying; Ho, David D.; Chen, Bing

    2010-01-01

    Summary Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry. PMID:21134642

  12. Crystal Structure of HIV-1 Primary Receptor CD4 i Complex with a Potent Antiviral Antibody

    SciTech Connect

    Freeman, M.M.; Hong, X.; Seaman, M.S.; Rits-Vollock, S.p Kao, C.Y.; Ho, D.D.; Chen, B.

    2010-06-18

    Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 {angstrom} resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.

  13. TAS-116, a highly selective inhibitor of heat shock protein 90α and β, demonstrates potent antitumor activity and minimal ocular toxicity in preclinical models.

    PubMed

    Ohkubo, Shuichi; Kodama, Yasuo; Muraoka, Hiromi; Hitotsumachi, Hiroko; Yoshimura, Chihoko; Kitade, Makoto; Hashimoto, Akihiro; Ito, Kenjiro; Gomori, Akira; Takahashi, Koichi; Shibata, Yoshihiro; Kanoh, Akira; Yonekura, Kazuhiko

    2015-01-01

    The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo[3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90α and β that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90α and β alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class. ©2014 American Association for Cancer Research.

  14. Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-β signal pathway

    PubMed Central

    Guo, Chunmei; Liu, Shuqing; Dong, Panpan; Zhao, Dongting; Wang, Chengyi; Tao, Zhiwei; Sun, Ming-Zhong

    2015-01-01

    Previously, we characterized the biological properties of Akbu-LAAO, a novel L-amino acid oxidase from Agkistrodon blomhoffii ussurensis snake venom (SV). Current work investigated its in vitro anti-tumor activity and underlying mechanism on HepG2 cells. Akbu-LAAO inhibited HepG2 growth time and dose-dependently with an IC50 of ~38.82 μg/mL. It could induce the apoptosis of HepG2 cells. Akbu-LAAO exhibited cytotoxicity by inhibiting growth and inducing apoptosis of HepG2 as it showed no effect on its cell cycle. The inhibition of Akbu-LAAO to HepG2 growth partially relied on enzymatic-released H2O2 as catalase only partially antagonized this effect. cDNA microarray results indicated TGF-β signaling pathway was linked to the cytotoxicity of Akbu-LAAO on HepG2. TGF-β pathway related molecules CYR61, p53, GDF15, TOB1, BTG2, BMP2, BMP6, SMAD9, JUN, JUNB, LOX, CCND1, CDK6, GADD45A, CDKN1A were deregulated in HepG2 following Akbu-LAAO stimulation. The presence of catalase only slightly restored the mRNA changes induced by Akbu-LAAO for differentially expressed genes. Meanwhile, LDN-193189, a TGF-β pathway inhibitor reduced Akbu-LAAO cytotoxicity on HepG2. Collectively, we reported, for the first time, SV-LAAO showed anti-tumor cell activity via TGF-β pathway. It provides new insight of SV-LAAO exhibiting anti-tumor effect via a novel signaling pathway. PMID:26655928

  15. Akbu-LAAO exhibits potent anti-tumor activity to HepG2 cells partially through produced H2O2 via TGF-β signal pathway.

    PubMed

    Guo, Chunmei; Liu, Shuqing; Dong, Panpan; Zhao, Dongting; Wang, Chengyi; Tao, Zhiwei; Sun, Ming-Zhong

    2015-12-14

    Previously, we characterized the biological properties of Akbu-LAAO, a novel L-amino acid oxidase from Agkistrodon blomhoffii ussurensis snake venom (SV). Current work investigated its in vitro anti-tumor activity and underlying mechanism on HepG2 cells. Akbu-LAAO inhibited HepG2 growth time and dose-dependently with an IC50 of ~38.82 μg/mL. It could induce the apoptosis of HepG2 cells. Akbu-LAAO exhibited cytotoxicity by inhibiting growth and inducing apoptosis of HepG2 as it showed no effect on its cell cycle. The inhibition of Akbu-LAAO to HepG2 growth partially relied on enzymatic-released H2O2 as catalase only partially antagonized this effect. cDNA microarray results indicated TGF-β signaling pathway was linked to the cytotoxicity of Akbu-LAAO on HepG2. TGF-β pathway related molecules CYR61, p53, GDF15, TOB1, BTG2, BMP2, BMP6, SMAD9, JUN, JUNB, LOX, CCND1, CDK6, GADD45A, CDKN1A were deregulated in HepG2 following Akbu-LAAO stimulation. The presence of catalase only slightly restored the mRNA changes induced by Akbu-LAAO for differentially expressed genes. Meanwhile, LDN-193189, a TGF-β pathway inhibitor reduced Akbu-LAAO cytotoxicity on HepG2. Collectively, we reported, for the first time, SV-LAAO showed anti-tumor cell activity via TGF-β pathway. It provides new insight of SV-LAAO exhibiting anti-tumor effect via a novel signaling pathway.

  16. Total Synthesis of the Potent HIF-1 Inhibitory Antitumor Natural Product, (8R)-Mycothiazole, via Baldwin-Lee CsF/CuI sp(3)-sp(2)-Stille Cross-Coupling. Confirmation of the Crews Reassignment.

    PubMed

    Wang, Liping; Hale, Karl J

    2015-09-04

    A convenient asymmetric total synthesis of the potent HIF-1 inhibitory antitumor natural product, (-)- or (+)-(8R)-mycothiazole (1), is described. Not only does our synthesis confirm the 2006 structural reassignment made by Crews ( Crews , P. , et al. J. Nat. Prod. 2006 , 69 , 145 ), it revises the [α]D data previously reported for this molecule in MeOH from -13.7° to +42.3°. The newly developed route to (8R)-1 sets the C(8)-OH stereocenter via Sharpless AE/2,3-epoxy alcohol reductive ring opening and utilizes two Baldwin-Lee CsF/cat. CuI Stille cross-coupling reactions with vinylstannanes 8 and 3 to efficiently elaborate the C(1)-C(4) and C(14)-C(18) sectors.

  17. Synthesis and SAR of 1-acetanilide-4-aminopyrazole-substituted quinazolines: selective inhibitors of Aurora B kinase with potent anti-tumor activity.

    PubMed

    Foote, Kevin M; Mortlock, Andrew A; Heron, Nicola M; Jung, Frédéric H; Hill, George B; Pasquet, Georges; Brady, Madeleine C; Green, Stephen; Heaton, Simon P; Kearney, Sarah; Keen, Nicholas J; Odedra, Rajesh; Wedge, Stephen R; Wilkinson, Robert W

    2008-03-15

    A new class of 1-acetanilide-4-aminopyrazole-substituted quinazoline Aurora kinase inhibitors has been discovered possessing highly potent cellular activity. Continuous infusion into athymic mice bearing SW620 tumors of the soluble phosphate derivative 2 led to dose-proportional exposure of the des-phosphate compound 8 with a high-unbound fraction. The combination of potent cell activity and high free-drug exposure led to pharmacodynamic changes in the tumor at low doses, indicative of Aurora B-kinase inhibition and a reduction in tumor volume.

  18. Behavior of the potential antitumor V(IV)O complexes formed by flavonoid ligands. 1. Coordination modes and geometry in solution and at the physiological pH.

    PubMed

    Sanna, Daniele; Ugone, Valeria; Lubinu, Giuseppe; Micera, Giovanni; Garribba, Eugenio

    2014-11-01

    The coordination modes and geometry assumed in solution by the potent antitumor oxidovanadium(IV) complexes formed by different flavonoids were studied by spectroscopic (Electron Paramagnetic Resonance, EPR) and computational (Density Functional Theory, DFT) methods. A series of bidentate flavonoid ligands (L) with increasing structural complexity was examined, which can involve (CO, O(-)) donors and formation of five- and six-membered chelate rings, or (O(-), O(-)) donors and five-membered chelate rings. The geometry corresponding to these coordination modes can be penta-coordinated, [VOL2], or cis-octahedral, cis-[VOL2(H2O)]. The results show that, at physiological pH, ligands provided with (CO, O(-)) donor set yield cis-octahedral species with "maltol-like" coordination when five-membered chelate rings are formed (as with 3-hydroxyflavone), while penta-coordinated structures with "acetylacetone-like" coordination are preferred when the chelate rings are six-membered (as with chrysin). When both the binding modes are possible, as with morin, the "acetylacetone-like" coordination is observed. For the ligands containing a catecholic donor set, such as 7,8-dihydroxyflavone, baicalein, fisetin, quercetin and rutin, the formation of square pyramidal complexes with (O(-), O(-)) "catechol-like" coordination and five-membered chelate rings is preferred at physiological pH. The determination of the different coordination modes and geometry is important to define the biotransformation in the blood and the interaction of these complexes with the biological membranes. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Structure of IL-17A in complex with a potent, fully human neutralizing antibody.

    PubMed

    Gerhardt, Stefan; Abbott, W Mark; Hargreaves, David; Pauptit, Richard A; Davies, Rick A; Needham, Maurice R C; Langham, Caroline; Barker, Wendy; Aziz, Azad; Snow, Melanie J; Dawson, Sarah; Welsh, Fraser; Wilkinson, Trevor; Vaugan, Tris; Beste, Gerald; Bishop, Sarah; Popovic, Bojana; Rees, Gareth; Sleeman, Matthew; Tuske, Steven J; Coales, Stephen J; Hamuro, Yoshitomo; Russell, Caroline

    2009-12-18

    IL-17A is a pro-inflammatory cytokine produced by the newly identified Th17 subset of T-cells. We have isolated a human monoclonal antibody to IL-17A (CAT-2200) that can potently neutralize the effects of recombinant and native human IL-17A. We determined the crystal structure of IL-17A in complex with the CAT-2200 Fab at 2.6 A resolution in order to provide a definitive characterization of the epitope and paratope regions. Approximately a third of the IL-17A dimer is disordered in this crystal structure. The disorder occurs in both independent copies of the complex in the asymmetric unit and does not appear to be influenced by crystal packing. The complex contains one IL-17A dimer sandwiched between two CAT-2200 Fab fragments. The IL-17A is a disulfide-linked homodimer that is similar in structure to IL-17F, adopting a cystine-knot fold. The structure is not inconsistent with the previous prediction of a receptor binding cavity on IL-17 family members. The epitope recognized by CAT-2200 is shown to involve 12 amino acid residues from the quaternary structure of IL-17A, with each Fab contacting both monomers in the dimer. All complementarity-determining regions (CDRs) in the Fab contribute to a total of 16 amino acid residues in the antibody paratope. In vitro affinity optimization was used to generate CAT-2200 from a parental lead antibody using random mutagenesis of CDR3 loops. This resulted in seven amino acid changes (three in VL-CDR3 and four in VH-CDR3) and gave an approximate 30-fold increase in potency in a cell-based neutralization assay. Two of the seven amino acids form part of the CAT-2200 paratope. The observed interaction site between CAT-2200 and IL-17A is consistent with data from hydrogen/deuterium exchange mass spectrometry and mutagenesis approaches.

  20. Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo.

    PubMed

    Chen, Chun-Han; Liu, Yi-Min; Pan, Shiow-Lin; Liu, Yun-Ru; Liou, Jing-Ping; Yen, Yun

    2016-05-03

    In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers.

  1. Design, synthesis, biological evaluation and preliminary mechanism study of novel benzothiazole derivatives bearing indole-based moiety as potent antitumor agents.

    PubMed

    Ma, Junjie; Bao, Guanglong; Wang, Limei; Li, Wanting; Xu, Boxuan; Du, Baoquan; Lv, Jie; Zhai, Xin; Gong, Ping

    2015-01-01

    Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 μM against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization.

  2. Induction of potent antitumor natural killer cell activity by herpes simplex virus-thymidine kinase and ganciclovir therapy in an orthotopic mouse model of prostate cancer.

    PubMed

    Hall, S J; Sanford, M A; Atkinson, G; Chen, S H

    1998-08-01

    Adenovirus-mediated transduction of the herpes simplex virus-thymidine kinase (HSV-tk) gene followed by ganciclovir is suspected to induce immune-mediated, systemic antitumor activities in the RM-1 mouse prostate cancer model (S. J. Hall et al., Int. J. Cancer, 70: 183-187, 1997). Although numerous investigators have also implied a role for the immune system in both local and systemic effects resulting from HSV-tk treatment, the candidate effector cell(s) mediating these activities are unknown. Fresh lymphocytes harvested from treated tumors (tumor-infiltrating lymphocytes) generated significant in vitro lytic activity against the parental cell line, RM-1, and an unrelated prostate cancer cell line. In vitro antibody and complement depletion of CD3+ T cells and natural killer (NK) cells from tumor-infiltrating lymphocytes indicated that NK cells were the dominant mediator of the observed tumor cell lysis. Concurrently, no cytotoxic T-cell activity was ascertained within splenocytes of treated mice. In vivo depletion of NK cells resulted in a 20% reduction in growth suppression within the primary tumor and complete abrogation of the inhibition of preestablished lung metastases. Depletion of T cells had no effect on either response. Here, we identify the presence of NK cells within adenovirus/HSV-tk- and ganciclovir-treated tumors, which serve to mediate both local and systemic antitumor activities in this model, and lay the mechanistic groundwork for further improvements in this gene therapy strategy.

  3. VEGFR2 targeted antibody fused with MICA stimulates NKG2D mediated immunosurveillance and exhibits potent anti-tumor activity against breast cancer

    PubMed Central

    Wang, Youfu; Ren, Xueyan; Wang, Tong; Chen, Zhiguo; Tang, Mingying; Sun, Fumou; Li, Zhaoting; Wang, Min; Zhang, Juan

    2016-01-01

    Binding of MHC class I-related chain molecules A and B (MICA/B) to the natural killer (NK) cell receptor NK group 2, member D (NKG2D) is thought critical for activating NK-mediated immunosurveillance. Angiogenesis is important for tumor growth and interfering with angiogenesis using the fully human IgG1 anti-VEGFR2 (vascular endothelial growth factor receptor 2) antibody (mAb04) can be effective in treating malignancy. In an effort to make mAb04 more effective we have generated a novel antibody fusion protein (mAb04-MICA) consisting of mAb04 and MICA. We found that mAb04-MICA maintained the anti-angiogenic and antineoplastic activities of mAb04, and also enhanced immunosurveillance activated by the NKG2D pathway. Moreover, in human breast tumor-bearing nude mice, mAb04-MICA demonstrated superior anti-tumor efficacy compared to combination therapy of mAb04 + Docetaxel or Avastin + Docetaxel, highlighting the immunostimulatory effect of MICA. In conclusion, mAb04-MICA provided new inspiration for anti-tumor treatment and had prospects for clinical application. PMID:26909862

  4. Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo

    PubMed Central

    Chen, Chun-Han; Liu, Yi-Min; Pan, Shiow-Lin; Liu, Yun-Ru

    2016-01-01

    In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers. PMID:27029060

  5. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor

    PubMed Central

    Mochalkin, Igor; Knafels, John D.; Lightle, Sandra

    2008-01-01

    The cell wall in Gram-negative bacteria is surrounded by an outer membrane comprised of charged lipopolysaccharide (LPS) molecules that prevent entry of hydrophobic agents into the cell and protect the bacterium from many antibiotics. The hydrophobic anchor of LPS is lipid A, the biosynthesis of which is essential for bacterial growth and viability. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is an essential zinc-dependant enzyme that catalyzes the conversion of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)glucosamine and acetate in the biosynthesis of lipid A, and for this reason, LpxC is an attractive target for antibacterial drug discovery. Here we disclose a 1.9 Å resolution crystal structure of LpxC from Pseudomonas aeruginosa (paLpxC) in a complex with the potent BB-78485 inhibitor. To our knowledge, this is the first crystal structure of LpxC with a small-molecule inhibitor that shows antibacterial activity against a wide range of Gram-negative pathogens. Accordingly, this structure can provide important information for lead optimization and rational design of the effective small-molecule LpxC inhibitors for successful treatment of Gram-negative infections. PMID:18287278

  6. Induction of potent adaptive immunity by the novel polyion complex nanoparticles.

    PubMed

    Uto, Tomofumi; Akagi, Takami; Akashi, Mitsuru; Baba, Masanori

    2015-05-01

    The development of effective and simple methods of vaccine preparation is desired for the prophylaxis and treatment of a variety of infectious diseases and cancers. We have created novel polyion complex (PIC) nanoparticles (NPs) composed of amphiphilic anionic biodegradable poly(γ-glutamic acid) (γ-PGA) and cationic polymers as a vaccine adjuvant. PIC NPs can be prepared by mixing γ-PGA-graft-l-phenylalanine ethylester (γ-PGA-Phe) polymer with cationic polymer in phosphate-buffered saline. We examined the efficacy of PIC NPs for antigen delivery and immunostimulatory activity in vitro and in vivo. PIC NPs enhanced the uptake of ovalbumin (OVA) by dendritic cells (DCs) and subsequently induced DC maturation. The immunization of mice with OVA-carrying PIC NPs induced potent and antigen-specific cellular and humoral immunity. Since PIC NPs can be created with water-soluble anionic γ-PGA-Phe and a cationic polymer by simple mixing in the absence of any organic solvents, PIC NPs may have potential as a novel candidate for an effective antigen carrier and vaccine adjuvant.

  7. Induction of Potent Adaptive Immunity by the Novel Polyion Complex Nanoparticles

    PubMed Central

    Uto, Tomofumi; Akagi, Takami; Akashi, Mitsuru

    2015-01-01

    The development of effective and simple methods of vaccine preparation is desired for the prophylaxis and treatment of a variety of infectious diseases and cancers. We have created novel polyion complex (PIC) nanoparticles (NPs) composed of amphiphilic anionic biodegradable poly(γ-glutamic acid) (γ-PGA) and cationic polymers as a vaccine adjuvant. PIC NPs can be prepared by mixing γ-PGA-graft-l-phenylalanine ethylester (γ-PGA-Phe) polymer with cationic polymer in phosphate-buffered saline. We examined the efficacy of PIC NPs for antigen delivery and immunostimulatory activity in vitro and in vivo. PIC NPs enhanced the uptake of ovalbumin (OVA) by dendritic cells (DCs) and subsequently induced DC maturation. The immunization of mice with OVA-carrying PIC NPs induced potent and antigen-specific cellular and humoral immunity. Since PIC NPs can be created with water-soluble anionic γ-PGA-Phe and a cationic polymer by simple mixing in the absence of any organic solvents, PIC NPs may have potential as a novel candidate for an effective antigen carrier and vaccine adjuvant. PMID:25809631

  8. Crystal structure of LpxC from Pseudomonas aeruginosa complexed with the potent BB-78485 inhibitor

    SciTech Connect

    Mochalkin, Igor; Knafels, John D.; Lightle, Sandra

    2008-04-02

    The cell wall in Gram-negative bacteria is surrounded by an outer membrane comprised of charged lipopolysaccharide (LPS) molecules that prevent entry of hydrophobic agents into the cell and protect the bacterium from many antibiotics. The hydrophobic anchor of LPS is lipid A, the biosynthesis of which is essential for bacterial growth and viability. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is an essential zinc-dependant enzyme that catalyzes the conversion of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine to UDP-3-O-(R-3-hydroxymyristoyl)glucosamine and acetate in the biosynthesis of lipid A, and for this reason, LpxC is an attractive target for antibacterial drug discovery. Here we disclose a 1.9 A resolution crystal structure of LpxC from Pseudomonas aeruginosa (paLpxC) in a complex with the potent BB-78485 inhibitor. To our knowledge, this is the first crystal structure of LpxC with a small-molecule inhibitor that shows antibacterial activity against a wide range of Gram-negative pathogens. Accordingly, this structure can provide important information for lead optimization and rational design of the effective small-molecule LpxC inhibitors for successful treatment of Gram-negative infections.

  9. Copper Complexation Screen Reveals Compounds with Potent Antibiotic Properties against Methicillin-Resistant Staphylococcus aureus

    PubMed Central

    Haeili, Mehri; Moore, Casey; Davis, Christopher J. C.; Cochran, James B.; Shah, Santosh; Shrestha, Tej B.; Zhang, Yaofang; Bossmann, Stefan H.; Benjamin, William H.

    2014-01-01

    Macrophages take advantage of the antibacterial properties of copper ions in the killing of bacterial intruders. However, despite the importance of copper for innate immune functions, coordinated efforts to exploit copper ions for therapeutic interventions against bacterial infections are not yet in place. Here we report a novel high-throughput screening platform specifically developed for the discovery and characterization of compounds with copper-dependent antibacterial properties toward methicillin-resistant Staphylococcus aureus (MRSA). We detail how one of the identified compounds, glyoxal-bis(N4-methylthiosemicarbazone) (GTSM), exerts its potent strictly copper-dependent antibacterial properties on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species- and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface. PMID:24752262

  10. Copper complexation screen reveals compounds with potent antibiotic properties against methicillin-resistant Staphylococcus aureus.

    PubMed

    Haeili, Mehri; Moore, Casey; Davis, Christopher J C; Cochran, James B; Shah, Santosh; Shrestha, Tej B; Zhang, Yaofang; Bossmann, Stefan H; Benjamin, William H; Kutsch, Olaf; Wolschendorf, Frank

    2014-07-01

    Macrophages take advantage of the antibacterial properties of copper ions in the killing of bacterial intruders. However, despite the importance of copper for innate immune functions, coordinated efforts to exploit copper ions for therapeutic interventions against bacterial infections are not yet in place. Here we report a novel high-throughput screening platform specifically developed for the discovery and characterization of compounds with copper-dependent antibacterial properties toward methicillin-resistant Staphylococcus aureus (MRSA). We detail how one of the identified compounds, glyoxal-bis(N4-methylthiosemicarbazone) (GTSM), exerts its potent strictly copper-dependent antibacterial properties on MRSA. Our data indicate that the activity of the GTSM-copper complex goes beyond the general antibacterial effects of accumulated copper ions and suggest that, in contrast to prevailing opinion, copper complexes can indeed exhibit species- and target-specific activities. Based on experimental evidence, we propose that copper ions impose structural changes upon binding to the otherwise inactive GTSM ligand and transfer antibacterial properties to the chelate. In turn, GTSM determines target specificity and utilizes a redox-sensitive release mechanism through which copper ions are deployed at or in close proximity to a putative target. According to our proof-of-concept screen, copper activation is not a rare event and even extends to already established drugs. Thus, copper-activated compounds could define a novel class of anti-MRSA agents that amplify copper-dependent innate immune functions of the host. To this end, we provide a blueprint for a high-throughput drug screening campaign which considers the antibacterial properties of copper ions at the host-pathogen interface.

  11. Synthesis and Evaluation of 1,5-Disubstituted Tetrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative and Antitumor Activity

    PubMed Central

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Preti, Delia; Tabrizi, Mojgan Aghazadeh; Brancale, Andrea; Fu, Xian-Hua; Li, Jun; Zhang, Su-Zhan; Hamel, Ernest; Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro

    2012-01-01

    Tubulin, the major structural component of microtubules, is a target for the development of anticancer agents. Two series of 1,5-diaryl substituted 1,2,3,4-tetrazoles were concisely synthesized, using a palladium-catalyzed cross-coupling reaction, and identified as potent antiproliferative agents and novel tubulin polymerization inhibitors that act at the colchicine site. SAR analysis indicated that compounds with a 4-ethoxyphenyl group at the N-1 or C-5 position of the 1,2,3,4-tetrazole ring exhibited maximal activity. Several of these compounds also had potent activity in inhibiting the growth of multidrug resistant cells overexpressing P-glycoprotein. Active compounds induced apoptosis through the mitochondrial pathway with activation of caspase-9 and caspase-3. Furthermore, compound 4l significantly reduced in vivo the growth of the HT-29 xenograft in a nude mouse model, suggesting that 4l is a promising new antimitotic agent with clinical potential. PMID:22136312

  12. Development and Characterization of a Humanized Anti-HER2 Antibody HuA21 with Potent Anti-Tumor Properties in Breast Cancer Cells.

    PubMed

    Li, Ruilin; Hu, Siyi; Chang, Yan; Zhang, Zhihui; Zha, Zhao; Huang, Hui; Shen, Guodong; Liu, Jing; Song, Lihua; Wei, Wei

    2016-04-15

    Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy.

  13. Development and Characterization of a Humanized Anti-HER2 Antibody HuA21 with Potent Anti-Tumor Properties in Breast Cancer Cells

    PubMed Central

    Li, Ruilin; Hu, Siyi; Chang, Yan; Zhang, Zhihui; Zha, Zhao; Huang, Hui; Shen, Guodong; Liu, Jing; Song, Lihua; Wei, Wei

    2016-01-01

    Human epidermal growth factor receptor 2 (HER2) is one of the most studied tumor-associated antigens for cancer immunotherapy. An engineered anti-HER-2 chimeric A21 antibody (chA21) is a chimeric antibody targeted to subdomain I of the HER2 extracellular domain. Here, we report the anti-tumor activity of the novel engineered monoclonal antibody humanized chA21 (HuA21) that targets HER2 on the basis of chA21, and we describe the underlying mechanisms. Our results reveal that HuA21 markedly inhibits the proliferation and migration of HER2-overexpressing breast cancer cells and causes enhanced antibody-dependent cell-mediated cytotoxicity potency against HER2-overexpressing tumor cells. In particular, HuA21, but not trastuzumab (Tra), markedly suppresses growth and enhances the internalization of the antibody in Tra-resistant BT-474 breast cancer cells. These characteristics are highly associated with the intrinsic ability of HuA21 to down-regulate HER2 activation and inhibit the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (Akt) signaling pathways. Furthermore, the combination of HuA21 with Tra synergistically enhances the anti-tumor effects in vitro and in vivo and inhibits HER2 activation and the ERK1/2 and Akt signaling pathways. Altogether, our results suggest that HuA21 may represent a unique anti-HER2 antibody with potential as a therapeutic candidate alone or in combination with other anti-HER2 reagents in cancer therapy. PMID:27092488

  14. Rational design, synthesis and preliminary antitumor activity evaluation of a chlorambucil derivative with potent DNA/HDAC dual-targeting inhibitory activity.

    PubMed

    Xie, Rui; Li, Yan; Tang, Pingwah; Yuan, Qipeng

    2017-09-15

    Histone deacetylases (HDACs) play a pivotal role not only in gene expression but also in DNA repair. Herein, we report the successful design, synthesis and evaluation of a chlorambucil derivative named vorambucil with a hydroxamic acid tail as a DNA/HDAC dual-targeting inhibitor. Vorambucil obtained both potent DNA and HDACs inhibitory activities. Molecular docking results supported the initial pharmacophoric hypothesis and rationalized the potent inhibitory activity of vorambucil against HDAC1, HDAC2 and HDAC6. Vorambucil showed potent antiproliferative activity against all the test four cancer cell lines with IC50 values of as low as 3.2-6.2μM and exhibited 5.0-18.3-fold enhanced antiproliferative activity than chlorambucil. Vorambucil also significantly inhibits colony formation of A375 cancer cells. Further investigation showed that vorambucil remarkably induced apoptosis and arrested the cell cycle of A375 cells at G2/M phase. Vorambucil could be a promising candidate and a useful tool to elucidate the role of those DNA/HDAC dual-targeting inhibitors for cancer therapy. Copyright © 2017. Published by Elsevier Ltd.

  15. Voltammetric and spectroscopic studies on binding of antitumor Morin, Morin-Cu complex and Morin-β-cyclodextrin with DNA

    NASA Astrophysics Data System (ADS)

    Temerk, Y. M.; Ibrahim, M. S.; Kotb, M.

    2009-01-01

    A systematic comparative study of the binding of antitumor Morin and its complexes with DNA has been investigated in the Britton-Robison (BR) buffer solutions using voltammetric and spectroscopic methods. The results show that Morin molecule, acting as an intercalator, is inserted into the cavity of the β-cyclodextrin (β-CD) as well as into the base stacking domain of the DNA double helix. The interaction of Morin-Cu complex or the inclusion complex of Morin-β-CD with ds-DNA causes hypochromism in the absorption spectra, along with pronounced changes in the electrochemical behavior of the Morin complexes. An isobestic point and a new spectrum band appeared indicating the formation of the new system of Morin-Cu-DNA at λm = 391 nm and Morin-β-CD-DNA at λm = 375 nm. The intercalation of Morin-Cu and Morin-β-CD complexes with DNA produces an electrochemically inactive supramolecular complex. The binding constants were calculated from the increase of the solubility, the strong hypochromism, and the decrease in peak current of Morin and its complexes upon the addition of the host molecules. Calculation of the thermodynamic parameters of the interaction of the inclusion complex of Morin-β-CD with DNA, including Gibbs free energy change, Helmholz free energy and entropy change shows that the complexation is a spontaneous process of association.

  16. Synthesis, spectroscopic studies, antimicrobial activities and antitumor of a new monodentate V-shaped Schiff base and its transition metal complexes

    NASA Astrophysics Data System (ADS)

    Ramadan, Ramadan M.; Abu Al-Nasr, Ahmad K.; Noureldeen, Amani F. H.

    2014-11-01

    Reaction of 4-aminoacetophenone and 4-bromobenzaldehyde in ethanol resulted in the formation of the monodentate V-shaped Schiff base (E)-1-(4-((4-bromo-benzylidene)amino)phenyl)ethanone (L). Interaction of L with different di- and trivalent metal ions revealed disubstituted derivatives. The ligand and its complexes were characterized by elemental analysis, mass, IR and NMR spectrometry. Biological activities of the ligand and complexes against the Escherchia coli and Staphylococcus aureus bacterias, and the two fungus Aspergillus flavus and Candida albicans were screened. The cytotoxicity of the compounds were checked as antitumor agents on liver carcinoma cell line (HepG2). They exhibited in vitro broad range of antitumor activities towards the cell line; the [ZnL2(H2O)2](NO3)2 complex was stronger antitumor towards HepG2 cell line as well as two breast cancer cell lines (MCF7 and T47D) relative to cis-platin.

  17. Antitumor Agents 266*. Design, Synthesis, and Biological Evaluation of Novel 2-(Furan-2-yl) naphthalen-1-ol Derivatives as Potent and Selective Anti-Breast Cancer Agents

    PubMed Central

    Dong, Yizhou; Shi, Qian; Liu, Yi-Nan; Wang, Xiang; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2009-01-01

    In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro anti-breast cancer activity. Accordingly, we discovered a novel class of anti-breast cancer agents, 2-(furan-2-yl) naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18 and 21, which showed decreased cytotoxic potency, but better selectivity than neo-tanshinlactone analog 2. Interestingly, compound 20 showed broad cytotoxicity against human cancer cell lines. PMID:19425534

  18. 6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione, a potent antitumor agent, induces cell cycle arrest and apoptosis

    PubMed Central

    2010-01-01

    Background Anticancer activities of several substituted naphthalimides (1H-benz[de]isoquinoline-1,3-diones) are well documented. Some of them have undergone Phase I-II clinical trials. Presently a series of ten N-(hydroxyalkyl) naphthalimides (compounds 1a-j) were evaluated as antitumor agents. Methods Compounds 1a-j were initially screened in MOLT-4, HL-60 and U-937 human tumor cell lines and results were compared with established clinical drugs. Cytotoxicities of compounds 1d and 1i were further evaluated in a battery of human tumor cell lines and in normal human peripheral blood mononuclear cells. Cell cycle analysis of compound 1i treated MOLT-4 cells was studied by flow cytometry. Its apoptosis inducing effect was carried out in MOLT-4 and HL-60 cells by flow cytometry using annexin V-FITC/PI double staining method. The activities of caspase-3 and caspase-6 in MOLT-4 cells following incubation with compound 1i were measured at different time intervals. Morphology of the MOLT-4 cells after treatment with 1i was examined under light microscope and transmission electron microscope. 3H-Thymidine and 3H-uridine incorporation in S-180 cells in vitro following treatment with 8 μM concentration of compounds 1d and 1i were studied. Results 6-Nitro-2-(3-hydroxypropyl)-1H-benz[de]isoquinoline-1,3-dione (compound 1i), has exhibited maximum activity as it induced significant cytotoxicity in 8 out of 13 cell lines employed. Interestingly it did not show any cytotoxicity against human PBMC (IC50 value 273 μM). Cell cycle analysis of compound 1i treated MOLT-4 cells demonstrated rise in sub-G1 fraction and concomitant accumulation of cells in S and G2/M phases, indicating up-regulation of apoptosis along with mitotic arrest and/or delay in exit of daughter cells from mitotic cycle respectively. Its apoptosis inducing effect was confirmed in flow cytometric study in MOLT-4 and the action was mediated by activation of both caspase 3 and 6. Light and transmission electron

  19. Synthesis, spectral properties, and antitumor activity of a new axially substituted phthalocyanine complex of zirconium(IV) with citric acid.

    PubMed

    Tomachynski, Larisa A; Chernii, Victor Y; Gorbenko, Helena N; Filonenko, Valeriy V; Volkov, Sergey V

    2004-06-01

    The new axially substituted phthalocyanine (pc) complex of zirconium(IV) with citric acid is reported. It has been shown that the replacement of two Cl-atoms with two citric acid fragments takes place as the result of the reaction between [ZrCl2(pc)] and citric acid. The complex [Zr(citrate)2(pc)] was formed. The spectroscopic properties of the synthesized compound in DMSO, RPMI 1640 medium with and without fetal calf serum (FCS), H2O, and buffer (Tris) solutions have been described. Antitumor activity of this compound has been studied. The cytostatic activity was observed in the concentration range of 6.1-9.0x10(9) molecules [Zr(citrate)2(pc)]/cell and occurred in 4-6 h after treatment with [Zr(citrate)2(pc)] solution.

  20. Inducible activation of MyD88 and CD40 in CAR T-cells results in controllable and potent antitumor activity in preclinical solid tumor models.

    PubMed

    Mata, Melinda; Gerken, Claudia; Nguyen, Phuong; Krenciute, Giedre; Spencer, David M; Gottschalk, Stephen

    2017-08-11

    Adoptive immunotherapy with T-cells expressing chimeric antigen receptors (CARs) has had limited success for solid tumors in early phase clinical studies. We reasoned that introducing into CAR T-cells an inducible co-stimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)-binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T-cells expressing HER2-CARζ and a MyD88/CD40-based iCO molecule (HER2ζ.iCO T-cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T-cells without CID and T-cells expressing HER2-CAR.CD28ζ. HER2ζ.iCO T-cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T-cells in vivo. Thus, expressing MyD88/CD40-based iCO molecules in CAR T-cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors. Copyright ©2017, American Association for Cancer Research.

  1. Potent CD4+ T cell-associated antitumor memory responses induced by trifunctional bispecific antibodies in combination with immune checkpoint inhibition

    PubMed Central

    Deppisch, Nina; Ruf, Peter; Eißler, Nina; Lindhofer, Horst; Mocikat, Ralph

    2017-01-01

    Combinatorial approaches of immunotherapy hold great promise for the treatment of malignant disease. Here, we examined the potential of combining an immune checkpoint inhibitor and trifunctional bispecific antibodies (trAbs) in a preclinical melanoma mouse model using surrogate antibodies of Ipilimumab and Catumaxomab, both of which have already been approved for clinical use. The specific binding arms of trAbs redirect T cells to tumor cells and trigger direct cytotoxicity, while the Fc region activates accessory cells eventually giving rise to a long-lasting immunologic memory. We show here that T cells redirected to tumor cells by trAbs strongly upregulate CTLA-4 expression in vitro and in vivo. This suggested that blocking of CTLA-4 in combination with trAb treatment enhances T-cell activation in a tumor-selective manner. However, when mice were challenged with melanoma cells and subsequently treated with antibodies, there was only a moderate beneficial effect of the combinatorial approach in vivo with regard to direct tumor destruction in comparison to trAb therapy alone. By contrast, a significantly improved vaccination effect was obtained by CTLA-4 blocking during trAb-dependent immunization. This resulted in enhanced rejection of melanoma cells given after pre-immunization. The improved immunologic memory induced by the combinatorial approach correlated with an increased humoral antitumor response as measured in the sera and an expansion of CD4+ memory T cells found in the spleens. PMID:27966460

  2. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade.

    PubMed

    Xue, Wei; Metheringham, Rachael L; Brentville, Victoria A; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M; Durrant, Lindy G

    2016-06-01

    Checkpoint blockade has demonstrated promising antitumor responses in approximately 10-40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses.

  3. Allorestricted T lymphocytes with a high avidity T-cell receptor towards NY-ESO-1 have potent anti-tumor activity.

    PubMed

    Krönig, Holger; Hofer, Kathrin; Conrad, Heinke; Guilaume, Philippe; Müller, Julia; Schiemann, Matthias; Lennerz, Volker; Cosma, Antonio; Peschel, Christian; Busch, Dirk H; Romero, Pedro; Bernhard, Helga

    2009-08-01

    The cancer-testis antigen NY-ESO-1 has been targeted as a tumor-associated antigen by immunotherapeutical strategies, such as cancer vaccines. The prerequisite for a T-cell-based therapy is the induction of T cells capable of recognizing the NY-ESO-1-expressing tumor cells. In this study, we generated human T lymphocytes directed against the immunodominant NY-ESO-1(157-165) epitope known to be naturally presented with HLA-A*0201. We succeeded to isolate autorestricted and allorestricted T lymphocytes with low, intermediate or high avidity TCRs against the NY-ESO-1 peptide. The avidity of the established CTL populations correlated with their capacity of lysing HLA-A2-positive, NY-ESO-1-expressing tumor cell lines derived from different origins, e.g. melanoma and myeloma. The allorestricted NY-ESO-1-specific T lymphocytes displayed TCRs with the highest avidity and best anti-tumor recognition activity. TCRs derived from allorestricted, NY-ESO-1-specific T cells may be useful reagents for redirecting primary T cells by TCR gene transfer and, therefore, may facilitate the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of NY-ESO-1-expressing hematological malignancies and solid tumors.

  4. Improvement of aqueous solubility of fenretinide and other hydrophobic anti-tumor drugs by complexation with amphiphilic dextrins.

    PubMed

    Orienti, I; Zuccari, G; Carosio, R; Montaldo, P G

    2009-10-01

    This study relates to the preparation of a series of amphiphilic dextrins and their evaluation as complexing agents for anti-tumor hydrophobic drugs such as fenretinide, paclitaxel, etoposide, and camptothecin. The amphiphilic dextrins were obtained by conjugation of low molecular weight dextrin (average molecular weight 1670, average polymerization degree 9.33 glucose monomer) with hydrocarbon chains at substitution degree of about 0.1 mole hydrocarbon chain per mole of glucose monomer, as confirmed by 1H-NMR spectra. The conjugates were highly soluble in water and dissolved with formation of nano-aggregates endowed with hydrophobic inner cores able to host hydrophobic drugs by complexation. Complexation raised hydrophobic drugs aqueous solubility; the best results were obtained with fenretinide. Solid complexes with fenretinide were prepared by using three different approaches: the kneading method, the co-solubilisation method, and the co-precipitation method. Kneading method provided the complexes endowed with the best functional properties. Thermogravimetric analysis on solid samples suggested a notable thermal stability up to 300 degrees C for both the conjugated dextrins and the solid complexes. In differential scanning calorimetry profiles no significant differences were observed among amphiphilic dextrins and complexed drug, indicating that the guest molecule exists in an amorphous state in the solid matrices. Particle size analysis confirmed the dimensional suitability of the complexes for parenteral administration. Moreover, sustained drug release, in vitro, has been observed from all the complexes analyzed. Regarding the biological effects, the cytotoxicity of complexed fenretinide towards HTLA-230 neuroblastoma cell line was always higher than the free drug, suggesting that complexation increased drug bioavailability. These findings, taken together, indicated that these biodegradable, self-assembling dextrin conjugates may be regarded as new potential

  5. Antitumor activity of resveratrol is independent of Cu(II) complex formation in MCF-7 cell line.

    PubMed

    Andrade Volkart, Priscylla; Benedetti Gassen, Rodrigo; Mühlen Nogueira, Bettina; Nery Porto, Bárbara; Eduardo Vargas, José; Arigony Souto, André

    2017-08-01

    Resveratrol (Rsv) is widely reported to possess anticarcinogenic properties in a plethora of cellular and animal models having limited toxicity toward normal cells. In the molecular level, Rsv can act as a suppressive agent for several impaired signaling pathways on cancer cells. However, Fukuhara and Miyata have shown a non-proteic reaction of Rsv, which can act as a prooxidant agent in the presence of copper (Cu), causing cellular oxidative stress accompanied of DNA damage. After this discovery, the complex Rsv-Cu was broadly explored as an antitumor mechanism in multiples tumor cell lines. The aim of the study is to explore the anticarcinogenic behavior of resveratrol-Cu(II) complex in MCF-7 cell line. Selectivity of Rsv binding to Cu ions was analyzed by HPLC and UV-VIS. The cells were enriched with concentrations of 10 and 50µM CuSO4 solution and treated with 25µM of Rsv. Copper uptake after enrichment of cells, as its intracellular distribution in MCF-7 line, was scanned by ICP-MS and TEM-EDS. Cell death and intracellular ROS production were determined by flow cytometry. Different from the extracellular model, no relationship of synergy between Rsv-Cu(II) and reactive oxidative species (ROS) production was detected in vitro. ICP-MS revealed intracellular copper accumulation to both chosen concentrations (0.33±0.09 and 1.18±0.13ppb) but there is no promotion of cell death by Rsv-Cu(II) complex. In addition, significant attenuation of ROS production was detected when cells were exposed to CuSO4 after Rsv treatment, falling from 7.54% of ROS production when treated only with Rsv to 3.07 and 2.72% with CuSO4. Based on these findings antitumor activity of resveratrol when in copper ions presence, is not mediated by Rsv-Cu complex formation in MCF-7 human cell line, suggesting that the antitumoral reaction is dependent of a cancer cellular model. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Chimeric, divalent and tetravalent anti-CD19 monoclonal antibodies with potent in vitro and in vivo antitumor activity against human B-cell lymphoma and pre-B acute lymphoblastic leukemia cell lines.

    PubMed

    Liu, Xiao-Yun; Pop, Laurentiu M; Tsai, Lydia; Pop, Iliodora V; Vitetta, Ellen S

    2011-07-15

    CD19 is an attractive therapeutic target for treating human B-cell tumors. In our study, chimeric (c) divalent (cHD37) and tetravalent (cHD37-DcVV) anti-CD19 monoclonal antibodies (MAbs) were constructed, expressed and evaluated for their binding to human 19-positive (CD19(+)) tumor cell lines. They were also tested for proapoptotic activity and the ability to mediate effector functions. The antitumor activity of these MAbs was further tested in mice xenografted with the CD19(+) Burkitt's lymphoma cell line, Daudi or the pre-B acute lymphoblastic leukemia (ALL) cell line, NALM-6. The cHD37 and cHD37-DcVV MAbs exhibited specific binding and comparable proapoptotic activity on CD19(+) tumor cell lines in vitro. In addition, the cHD37 and cHD37-DcVV MAbs were similar in their ability to mediate antibody-dependent cell-mediated phagocytosis (ADCP). However, the tetravalent cHD37-DcVV MAb bound more avidly, had a slower dissociation rate, and did not internalize as well. It also had enhanced antibody-dependent cellular cytotoxicity (ADCC) with human but not murine effector cells. The cHD37 and cHD37-DcVV MAbs exhibited comparable affinity for the human neonatal Fc receptor (FcRn) and similar pharmacokinetics (PKs) in mice. Moreover, all the HD37 constructs were similar in extending the survival of mice xenografted with Daudi or NALM-6 tumor cells. Therefore, the cHD37 and cHD37-DcVV MAbs have potent antitumor activity and should be further developed for use in humans. Although not evident in mice, due to its increased ability to mediate ADCC with human but not mouse effector cells, the cHD37-DcVV MAb should have superior therapeutic efficacy in humans.

  7. New binary and ternary platinum(II) formamidine complexes: Synthesis, characterization, structural studies and in-vitro antitumor activity

    NASA Astrophysics Data System (ADS)

    Soliman, Ahmed A.; Alajrawy, Othman I.; Attaby, Fawzy A.; Linert, W.

    2016-07-01

    A series of new binary and ternary platinum(II) complexes of the type [Pt(L1-4)Cl2].xH2O and [Pt(L1-4)ox].xH2O where L = formamidine ligands and ox = oxalate, have been synthesized and characterized by elemental analyses, magnetic susceptibility, UV-vis, infrared (IR), mass spectroscopy, thermal analysis and theoretical calculations. The spectroscopic data indicated that the formamidine ligands act as bidentate N2 donors. The complexes (1-8) are diamagnetic and the optimization of their structures indicated that the geometry is distorted square planar with Cl-Pt-Cl, O-Pt-O and N-Pt-N bond angles ranged 81.73°-95.82° which is acceptable for the heteroleptic complexes. The electronic energies (a.u.) of the complexes (-893.53 to -1989.84) indicate that the complexes are more stable than the ligands. The energies of the HOMO (-0.218 to -0.244) and LUMO (-.0111to -0.134) orbitals of the complexes were negative which indicates that the complexes are stable compounds. The dipole moment of the complexes (6.23-19.89 Debye) indicates that the complexes are polarized. The complexes are thermally stable as shown from their relatively higher overall activation energies (889-2066 kJ mol-1). The complexes are proved to have a good cytotoxicity with IC50 (μM) against MCF-7 (0.040-0.117), HCT-116 (0.085-0.119) and HepG-2 (0.058-0.131) cell lines, which open the field for further application as antitumor compounds.

  8. Ganetespib (STA-9090), a nongeldanamycin HSP90 inhibitor, has potent antitumor activity in in vitro and in vivo models of non-small cell lung cancer.

    PubMed

    Shimamura, Takeshi; Perera, Samanthi A; Foley, Kevin P; Sang, Jim; Rodig, Scott J; Inoue, Takayo; Chen, Liang; Li, Danan; Carretero, Julian; Li, Yu-Chen; Sinha, Papiya; Carey, Christopher D; Borgman, Christa L; Jimenez, John-Paul; Meyerson, Matthew; Ying, Weiwen; Barsoum, James; Wong, Kwok-Kin; Shapiro, Geoffrey I

    2012-09-15

    We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20-3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA. Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation. ©2012 AACR.

  9. Ganetespib (STA-9090), a Non-Geldanamycin HSP90 Inhibitor, has Potent Antitumor Activity in In Vitro and In Vivo Models of Non-Small Cell Lung Cancer

    PubMed Central

    Shimamura, Takeshi; Perera, Samanthi A.; Foley, Kevin P.; Sang, Jim; Rodig, Scott J.; Inoue, Takayo; Chen, Liang; Li, Danan; Carretero, Julian; Li, Yu-Chen; Sinha, Papiya; Carey, Christopher D.; Borgman, Christa L.; Jimenez, John-Paul; Meyerson, Matthew; Ying, Weiwen; Barsoum, James; Wong, Kwok-Kin; Shapiro, Geoffrey I.

    2012-01-01

    Purpose We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models. Experimental Design The activity of ganetespib was compared to that of the geldanamycin 17-AAG in biochemical assays, cell lines and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model. Results Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its co-chaperone, p23, more potently than 17-AAG. In genomically-defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC50 values ranging 2–30 nM, substantially lower than those required for 17-AAG (20– 3,500 nM). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t1/2 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, re-expression of mutant EGFR occurred by 72 hours, correlating with reversal of anti-proliferative and pro-apoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also demonstrated activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA. Conclusions Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation. PMID:22806877

  10. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade

    PubMed Central

    Xue, Wei; Metheringham, Rachael L.; Brentville, Victoria A.; Gunn, Barbara; Symonds, Peter; Yagita, Hideo; Ramage, Judith M.; Durrant, Lindy G.

    2016-01-01

    ABSTRACT Checkpoint blockade has demonstrated promising antitumor responses in approximately 10–40% of patients. However, the majority of patients do not make a productive immune response to their tumors and do not respond to checkpoint blockade. These patients may benefit from an effective vaccine that stimulates high-avidity T cell responses in combination with checkpoint blockade. We have previously shown that incorporating TRP-2 and gp100 epitopes into the CDR regions of a human IgG1 DNA (ImmunoBody®: IB) results in significant tumor regression both in animal models and patients. This vaccination strategy is superior to others as it targets antigen to antigen-presenting cells and stimulates high-avidity T cell responses. To broaden the application of this vaccination strategy, 16 NY-ESO-1 epitopes, covering over 80% of HLA phenotypes, were incorporated into the IB (SCIB2). They produced higher frequency and avidity T cell responses than peptide vaccination. These T cells were of sufficient avidity to kill NY-ESO-1-expressing tumor cells, and in vivo controlled the growth of established B16-NY-ESO-1 tumors, resulting in long-term survival (35%). When SCIB2 was given in combination with Treg depletion, CTLA-4 blockade or PD-1 blockade, long-term survival from established tumors was significantly enhanced to 56, 67 and 100%, respectively. Translating these responses into the clinic by using a combination of SCIB2 vaccination and checkpoint blockade can only further improve clinical responses. PMID:27471648

  11. Biomarkers of sensitivity to potent and selective antitumor 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203) in ovarian cancer.

    PubMed

    Callero, Mariana A; Luzzani, Gabriela A; De Dios, Diana O; Bradshaw, Tracey D; Perez, Andrea I Loaiza

    2013-10-01

    2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole (5F203, NSC 703786) lysylamide belongs to a novel mechanistic class of antitumor agents. It elicits activity against ovarian, breast, kidney and colorectal cancer models. In sensitive breast cancer cells, 5F203 activates aryl hydrocarbon receptor (AhR) signaling. Herein, we evaluate the role of AhR in 5F203 activity in two ovarian cancer cell lines: IGROV-1 (sensitive to 5F203), SKOV-3 (resistant to this agent). In addition, cancer cells have been isolated from ascites fluid of ovarian cancer patients; sensitivity to 5F203 and concurrent AhR signal transduction has been examined in ascites-isolated ovarian cancer patients' cells. 5F203 induced enhanced CYP1A1 expression, AhR translocation and ROS formation in IGROV-1 cells and ascites-isolated ovarian cancer cells that were sensitive to 5F203. In IGROV-1 cells 5F203-induced ROS formation was accompanied by JNK, ERK and P38MAPK phosphorylation, DNA damage and cell cycle arrest prior to apoptosis. In contrast, 5F203 failed to induce CYP1A1 expression, AhR translocation or oxidative stress in 5F203-resistant SKOV-3 cells, or in ovarian cancer ascites cells inherently resistant to this agent. We propose that AhR may represent a new molecular target in the treatment of ovarian tumors and 5F203 may exemplify a potential novel treatment. Furthermore, putative biomarkers of sensitivity to this agent have been identified.

  12. Low-Dose Metronomic Cyclophosphamide Combined with Vascular Disrupting Therapy Induces Potent Anti-Tumor Activity in Preclinical Human Tumor Xenograft Models

    PubMed Central

    Daenen, Laura G.; Shaked, Yuval; Man, Shan; Xu, Ping; Voest, Emile E.; Hoffman, Robert M.; Chaplin, David; Kerbel, Robert S.

    2009-01-01

    Purpose Vascular disrupting agents (VDAs) preferentially target the established but abnormal tumor vasculature, resulting in extensive intratumoral hypoxia and cell death. However, a rim of viable tumor tissue remains from which angiogenesis-dependent regrowth can occur, in part via mobilization and tumor colonization of circulating endothelial progenitor cells (CEPs). Co-treatment with an agent that blocks CEPs, such as VEGF-pathway targeting biologic antiangiogenic drugs, results in enhanced anti-tumor efficacy. We asked whether an alternative therapeutic modality – low-dose metronomic (LDM) chemotherapy could achieve the same result, given its CEP targeting effects. Experimental Design We studied the combination of the VDA OXi-4503 with daily administration of CEP-inhibiting, low-dose metronomic (LDM) cyclophosphamide to treat primary orthotopic tumors using the 231/LM2-4 breast cancer cell line and MeWo melanoma cell line. In addition, CEP mobilization and various tumor characteristics were assessed. Results We found that daily oral LDM cyclophosphamide was capable of preventing the CEP spike and tumor colonization induced by OXi-4503; this was associated with a decrease in the tumor rim and marked suppression of primary 231/LM2-4 growth in nude as well as SCID mice. Similar results were found in MeWo bearing nude mice. The delay in tumor growth was accompanied by significant decreases in micro-vessel density, perfusion and proliferation, and a significant increase in tumor cell apoptosis. No overt toxicity was observed. Conclusions The combination of OXi-4503 and metronomic chemotherapy results in prolonged tumor control, thereby expanding the list of therapeutic agents that can be successfully integrated with metronomic low-dose chemotherapy. PMID:19825805

  13. Optimized S-trityl-L-cysteine-based inhibitors of kinesin spindle protein with potent in vivo antitumor activity in lung cancer xenograft models.

    PubMed

    Good, James A D; Wang, Fang; Rath, Oliver; Kaan, Hung Yi Kristal; Talapatra, Sandeep K; Podgórski, Dawid; MacKay, Simon P; Kozielski, Frank

    2013-03-14

    The mitotic kinesin Eg5 is critical for the assembly of the mitotic spindle and is a promising chemotherapy target. Previously, we identified S-trityl-L-cysteine as a selective inhibitor of Eg5 and developed triphenylbutanamine analogues with improved potency, favorable drug-like properties, but moderate in vivo activity. We report here their further optimization to produce extremely potent inhibitors of Eg5 (K(i)(app) < 10 nM) with broad-spectrum activity against cancer cell lines comparable to the Phase II drug candidates ispinesib and SB-743921. They have good oral bioavailability and pharmacokinetics and induced complete tumor regression in nude mice explanted with lung cancer patient xenografts. Furthermore, they display fewer liabilities with CYP-metabolizing enzymes and hERG compared with ispinesib and SB-743921, which is important given the likely application of Eg5 inhibitors in combination therapies. We present the case for this preclinical series to be investigated in single and combination chemotherapies, especially targeting hematological malignancies.

  14. Effect of U-995, a potent shark cartilage-derived angiogenesis inhibitor, on anti-angiogenesis and anti-tumor activities.

    PubMed

    Sheu, J R; Fu, C C; Tsai, M L; Chung, W J

    1998-01-01

    A potent angiogenesis inhibitor, U-995, has been purified from the cartilage of the blue shark (Prionace glauca). U-995 is composed of two single peptides with molecular mass of 10 and 14 kDa, respectively. U-995 was designed to study human umbilical vein endothelial cell (HUVEC) migration and proliferation in vitro and angiogenesis induced by TNF alpha in chicken chorioallantoic membrane (CAM). Furthermore, we determined the ability of U-995 to inhibiting tumor cell growth and metastasis. U-995 (15 and 30 micrograms/ml) markedly inhibited HUVEC migration and, at 15-50 micrograms/ml produced a dose-dependent decline in [3H]-thymidine incorporation. 30 and 50 micrograms/ml of U-995, when added to TNF alpha-induced angiogenesis caused discontinuous and disrupted blood vessels. Moreover, U-995 (30 micrograms/ml) markedly prevented collagenase-induced collagenolysis. In addition, when 200 micrograms U-995 was injected i.p. into mice it suppressed sarcoma-180 cell growth and B16-F10 mouse melanoma cell metastasis in vivo. These results suggest that the anti-angiogenic effects of U-995 may be be due to interference with the proliferation and migration of HUVECs as well as inhibition of collagenolysis, thereby leading to inhibition of both angiogenesis and tumor cell growth.

  15. Design, synthesis, and preclinical evaluation of new 5,6- (or 6,7-) disubstituted-2-(fluorophenyl)quinolin-4-one derivatives as potent antitumor agents.

    PubMed

    Chou, Li-Chen; Tsai, Meng-Tung; Hsu, Mei-Hua; Wang, Sheng-Hung; Way, Tzong-Der; Huang, Chi-Hung; Lin, Hui-Yi; Qian, Keduo; Dong, Yizhou; Lee, Kuo-Hsiung; Huang, Li-Jiau; Kuo, Sheng-Chu

    2010-11-25

    Our previous exploration of 2-phenylquinolin-4-ones (2-PQs) has led to an anticancer drug candidate 2-(2-fluorophenyl)-6,7-methylenedioxyquinolin-4-one monosodium phosphate (CHM-1-P-Na). In order to develop additional new drug candidates, novel 2-PQs were designed, synthesized, and evaluated for cytotoxic activity. Most analogues, including 1b, 2a,b, 3a,b, 4a,b, and 5a,b, exhibited significant inhibitory activity (IC(50) of 0.03-8.2 μM) against all tested tumor cell lines. As one of the most potent analogue, 2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (3b) selectively inhibited 14 out of 60 cancer cell lines in a National Cancer Institute (NCI) evaluation. Preliminary mechanism of action study suggested that 3b had a significant effect on the tyrosine autophosphorylation of insulin-like growth factor-1 receptor (IGF-1R). Safety pharmacology profiling of 3b showed no significant effect on normal biological functions of most enzymes tested. Furthermore, sodium 2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl phosphate (15), the monophosphate of 3b, exceeded the activity of doxorubicin and was comparable to CHM-1-P-Na in a Hep3B xenograft nude mice model. In summary, 15 is a promising clinical candidate and is currently under preclinical study.

  16. Design, Synthesis and Antitumor Activity of Novel link-bridge and B-Ring Modified Combretastatin A-4 (CA-4) Analogues as Potent Antitubulin Agents

    PubMed Central

    Duan, Yong-Tao; Man, Ruo-Jun; Tang, Dan-Jie; Yao, Yong-Fang; Tao, Xiang-Xiang; Yu, Chen; Liang, Xin-Yi; Makawana, Jigar A.; Zou, Mei-Juan; Wang, Zhong-Chang; Zhu, Hai-Liang

    2016-01-01

    A series of 12 novel acylhydrazone, chalcone and amide–bridged analogues of combretastatin A-4 were designed and synthesized toward tubulin. All these compounds were determined by elemental analysis, 1H NMR, and MS. Among them, compound 7 with acylhydrazone-bridge, bearing a benzyl at the indole-N position, was identified as a potent antiproliferative agent against a panel of cancer cell lines with IC50 values ranging from 0.08 to 35.6 μM. In contrast, its cytotoxic effects on three normal human cells were minimal. Cellular studies have revealed that the induction of apoptosis by compound 7 was associated with a collapse of mitochondrial membrane potential, accumulation of reactive oxygen species, alterations in the expression of some cell cycle-related proteins (Cyclin B1, Cdc25c, Cdc2, P21) and some apoptosis-related proteins (Bax, PARP, Bcl-2, Caspase3). The docking mode showed the binding posture of CA-4 and compound 7 are similar in the colchicine-binding pocket of tubulin, as confirmed by colchicine-tubulin competitive binding assay, tubulin polymerization inhibitory activity, extracellular protein expression determination assay and confocal immunofluorescence microscopy. In vivo study, compound 7 effectively inhibited A549 xenograft tumor growth without causing significant loss of body weight suggesting that compound 7 is a promising new antimitotic agent with clinical potential. PMID:27138035

  17. Selective inhibition of EZH2 by ZLD1039 blocks H3K27methylation and leads to potent anti-tumor activity in breast cancer

    PubMed Central

    Song, Xuejiao; Gao, Tiantao; Wang, Ningyu; Feng, Qiang; You, Xinyu; Ye, Tinghong; Lei, Qian; Zhu, Yongxia; Xiong, Menghua; Xia, Yong; Yang, Fangfang; Shi, Yaojie; Wei, Yuquan; Zhang, Lidan; Yu, Luoting

    2016-01-01

    Enhancer of zeste homolog 2 (EZH2) is a candidate oncogenic driver due to its prevalent overexpression and aberrant repression of tumor suppressor genes in diverse cancers. Therefore, blocking EZH2 enzyme activity may present a valid therapeutic strategy for the treatment of cancers with EZH2 overexpression including breast cancers. Here, we described ZLD1039 a potent, highly selective, and orally bioavailable small molecule inhibitor of EZH2, which inhibited breast tumor growth and metastasis. ZLD1039 considerably inhibited EZH2 methyltransferase activity with nanomolar potency, decreased global histone-3 lysine-27 (H3K27) methylation, and reactivated silenced tumor suppressors connected to increased survival of patients with breast cancer. Comparable to conditional silencing of EZH2, its inhibition by ZLD1039 decreased cell proliferation, cell cycle arrest, and induced apoptosis. Comparably, treatment of xenograft-bearing mice with ZLD1039 led to tumor growth regression and metastasis inhibition. These data confirmed the dependency of breast cancer progression on EZH2 activity and the usefulness of ZLD1039 as a promising treatment for breast cancer. PMID:26868841

  18. Real-time in situ monitoring via europium emission of the photo-release of antitumor cisplatin from a Eu-Pt complex.

    PubMed

    Li, Hongguang; Lan, Rongfeng; Chan, Chi-Fai; Jiang, Lijun; Dai, Lixiong; Kwong, Daniel W J; Lam, Michael Hon-Wah; Wong, Ka-Leung

    2015-09-25

    A water-soluble light-responsive antitumor agent, PtEuL, based on a cisplatin-linked europium-cyclen complex has been synthesized and evaluated for controlled cisplatin release by linear/two-photon excitation in vitro with concomitant turn-on and long-lived europium emission as a responsive traceable signal.

  19. A Novel Sulindac Derivative That Does Not Inhibit Cyclooxygenases but Potently Inhibits Colon Tumor Cell Growth and Induces Apoptosis with Antitumor Activity

    PubMed Central

    Piazza, Gary A.; Keeton, Adam B.; Tinsley, Heather N.; Gary, Bernard D.; Whitt, Jason D.; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V.; Maxuitenko, Yulia Y.; Reynolds, Robert C.

    2011-01-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC50 values of 2 to 5 µmol/L compared with 73 to 85 µmol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC50 for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy. PMID:19470791

  20. A novel sulindac derivative that does not inhibit cyclooxygenases but potently inhibits colon tumor cell growth and induces apoptosis with antitumor activity.

    PubMed

    Piazza, Gary A; Keeton, Adam B; Tinsley, Heather N; Gary, Bernard D; Whitt, Jason D; Mathew, Bini; Thaiparambil, Jose; Coward, Lori; Gorman, Gregory; Li, Yonghe; Sani, Brahma; Hobrath, Judith V; Maxuitenko, Yulia Y; Reynolds, Robert C

    2009-06-01

    Nonsteroidal anti-inflammatory drugs such as sulindac have shown promising antineoplastic activity, although toxicity from cyclooxygenase (COX) inhibition and the suppression of prostaglandin synthesis limits their use for chemoprevention. Previous studies have concluded that the mechanism responsible for their antineoplastic activity may be COX independent. To selectively design out the COX inhibitory activity of sulindac sulfide (SS), in silico modeling studies were done that revealed the crucial role of the carboxylate moiety for COX-1 and COX-2 binding. These studies prompted the synthesis of a series of SS derivatives with carboxylate modifications that were screened for tumor cell growth and COX inhibitory activity. A SS amide (SSA) with a N,N-dimethylethyl amine substitution was found to lack COX-1 and COX-2 inhibitory activity, yet potently inhibit the growth of human colon tumor cell lines, HT-29, SW480, and HCT116 with IC(50) values of 2 to 5 micromol/L compared with 73 to 85 micromol/L for SS. The mechanism of growth inhibition involved the suppression of DNA synthesis and apoptosis induction. Oral administration of SSA was well-tolerated in mice and generated plasma levels that exceeded its in vitro IC(50) for tumor growth inhibition. In the human HT-29 colon tumor xenograft mouse model, SSA significantly inhibited tumor growth at a dosage of 250 mg/kg. Combined treatment of SSA with the chemotherapeutic drug, Camptosar, caused a more sustained suppression of tumor growth compared with Camptosar treatment alone. These results indicate that SSA has potential safety and efficacy advantages for colon cancer chemoprevention as well as utility for treating malignant disease if combined with chemotherapy.

  1. Humanized Affinity-matured Monoclonal Antibody 8H9 Has Potent Antitumor Activity and Binds to FG Loop of Tumor Antigen B7-H3.

    PubMed

    Ahmed, Mahiuddin; Cheng, Ming; Zhao, Qi; Goldgur, Yehuda; Cheal, Sarah M; Guo, Hong-fen; Larson, Steven M; Cheung, Nai-kong V

    2015-12-11

    B7-H3 (CD276) is both an inhibitory ligand for natural killer cells and T cells and a tumor antigen that is widely expressed among human solid tumors. Anti-B7-H3 mouse monoclonal antibody 8H9 has been successfully used for radioimmunotherapy for patients with B7-H3(+) tumors. We present the humanization, affinity maturation, and epitope mapping of 8H9 based on structure determination, modeling, and yeast display methods. The crystal structure of ch8H9 Fab fragment was solved to 2.5-Å resolution and used as a template for humanization. By displaying the humanized 8H9 single chain Fv (scFv) on the surface of yeast, the affinity was matured by sequential random mutagenesis and fluorescence-activated cell sorting. Six mutations (three in the complementarity-determining region and three in the framework regions) were identified and incorporated into an affinity-matured humanized 8H9 construct (hu8H9-6m) and an affinity-matured chimeric 8H9 construct (ch8H9-6m). The hu8H9-6m scFv had a 160-fold improvement in affinity (0.9 nm KD) compared with parental hu8H9 scFv (144 nm KD). The IgG formats of ch8H9-6m and hu8H9-6m (nanomolar to subnanomolar KD) had 2-9-fold enhancements in affinity compared with their parental forms, potent in vitro antibody-dependent cell-mediated cytotoxicity (0.1-0.3 μg/ml EC50), and high tumor uptake in mouse xenografts. Based on in silico docking studies and experimental validation, the molecular epitope of 8H9 was determined to be dependent on the FG loop of B7-H3, a region critical to its function in immunologic blockade and unique among anti-B7-H3 antibodies published to date. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  2. Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes.

    PubMed

    Xi, Zhaoyong; Guo, Wei; Tian, Changlin; Wang, Fuyi; Liu, Yangzhong

    2014-03-01

    The transport system of platinum-based anticancer agents is crucial for drug sensitivity. Increasing evidence indicates that the copper transport system is also involved in the cellular influx and efflux of platinum drugs. The copper chaperone Atox1 has been shown to bind to cisplatin in vitro and in cells. Previous results reveal that copper binding promotes the reaction between Atox1 and cisplatin. Here, we have performed detailed solution NMR and ESI-MS experiments to investigate the effect of Cu(i) binding on the reactions of Atox1 with two antitumor active trans-platinum agents, trans-EE and trans-PtTz. Results indicate that, similar to the reaction of cisplatin, copper coordination also enhances the platination of Atox1 by two trans-platinum complexes, and platinum binds to the copper coordinating residues. However, copper binding promotes the trans-platinum transfer from Atox1 to dithiothreitol (DTT). This result is in contrast to the reaction of Atox1 with cisplatin, in which the presence of copper largely suppresses the platination of DTT. Additionally, both apo- and Cu(I)-Atox1 react faster with trans-platinum complexes than with cisplatin, however, less protein aggregation is observed in the reaction of trans-platinum complexes. These results indicate that the roles of Atox1 in the regulation of cellular trafficking of platinum drugs are dependent on the coordination configurations.

  3. Refolding and unfolding of CT-DNA by newly designed Pd(II) complexes. Their synthesis, characterization and antitumor effects.

    PubMed

    Dustkami, Mahin; Mansouri-Torshizi, Hassan

    2017-06-01

    New antitumor Pd(II) compounds derived from oxygen donor ligands salicylate (SA) (1) and sulfosalicylate (SSA) (2) dianions and nitrogen donor heterocyclic ligand 2,2'-bipyridine (bpy) were synthesized and characterized by elemental analysis, UV-Vis, FT-IR, (1)H NMR and conductivity measurements. The complexes evaluated for their cytotoxicity effects towards cancer cell line of K562 using MTT assay. They are more cytotoxic than cisplatin. The dependence of their interaction modes with CT-DNA on concentration of the compounds has been discovered in this work. CT-DNA binding studies of these complexes have been investigated by UV-Vis absorption, ethidium bromide (EB) displacement, fluorescence, circular dichroism and gel electrophoresis techniques. The apparent binding constants (Kapp) has been obtained 3.9 and 10.9×10(4)M(-1) at lower concentration range and 1.03 and 1.59×10(4)M(-1) at higher concentration range for complexes (1) and (2), respectively. These complexes effectively interact with CT-DNA in the order of (2)>(1). Fluorescence studies exhibited that the complexes quench CT-DNA-EB by simultaneous static and dynamic quenching processes. The calculated binding (Kapp, kq, KSV, n) and thermodynamic (ΔG°, ΔH°, ΔS°) parameters revealed that hydrophobic, van der Waals forces and hydrogen binding holds the Pd(II) complexes in the CT-DNA grooves. Gel electrophoresis supports the spectroscopic experiments. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Antimicrobial and antitumor activity of platinum and palladium complexes of novel spherical aramides nanoparticles containing flexibilizing linkages: structure-property relationship.

    PubMed

    Elhusseiny, Amel F; Hassan, Hammed H A M

    2013-02-15

    Square planar Pd (II) and octahedral Pt (IV) complexes with novel spherical aramides nanoparticles containing flexible linkages ligands have been synthesized and characterized using analytical and spectral techniques. The synthesized complexes have been tested for their antimicrobial activity using Kirby-Bauer disc diffusion method. The antitumor activity has been performed using liver carcinoma (HEPG2), breast carcinoma (MCF7) and colon carcinoma (HCT 116) cell lines. Palladium complexes of polyamides containing sulfones showed the highest potency as antibacterial and antifungal agents. Platinum complexes containing sulfone and ether flexible linkages and chloro groups exhibited high potency as antitumor and antimicrobial agents. The uniform sizes of these nanomaterials could find biological uses such as immune assay and other medical purposes. Copyright © 2012 Elsevier B.V. All rights reserved.

  5. Antimicrobial and antitumor activity of platinum and palladium complexes of novel spherical aramides nanoparticles containing flexibilizing linkages: Structure-property relationship

    NASA Astrophysics Data System (ADS)

    Elhusseiny, Amel F.; Hassan, Hammed H. A. M.

    2013-02-01

    Square planar Pd (II) and octahedral Pt (IV) complexes with novel spherical aramides nanoparticles containing flexible linkages ligands have been synthesized and characterized using analytical and spectral techniques. The synthesized complexes have been tested for their antimicrobial activity using Kirby-Bauer disc diffusion method. The antitumor activity has been performed using liver carcinoma (HEPG2), breast carcinoma (MCF7) and colon carcinoma (HCT 116) cell lines. Palladium complexes of polyamides containing sulfones showed the highest potency as antibacterial and antifungal agents. Platinum complexes containing sulfone and ether flexible linkages and chloro groups exhibited high potency as antitumor and antimicrobial agents. The uniform sizes of these nanomaterials could find biological uses such as immune assay and other medical purposes.

  6. Ru(η6-arene) complexes of combretastatin-analogous oxazoles with enhanced anti-tumoral impact.

    PubMed

    Biersack, Bernhard; Effenberger, Katharina; Knauer, Sebastian; Ocker, Matthias; Schobert, Rainer

    2010-11-01

    Oxazole-bridged combretastatin A-4 analogues bind to tubulin and exert anti-vascular and anti-angiogenic effects. When linked to Ru(η(6)-arene) complex fragments, conjugates with additional cytotoxic activity result which can ruthenate bionucleophiles such as DNA and proteins. For instance, the Ru(II)(p-cymene)(isonicotinate)Cl(2) complex 6a of the known 4-(3,4,5-trimethoxyphenyl)-5-(3-hydroxy-4-methoxyphenyl)-oxazole 4a was far more active than the latter against cells of the p53-competent wild-type form of HCT-116 colon carcinoma at low 0.01 μM concentrations. A fast reaction of 6a with nucleophilic N-acetyl-L-cysteine was observed in NMR studies. The Ru(arene) complexes 6a-c were also more efficacious against combretastatin-refractory p53(+) cells of human HT-29 colon carcinoma when compared to their parent 4-(3,4-dimethoxy-5-methoxy/halo-phenyl)-5-(3-hydroxy-4-methoxyphenyl)-oxazoles 4a-c. These cells are rich in ABC-transporters which are responsible for their multi-drug resistance and for which conjugates 6 are less good substrates than the phenols 4. Unlike 4a, its complex 6a also diminished the motility of human 518A2 melanoma cells in a wound-healing assay which is indicative of anti-metastatic activity in solid tumors. Overall, the Ru(arene) complex conjugates 6 broaden the anti-tumoral spectrum of the combretastatin A-4 analogues 4 considerably.

  7. BU74, a complex oripavine derivative with potent kappa opioid receptor agonism and delayed opioid antagonism.

    PubMed

    Husbands, Stephen M; Neilan, Claire L; Broadbear, Jillian; Grundt, Peter; Breeden, Simon; Aceto, Mario D; Woods, James H; Lewis, John W; Traynor, John R

    2005-02-21

    In the search for opioid agonists with delayed antagonist actions as potential treatments for substance abuse, the bridged morphinan BU74 (17-cyclopropylmethyl-3-hydroxy-[5beta,7beta,3',5']-pyrrolidino-2'[S]-phenyl-7alpha-methyl-6,14-endoetheno morphinan) (3f) was synthesized. In isolated tissue and [35S]GTPgammaS opioid receptor functional assays BU74 was shown to be a potent long-lasting kappa opioid receptor agonist, delta opioid receptor partial agonist and mu opioid receptor antagonist. In antinociceptive tests in the mouse, BU74 showed high efficacy and potent kappa opioid receptor agonism. When its agonist action had waned BU74 became an antagonist of kappa and mu opioid receptor agonists in the tail flick assay and of delta, kappa and mu opioid receptor agonists in the acetic acid writhing assay. The slow onset, long-duration kappa opioid receptor agonist effects of BU74 suggests that it could be a lead compound for the discovery of a treatment for cocaine abuse.

  8. Synthesis, characterization, DNA and HSA binding studies of isomeric Pd (II) antitumor complexes using spectrophotometry techniques.

    PubMed

    Zareian-Jahromi, Sareh; Mansouri-Torshizi, Hassan

    2017-05-07

    Two new Palladium(II) isomeric complexes, [Pd (Gly)(Leu)](I) and [Pd (Gly)(Ile)](II), where Gly is glycine, and Leu and Ile are isomeric amino acids (leucine and isoleucine), have been synthesized and characterized by elemental analysis, molar conductivity measurements, FT-IR, (1)H NMR, and UV-Vis. The complexes have been tested for their In vitro cytotoxicity against cancer cell line K562 and their binding properties to calf thymus DNA (CT-DNA) and human serum albumin (HSA) have also been investigated by multispectroscopic techniques. Interactions of these complexes with CT-DNA were monitored using gel electrophoresis. The energy transfer from HSA to these complexes and the binding distance between HSA and the complexes (r) were calculated. The results obtained from these studies indicated that at very low concentrations, both complexes effectively interact with CT-DNA and HSA. Fluorescence studies revealed that the complexes strongly quench DNA bound ethidium bromide as well as the intrinsic fluorescence of HSA through the static quenching procedures. Binding constant (Kb), apparent biomolecular quenching constant (kq), and number of binding sites (n) for CT-DNA and HSA were calculated using Stern-Volmer equation. The calculated thermodynamic parameters indicated that the hydrogen binding and vander Waals forces might play a major role in the interaction of these complexes with HSA and DNA. Thus, we propose that the complexes exhibit the groove binding with CT-DNA and interact with the main binding pocket of HSA. The complexes follow the binding affinity order of I > II with DNA- and II > I with HSA-binding.

  9. Synthesis, biological evaluation and SAR studies of novel bicyclic antitumor platinum(IV) complexes.

    PubMed

    Lorenzo, Julia; Delgado, Aida; Montaña, Ángel M; Mesas, Juan M; Alegre, María-Teresa; Rodríguez, María del Carmen; Avilés, Francesc-Xavier

    2014-08-18

    The present study describes the synthesis, anticancer activity and SAR studies of novel platinum(IV) complexes having 1,2-bis(aminomethyl)carbobicyclic or oxabicyclic carrier ligands, bearing chlorido and/or hydroxido ligands in axial position and chlorido or malonato ligands in equatorial position (labile ligands). These complexes were synthetized with the aim of obtaining new anticancer principles more soluble in water and therefore more bioavailable. Several substitution patterns on the platinum atom have been designed in order to evaluate their antiproliferative activity and to establish structure-activity relationship rules. The synthesis of platinum(IV) complexes with axial hydroxyl ligands on the platinum(IV) were carried out by reaction of K2Pt(OH)2Cl4 with the corresponding diamines. The complexes with axial chlorido ligands on the platinum(IV) atom were synthesized by direct reaction of diamines with K2PtCl6. Carboxylated complexes were synthesized by the substitution reaction of equatorial chlorido ligands by silver dicarboxylates. The most actives complexes were those having malonate as a labile ligand, no matter of the structure of the carrier ligand. Regarding the influence of the structure of the non-labile 1,4-diamine carrier ligand on the cytotoxicity, it was found that the complexes having the more lipophilic and symmetrical bicyclo[2.2.2]octane framework were much more active than those having an oxygen or methylene bridge. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  10. Block ionomer complex micelles based on the self-assembly of poly(ethylene glycol)-block-poly(acrylic acid) and CdCl₂ for anti-tumor drug delivery.

    PubMed

    An, Liping; Wang, Yapei; Liu, Xiaomei; Ma, Ning; Du, Haiying; Jin, Minghua; Liu, Ying; Zhang, Long; Xu, Yanling; Huang, Peili; Sun, Zhiwei

    2011-01-01

    A novel block ionomer complex micelles as drug carrier is developed utilizing self-assemble of poly(ethylene glycol)-block-poly(acrylic acid) (PEG-b-PAA) and cadmium chloride. This micelles are characterized to be have good bio-compatibility, hydrophilicity, passive targeting and sustained slow release property which shows great potential for liver cancer therapy. Block ionomer complex micelles based on PEG-b-PAA and cadmium chloride can self-assemble in distilled water, and Cd(²+) agent is entrapped into the core stabilized by PEG shells. Results showed the block ionomer complex micelles to be spherically shaped. Cadmium was incorporated easily into the ionic core with remarkably high efficiency (34.25% weight (wt)/wt). The cadmium-loaded polymeric micelles exhibited sustained and slow release behavior of cadmium and a potent cytotoxicity against SMMC-7721 in vitro. This novel block ionomer complex micelles with cores of metal antitumor drug indicates to be potential carriers for effective drug delivery.

  11. One-dimensional chiral copper (II) complexes with novel nano-structures and superior antitumor activity.

    PubMed

    Zhang, Wei Chuan; Tang, Xue; Lu, Xiaoming

    2016-03-01

    Three novel copper(II) compounds of formulas {[Cu(Phen)(Ala)]·NO3·H2O}n (1), {[Cu(Phen)(Ala)]·NO3}n (2) and [Cu(Ala)2]n (3) have been synthesized and determined by X-ray diffraction. 1 and 2 are shown in one dimensional long-chain chiral structures, and 3 is a two dimensional checkerboard-type structure. Both 1 and 2 displayed a higher anticancer activity than 3 against various cancer cells, even higher than the similar mononuclear complexes and clinical anticancer drug 5-fluorouracil. The noncancerous cell lines (CCC-HEL-1) have showed that complexes 1-3 have hardly any cytotoxicity. Transmission electron microscopy was studied to show the nano-structure and π function of two complexes. The ligand 1,10-phenanthroline inserted into its enantiomer lead complex 1 stable, and the π-π interaction outside the chain made complex 2 active, which is easy to crack and pile up together. In addition, the energy gaps, UV-vis, luminescent and cyclic voltammetry were experimented to show the stable one dimensional long-chain chiral structure and the π function of two complexes.

  12. Polypeptide-based nanogels co-encapsulating a synergistic combination of doxorubicin with 17-AAG show potent anti-tumor activity in ErbB2-driven breast cancer models.

    PubMed

    Desale, Swapnil S; Raja, Srikumar M; Kim, Jong Oh; Mohapatra, Bhopal; Soni, Kruti S; Luan, Haitao; Williams, Stetson H; Bielecki, Timothy A; Feng, Dan; Storck, Matthew; Band, Vimla; Cohen, Samuel M; Band, Hamid; Bronich, Tatiana K

    2015-06-28

    ErbB2-driven breast cancers constitute 20-25% of the cases diagnosed within the USA. The humanized anti-ErbB2 monoclonal antibody, Trastuzumab (Herceptin™; Genentech), with chemotherapy is the current standard of treatment. Novel agents and strategies continue to be explored, given the challenges posed by Trastuzumab-resistance development in most patients. The HSP90 inhibitor, 17-allylaminodemethoxygeldanamycin (17-AAG), which induces ErbB2 degradation and attenuates downstream oncogenic signaling, is one such agent that showed significant promise in early phase I and II clinical trials. Its low water solubility, potential toxicities and undesirable side effects observed in patients, partly due to the Cremophor-based formulation, have been discouraging factors in the advancement of this promising drug into clinical use. Encapsulation of 17-AAG into polymeric nanoparticle formulations, particularly in synergistic combination with conventional chemotherapeutics, represents an alternative approach to overcome these problems. Herein, we report an efficient co-encapsulation of 17-AAG and doxorubicin, a clinically well-established and effective modality in breast cancer treatment, into biodegradable and biocompatible polypeptide-based nanogels. Dual drug-loaded nanogels displayed potent cytotoxicity in a breast cancer cell panel and exerted selective synergistic anticancer activity against ErbB2-overexpressing breast cancer cell lines. Analysis of ErbB2 degradation confirmed efficient 17-AAG release from nanogels with activity comparable to free 17-AAG. Furthermore, nanogels containing both 17-AAG and doxorubicin exhibited superior antitumor efficacy in vivo in an ErbB2-driven xenograft model compared to the combination of free drugs. These studies demonstrate that polypeptide-based nanogels can serve as novel nanocarriers for encapsulating 17-AAG along with other chemotherapeutics, providing an opportunity to overcome solubility issues and thereby exploit its full

  13. Nitro/Nitrosyl-Ruthenium Complexes Are Potent and Selective Anti-Trypanosoma cruzi Agents Causing Autophagy and Necrotic Parasite Death

    PubMed Central

    Bastos, Tanira M.; Barbosa, Marília I. F.; da Silva, Monize M.; da C. Júnior, José W.; Meira, Cássio S.; Guimaraes, Elisalva T.; Ellena, Javier; Moreira, Diogo R. M.; Batista, Alzir A.

    2014-01-01

    cis-[RuCl(NO2)(dppb)(5,5′-mebipy)] (complex 1), cis-[Ru(NO2)2(dppb)(5,5′-mebipy)] (complex 2), ct-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2 (complex 3), and cc-[RuCl(NO)(dppb)(5,5′-mebipy)](PF6)2 (complex 4), where 5,5′-mebipy is 5,5′-dimethyl-2,2′-bipyridine and dppb is 1,4-bis(diphenylphosphino)butane, were synthesized and characterized. The structure of complex 2 was determined by X-ray crystallography. These complexes exhibited a higher anti-Trypanosoma cruzi activity than benznidazole, the current antiparasitic drug. Complex 3 was the most potent, displaying a 50% effective concentration (EC50) of 2.1 ± 0.6 μM against trypomastigotes and a 50% inhibitory concentration (IC50) of 1.3 ± 0.2 μM against amastigotes, while it displayed a 50% cytotoxic concentration (CC50) of 51.4 ± 0.2 μM in macrophages. It was observed that the nitrosyl complex 3, but not its analog lacking the nitrosyl group, releases nitric oxide into parasite cells. This release has a diminished effect on the trypanosomal protease cruzain but induces substantial parasite autophagy, which is followed by a series of irreversible morphological impairments to the parasites and finally results in cell death by necrosis. In infected mice, orally administered complex 3 (five times at a dose of 75 μmol/kg of body weight) reduced blood parasitemia and increased the survival rate of the mice. Combination index analysis of complex 3 indicated that its in vitro activity against trypomastigotes is synergic with benznidazole. In addition, drug combination enhanced efficacy in infected mice, suggesting that ruthenium-nitrosyl complexes are potential constituents for drug combinations. PMID:25092707

  14. Activation of C-H bonds in nitrones leads to iridium hydrides with antitumor activity.

    PubMed

    Song, Xiaoda; Qian, Yong; Ben, Rong; Lu, Xiang; Zhu, Hai-Liang; Chao, Hui; Zhao, Jing

    2013-08-22

    We report the design and synthesis of a series of new cyclometalated iridium hydrides derived from the C-H bond activation of aromatic nitrones and the biological evaluation of these iridium hydrides as antitumor agents. The nitrone ligands are based on the structure of a popular antioxidant, α-phenyl-N-tert-butylnitrone (PBN). Compared to cisplatin, the iridium hydrides exhibit excellent antitumor activity on HepG2 cells. The metal-coordinated compound with the most potent anticancer activity, 2f, was selected for further analysis because of its ability to induce apoptosis and interact with DNA. During in vitro studies and in vivo efficacy analysis with tumor xenograft models in Institute of Cancer Research (ICR) mice, complex 2f exhibited antitumor activity that was markedly superior to that of cisplatin. Our results suggest, for the first time, that metal hydrides could be a new type of metal-based antitumor agent.

  15. Anti-tumor activity and mechanism of apoptosis of A549 induced by ruthenium complex.

    PubMed

    Sun, Dongdong; Mou, Zhipeng; Li, Nuan; Zhang, Weiwei; Wang, Yazhe; Yang, Endong; Wang, Weiyun

    2016-12-01

    Two new ruthenium (II) polypyridyl complexes [Ru(MeIm)4(pip)](2+) (1) and [Ru(MeIm)4(4-npip)](2+) (2) were synthesized under the guidance of computational studies (DFT). Their binding property to human telomeric G-quadruplex studied by UV-Vis absorption spectroscopy, the fluorescent resonance energy transfer (FRET) melting assay and circular dichroism (CD) spectroscopy for validating the theoretical prediction. Both of them were evaluated for their potential anti-proliferative activity against four human tumor cell lines. Complex 2 shows growth inhibition against all the cell lines tested, especially the human lung tumor cell (A549). The RTCA analysis not only validated the inhibition activity but also showed the ability of reducing A549 cells' migration. DNA-flow cytometric analysis, mitochondrial membrane potential (ΔΨm) and the scavenger measurements of reactive oxygen species (ROS) analysis carried out to investigate the mechanism of cell growth inhibition and apoptosis-inducing effect of complex 2. The results demonstrated that complex 2 induces tumor cells apoptosis by acting on both mitochondrial homeostasis destruction and death receptor signaling pathways. And those suggested that complex 2 could be a candidate for further evaluation as a chemotherapeutic agent against human tumor.

  16. Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light-activated antitumor platinum complex that kills human cancer cells by an apoptosis-independent mechanism.

    PubMed

    Westendorf, Aron F; Woods, Julie A; Korpis, Katharina; Farrer, Nicola J; Salassa, Luca; Robinson, Kim; Appleyard, Virginia; Murray, Karen; Grünert, Renate; Thompson, Alastair M; Sadler, Peter J; Bednarski, Patrick J

    2012-09-01

    Photoactivatable Pt(IV) diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC(50) value in 13 cell lines of 55 ± 28 μmol/L after 30 minutes (0.12 mW/cm(2)) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated complex 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of complex 3 have been obtained from (14)N{(1)H} nuclear magnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3, which gives rise to reactive, possibly cytotoxic azidyl radicals. ©2012 AACR.

  17. Group 11 complexes with amino acid derivatives: Synthesis and antitumoral studies.

    PubMed

    Ortego, Lourdes; Meireles, Margarida; Kasper, Cornelia; Laguna, Antonio; Villacampa, M Dolores; Gimeno, M Concepción

    2016-03-01

    Gold(I), gold(III), silver(I) and copper(I) complexes with modified amino acid esters and phosphine ligands have been prepared in order to test their cytotoxic activity. Two different phosphine fragments, PPh3 and PPh2py (py=pyridine), have been used. The amino acid esters have been modified by introducing an aromatic amine as pyridine that coordinates metal fragments through the nitrogen atom, giving complexes of the type [M(L)(PR3)](+) or [AuCl3(L)] (L=l-valine-N-(4-pyridylcarbonyl) methyl ester (L1), l-alanine-N-(4-pyridylcarbonyl) methyl ester (L2), l-phenylalanine-N-(4-pyridylcarbonyl) methyl-ester) (L3); M=Au(I), Ag(I), Cu(I), PR3=PPh3, PPh2py). The in vitro cytotoxic activity of metal complexes was tested against four tumor human cell lines and one tumor mouse cell line. A metabolic activity test (3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) was used and IC50 values were compared with those obtained for cisplatin. Several complexes displayed significant cytotoxic activities. In order to determine whether antiproliferation and cell death are associated with apoptosis, NIH-3T3 cells were exposed to five selected complexes (Annexin V+ FITC, PI) and analyzed by flow cytometry. These experiments showed that the mechanism by which the complexes inhibit cell proliferation inducing cell death in NIH-3T3 cells is mainly apoptotic. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Synthesis and antitumor activity of a series of osmium(VI) nitrido complexes bearing quinolinolato ligands.

    PubMed

    Tang, Quan; Ni, Wen-Xiu; Leung, Chi-Fai; Man, Wai-Lun; Lau, Kenneth King-Kwan; Liang, Yimin; Lam, Yun-Wah; Wong, Wai-Yeung; Peng, Shie-Ming; Liu, Gui-Jian; Lau, Tai-Chu

    2013-11-04

    A series of osmium(VI) nitrido complexes supported by quinolinolato ligands have been prepared and they exhibit promising in vitro anti-cancer activities. These results establish that Os(VI)≡N is a potentially versatile and promising platform for the design of a variety of high-valent anti-cancer drugs.

  19. Guanidine platinum(II) complexes: synthesis, in vitro antitumor activity, and DNA interactions☆

    PubMed Central

    Legin, Anton A.; Jakupec, Michael A.; Bokach, Nadezhda A.; Tyan, Marina R.; Kukushkin, Vadim Yu.; Keppler, Bernhard K.

    2014-01-01

    The novel guanidine compounds trans-[Pt(NH2Me)2{NH=C(NHMe)NR}2](Cl)2 (R = NEt2 [7], NC5H10 [8]) (trans-7,8) were synthesized by the nucleophilic addition of methylamine to dialkylcyanamide ligands of the push–pull nitrile complexes trans-[PtCl2(RCN)2] (R = NEt2, NC5H10). In vitro cytotoxicity tests conducted for the entire series of the guanidine complexes, i.e. trans-7,8, the neutral cis- or trans-[PtCl2{NH=C(NH2)R}2] (cis-1–3 and trans-1–3) and the cationic cis- or trans-[Pt(NH3)2{NH=C(NH2)R}2](Cl)2 (cis-4–6 and trans-4–6) (R = NMe2 [1,4], NEt2 [2,5], NC5H10 [3,6]) in two human cancer cell lines, CH1 (ovarian carcinoma) and SW480 (colon cancer), confirmed that the cytotoxicity of several trans-configured (trans-3,6) complexes is higher than that of cis-congeners (cis-3,6). Cellular platinum levels were analyzed by inductively coupled plasma mass spectrometry upon treatment of SW480 cells, revealing a dependence of cellular accumulation on the geometrical isomerism and the steric hindrance of the variable substituent R on the guanidine ligand. DNA interactions of selected guanidine complexes were studied in order to find hints for the possible reasons for their different activities. Changes induced to the electrophoretic mobility of a dsDNA plasmid confirmed the potency of the guanidine complexes (e.g. trans-1,3,5,6 and cis-1,3,4) to significantly alter DNA secondary structure, indicating DNA as a possible critical target of these compounds. PMID:24444821

  20. Inhibition of endonuclease cleavage and DNA replication of E. coli plasmid by the antitumor rhodium(II) complex.

    PubMed

    Rahman, Md Masudur; Yasuda, Hachiro; Katsura, Shinji; Mizuno, Akira

    2007-08-01

    Binding effect of the antitumor complex rhodium(II) acetate [Rh(2)(O(2)CCH(3))(4)] (Rh1) to the plasmid pUC19 DNA has been studied under different molar ratio of Rh1 compound to base pair of pUC19 DNA (R(f)) and reaction time. The Rh1 binding inhibited the activity of restriction enzyme. The binding effect was monitored using gel electrophoresis. The results indicate that at least one Rh1 binds with the recognition sequence and the binding has no preference between A-T and G-C pairs. At high value of R(f)=100, ICP-MS (Inductively Coupled Plasma Mass Spectrometry) measurement confirmed that 46% of Rh1 binds to DNA. PCR amplification of the DNA was also inhibited by the Rh1 binding. The transformation experiment using Escherichia coli suggested that the cell growth was inhibited after binding the Rh1 to the plasmid. These results indicated that DNA synthesis could be inhibited both in vitro and in vivo by the Rh(2)(O(2)CCH(3))(4) binding.

  1. Potent anticancer activity of photo-activated oxo-bridged diiron(III) complexes.

    PubMed

    Chanu, S Binita; Banerjee, Samya; Roy, Mithun

    2017-01-05

    Cancer-specific anticancer drugs are still an elusive goal. Using light as the temporal control to generate cytotoxic species from photo-activated prodrug in the presence or absence of molecular oxygen has shown potential application targeted chemotherapy as in photodynamic therapy (PDT). In the present work we explored the chemistry of several photo-active (μ-oxo)diiron(III) complexes of the following formulation [{Fe(μ-O) (L-his)(B)}2](ClO4)2 (1a-1c), [Fe2(μ-O)(H2O)2B4](ClO4)4 (2b, 2c) and [Fe2(μ-O)(μ-O2CMe)B4](ClO4)3 (3b, 3c), L-his = l-histidine, B is 2,2'-bipyridine, 1,10-phenanthroline (phen) and dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) complexes for tumor-specific anticancer activity. Facile redox chemistry and photochemical aspects of the complexes prompted us to investigate the cytotoxic as well as the photo-activated cytotoxic properties of the complexes to the cancer cells. In the present investigation we explored the cancer-specific condition of excess concentration of H2O2 for our approach to targeted chemotherapy. Cytotoxic effect of the complexes to the cancer cells was found to be significantly higher than in normal cells indicating tumor-specific anticancer activity of the complexes. Cytotoxic effect was even more pronounced when the cancer cells treated with the complexes were exposed to the visible light (400-700 nm). There was >12 fold increase in cytotoxicity of the photoactivated complexes in cancer cells (MCF-7) in comparison to the normal cells (MCF-10a). We have defined a factor viz. cancer cell specificity factor (f) describing the targeted photochemotherapeutic effect of the complexes at their specific concentration. The factor (f) > 1 indicated the cancer cell specificity of the complexes, while f > 2.5 for the complexes under the visible light exposure suggested photodynamic effect. DCFDA assay indicated the presence of excess of ROS in the treated HeLa cells. ROS concentration was found to increase even more on visible

  2. In Vitro Antitumor Active Gold(I) Triphenylphosphane Complexes Containing 7-Azaindoles

    PubMed Central

    Štarha, Pavel; Trávníček, Zdeněk; Drahoš, Bohuslav; Dvořák, Zdeněk

    2016-01-01

    A series of gold(I) complexes of the general composition [Au(naza)(PPh3)] (1–8) was prepared and thoroughly characterized (e.g., electrospray ionization (ESI) mass spectrometry and multinuclear nuclear magnetic resonance (NMR) spectroscopy). The N1-deprotonated anions of 7-azaindole or its derivatives (naza) are coordinated to the metal centre through the N1 atom of their pyrrole ring, as proved by a single crystal X-ray analysis of the complexes [Au(3I5Braza)(PPh3)] (7) and [Au(2Me4Claza)(PPh3)]·½H2O (8′). The in vitro cytotoxicity of the complexes 1–8 was studied against both the cisplatin-sensitive and -resistant variants of the A2780 human ovarian carcinoma cell line, as well as against the MRC-5 human normal fibroblast cell line. The complexes 4, 5, and 8, containing deprotonated 3-iodo-7-azaindole, 5-bromo-7-azaindole, and 2-methyl-4-chloro-7-azaindole (2Me4Claza), respectively, showed significantly higher potency (IC50 = 2.8–3.5 µM) than cisplatin (IC50 = 20.3 µM) against the A2780 cells and markedly lower effect towards the MRC-5 non-cancerous cells (IC50 = 26.0–29.2 µM), as compared with the mentioned A2780 cancer cells. The results of the flow cytometric studies of the A2780 cell cycle perturbations revealed a G2-cell cycle phase arrest of the cells treated by the representative complexes 1 and 5, which is indicative of a different mechanism of action from cisplatin (induced S-cell cycle phase arrest). The stability of the representative complex 8 in the water-containing solution as well as its ability to interact with the reduced glutathione, cysteine and bovine serum albumin was also studied using 1H and 31P-NMR spectroscopy (studied in the 50% DMF-d7/50% D2O mixture) and ESI+ mass spectrometry (studied in the 50% DMF/50% H2O mixture); DMF = dimethylformamide. The obtained results are indicative for the release of the N-donor azaindole-based ligand in the presence of the used biomolecules. PMID:27973440

  3. Synthesis, cytotoxicity, and apoptosis induction study of antitumor dinuclear platinum(II) complexes.

    PubMed

    Xu, Gang; Gou, Shaohua; Gao, Chuanzhu

    2013-04-01

    Five novel dinuclear platinum(II) complexes with a new chiral ligand, 3-(2-amino-cyclohexylamino)-propionic acid (HP), were designed, prepared and spectrally characterized. The in vitro cytotoxicities of these compounds were evaluated against the HepG-2, MCF-7, A549, and HCT-116 cell lines. The results indicated that all compounds showed cytotoxicity towards the HepG-2 cell line. Particularly, complex X5, which has SO 4₂₋ as a bridge, exhibited better cytotoxicity than carboplatin or oxaliplatin against all selected cell lines. Moreover, double dyeing flow cytometric resection indicated that the target compounds inhibited tumor cell growth by inducing apoptosis. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. The DREAM complex in anti-tumor activity of imatinib mesylate in gastrointestinal stromal tumors (GISTs)

    PubMed Central

    DeCaprio, James A.; Duensing, Anette

    2014-01-01

    Purpose of review Although most gastrointestinal stromal tumors (GISTs) respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), the majority of patients achieve disease stabilization and complete remissions are rare. Furthermore, discontinuation of treatment in the presence of residual tumor mass almost inevitably leads to tumor progression. These observations suggest that a subset of tumor cells not only persists under imatinib treatment, but remains viable. The current article reviews the molecular basis for these findings and explores strategies to exploit them therapeutically. Recent findings Although imatinib can induce apoptosis in a subset of GIST cells, it can induce a reversible exit from the cell division cycle and entry into G0, a cell cycle state called quiescence, in the remaining cells. Mechanistically, this process involves the DREAM complex, a newly identified key regulator of quiescence. Interfering with DREAM complex formation either by siRNA-mediated knockdown or by pharmacological inhibition of the regulatory kinase DYRK1A was shown to enhance imatinib-induced GIST cell death. Summary Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses. PMID:24840522

  5. Gene-carried hepatoma targeting complex induced high gene transfection efficiency with low toxicity and significant antitumor activity

    PubMed Central

    Zhao, Qing-Qing; Hu, Yu-Lan; Zhou, Yang; Li, Ni; Han, Min; Tang, Gu-Ping; Qiu, Feng; Tabata, Yasuhiko; Gao, Jian-Qing

    2012-01-01

    Background The success of gene transfection is largely dependent on the development of a vehicle or vector that can efficiently deliver a gene to cells with minimal toxicity. Methods A liver cancer-targeted specific peptide (FQHPSF sequence) was successfully synthesized and linked with chitosan-linked polyethylenimine (CP) to form a new targeted gene delivery vector called CPT (CP/peptide). The structure of CPT was confirmed by 1H nuclear magnetic resonance spectroscopy and ultraviolet spectrophotometry. The particle size of CPT/ DNA complexes was measured using laser diffraction spectrometry and the cytotoxicity of the copolymer was evaluated by methylthiazol tetrazolium method. The transfection efficiency evaluation of the CP copolymer was performed using luciferase activity assay. Cellular internalization of the CP/DNA complex was observed under confocal laser scanning microscopy. The targeting specificity of the polymer coupled to peptide was measured by competitive inhibition transfection study. The liver targeting specificity of the CPT copolymer in vivo was demonstrated by combining the copolymer with a therapeutic gene, interleukin-12, and assessed by its abilities in suppressing the growth of ascites tumor in mouse model. Results The results showed that the liver cancer-targeted specific peptide was successfully synthesized and linked with CP to form a new targeted gene delivery vector called CPT. The composition of CPT was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa), CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer. Conclusion The synthesized CPT copolymer was proven to be an effective liver cancer

  6. Verteporfin, a suppressor of YAP-TEAD complex, presents promising antitumor properties on ovarian cancer.

    PubMed

    Feng, Juntao; Gou, Jinhai; Jia, Jia; Yi, Tao; Cui, Tao; Li, Zhengyu

    2016-01-01

    Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP-TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP-TEAD complex.

  7. Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

    PubMed Central

    Feng, Juntao; Gou, Jinhai; Jia, Jia; Yi, Tao; Cui, Tao; Li, Zhengyu

    2016-01-01

    Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex. PMID:27621651

  8. Synthesis, spectroscopic studies, antimicrobial activities and antitumor of a new monodentate V-shaped Schiff base and its transition metal complexes.

    PubMed

    Ramadan, Ramadan M; Abu Al-Nasr, Ahmad K; Noureldeen, Amani F H

    2014-11-11

    Reaction of 4-aminoacetophenone and 4-bromobenzaldehyde in ethanol resulted in the formation of the monodentate V-shaped Schiff base (E)-1-(4-((4-bromo-benzylidene)amino)phenyl)ethanone (L). Interaction of L with different di- and trivalent metal ions revealed disubstituted derivatives. The ligand and its complexes were characterized by elemental analysis, mass, IR and NMR spectrometry. Biological activities of the ligand and complexes against the Escherchia coli and Staphylococcus aureus bacterias, and the two fungus Aspergillus flavus and Candida albicans were screened. The cytotoxicity of the compounds were checked as antitumor agents on liver carcinoma cell line (HepG2). They exhibited in vitro broad range of antitumor activities towards the cell line; the [ZnL2(H2O)2](NO3)2 complex was stronger antitumor towards HepG2 cell line as well as two breast cancer cell lines (MCF7 and T47D) relative to cis-platin. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Discovery of an Octahedral Silicon Complex as a Potent Antifungal Agent.

    PubMed

    Fu, Chen; Fu, Bin; Peng, Xixi; Liao, Guojian

    2017-04-15

    Octahedral transition metal complexes have been shown to have tremendous applications in chemical biology and medicinal chemistry. Meanwhile, structural transition metals can be replaced by inert octahedral silicon in a proof-of-principle study. We here introduce the first example of octahedral silicon complexes, which can very well serve as an efficient antimicrobial agent. The typical silicon arenediolate complex 1 {[(phen)₂Si(OO)](PF₆)₂, with phen = 1,10-phenanthroline, OO = 9,10-phenanthrenediolate} exhibited significant inhibition towards the growth of Cryptococcus neoformans with MIC and MFC values of 4.5 and 11.3 μM, respectively. Moreover, it was fungicidal against both proliferative and quiescent Cryptococcus cells. This work may set the stage for the development of novel antifungal drugs based upon hexacoodinate silicon scaffolds.

  10. Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands.

    PubMed

    Yang, Qing; Chang, Jun; Song, Jiao; Qian, Meng-Ting; Yu, Jian-Ming; Sun, Xun

    2013-08-15

    Four novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands were designed, synthesized, and characterized by FT-IR, NMR, and MS. The cytotoxicities of all of the complexes against the human solid tumor cell lines A2780, A549, KB, and MDA-MB-231 were evaluated. Both R,R-configured complexes (R,R)-5a and (R,R)-5b exhibited more potent or similar activity compared with oxaliplatin, whereas their corresponding (S,S)-isomers (S,S)-5a and (S,S)-5b were found to be mostly inactive. As indicated by the activation of caspase-3, the cleavage of PARP, and the upregulation of p53, the preliminary mechanism studies revealed that the mode of cell death initiated by (R,R)-5a in A2780 cells was predominantly p53-mediated apoptosis. In addition, the structure of (R,R)-5a was unambiguously confirmed through single crystal X-ray structure determination. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Structure-activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity.

    PubMed

    Fu, Ying; Habtemariam, Abraha; Basri, Aida M B H; Braddick, Darren; Clarkson, Guy J; Sadler, Peter J

    2011-10-28

    We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(η(6)-arene)(phenylazopyridine)X](+) in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF(3), OH or NO(2)). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity. In general the introduction of an electron-withdrawing group (e.g. F, Cl, Br or I) at specific positions on the pyridine ring significantly increases cytotoxic activity and aqueous solubility. Changing the arene from p-cymene to biphenyl and the monodentate ligand X from chloride to iodide also increases the activity significantly. Activation by hydrolysis and DNA binding appears not to be the major mechanism of action since both the highly active complex [Os(η(6)-bip)(2-F-azpy)I]PF(6) (9) and the moderately active complex [Os(η(6)-bip)(3-Cl-azpy)I]PF(6) (23) are very stable and inert towards aquation. Studies of octanol-water partition coefficients (log P) and subcellular distributions of osmium in A2780 human ovarian cancer cells suggested that cell uptake and targeting to cellular organelles play important roles in determining activity. Although complex 9 induced the production of reactive oxygen species (ROS) in A2780 cells, the ROS level did not appear to play a role in the mechanism of anticancer activity. This class of organometallic osmium complexes has new and unusual features worthy of further exploration for the design of novel anticancer drugs.

  12. Breast Cancer Stem Cell Potent Copper(II)-Non-Steroidal Anti-Inflammatory Drug Complexes.

    PubMed

    Boodram, Janine N; Mcgregor, Iain J; Bruno, Peter M; Cressey, Paul B; Hemann, Michael T; Suntharalingam, Kogularamanan

    2016-02-18

    The breast cancer stem cell (CSC) potency of a series of copper(II)-phenanthroline complexes containing the nonsteroidal anti-inflammatory drug (NSAID), indomethacin, is reported. The most effective copper(II) complex in this series, 4, selectivity kills breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Furthermore, 4 reduces the formation, size, and viability of mammospheres, to a greater extent than salinomycin, a potassium ionophore known to selectively inhibit CSCs. Mechanistic studies revealed that the CSC-specificity observed for 4 arises from its ability to generate intracellular reactive oxygen species (ROS) and inhibit cyclooxygenase-2 (COX-2), an enzyme that is overexpressed in breast CSCs. The former induces DNA damage, activates JNK and p38 pathways, and leads to apoptosis.

  13. Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors

    PubMed Central

    Lee, Youngjin; Ryu, Young Bae; Youn, Hyung-Seop; Cho, Jung Keun; Kim, Young Min; Park, Ji-Young; Lee, Woo Song; Park, Ki Hun; Eom, Soo Hyun

    2014-01-01

    Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme–inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents. PMID:24816104

  14. A breast cancer stem cell-selective, mammospheres-potent osmium(VI) nitrido complex.

    PubMed

    Suntharalingam, Kogularamanan; Lin, Wei; Johnstone, Timothy C; Bruno, Peter M; Zheng, Yao-Rong; Hemann, Michael T; Lippard, Stephen J

    2014-10-15

    The effect of a newly developed osmium(VI) nitrido complex, 1, on breast cancer stem cells (CSCs) is reported. The complex displays selective toxicity for HMLER breast cancer cells enriched with CD44-positive, CSC-like cells over the same cells having reduced CSC character. Remarkably, 1 also reduces the proportion of CSCs within a heterogeneous breast cancer cell population and irreversibly inhibits the formation of free-floating mammospheres to an extent similar to that of salinomycin, a natural product that targets CSCs. Detailed mechanistic studies reveal that in breast cancer cells 1 induces DNA damage and endoplasmic reticulum stress, the latter being responsible for the CSC selectivity. The anti-CSC properties of 1 provide a strong impetus for the development of new metal-based compounds to target CSCs and to treat chemotherapy-resistant and relapsed tumors.

  15. Structural basis of sialidase in complex with geranylated flavonoids as potent natural inhibitors.

    PubMed

    Lee, Youngjin; Ryu, Young Bae; Youn, Hyung-Seop; Cho, Jung Keun; Kim, Young Min; Park, Ji-Young; Lee, Woo Song; Park, Ki Hun; Eom, Soo Hyun

    2014-05-01

    Sialidase catalyzes the removal of a terminal sialic acid from glycoconjugates and plays a pivotal role in nutrition, cellular interactions and pathogenesis mediating various infectious diseases including cholera, influenza and sepsis. An array of antiviral sialidase agents have been developed and are commercially available, such as zanamivir and oseltamivir for treating influenza. However, the development of bacterial sialidase inhibitors has been much less successful. Here, natural polyphenolic geranylated flavonoids which show significant inhibitory effects against Cp-NanI, a sialidase from Clostridium perfringens, are reported. This bacterium causes various gastrointestinal diseases. The crystal structure of the Cp-NanI catalytic domain in complex with the best inhibitor, diplacone, is also presented. This structure explains how diplacone generates a stable enzyme-inhibitor complex. These results provide a structural framework for understanding the interaction between sialidase and natural flavonoids, which are promising scaffolds on which to discover new anti-sialidase agents.

  16. Novel Biologically Potent Diorganosilicon(IV) Complexes of Indole-2,3-Dione Derivatives

    PubMed Central

    Nagpal, Pooja

    2005-01-01

    The aim of the present study is to synthesize some novel ecofriendly fungicides and bactericides of indole-2,3-dione derivatives, having important pharmacodynamic significance. The ligands used in the present account are derived by the condensation of 1,3-dihydro-3-[2-(phenyl)-2-oxoethylidene]-2H-indol-2- one, 1,3-dihydro-3-[2-(4-nitrophenyl)-2-oxoethylidene]-2H-indol-2-one and 1,3-dihydro-3-[2-(4-nitro-3-methylphenyl)- 2-oxoethylidene]-2H-indol-2-one with hydrazinecarboxamide and hydrazinecarbothioamide. These imines, on interaction with diorganosilicon(IV) chlorides, yield complexes having Si–O or Si–S and Si←N bonds. The structure of these compounds have been elucidated by elemental microanalyses and spectral [(UV), (IR), 1H, 13C and 29Si NMR)] studies which unerringly point to a trigonal bipyramidal and octahedral geometries for unimolar and bimolar reactions, respectively. The potency of the synthesized compounds have been assessed by growth inhibiting potential of the complexes against variety of fungal and bacterial strains and male albino rats. The results of these biological studies have been compared with the standard fungicide, Bavistin. The studies demonstrate that, 1,3-dihydro-3-[2-(4-nitrophenyl)-2-oxoethylidene]-2H-indol-2-onehydrazincarbothioamide and its diphenylsilicon(IV) complexes have comparable antimicrobial activity and are less toxic to male albino rats than Bavistin. PMID:18365103

  17. Phase 2 Study of the Safety and Antitumor Activity of Apalutamide (ARN-509), a Potent Androgen Receptor Antagonist, in the High-risk Nonmetastatic Castration-resistant Prostate Cancer Cohort.

    PubMed

    Smith, Matthew R; Antonarakis, Emmanuel S; Ryan, Charles J; Berry, William R; Shore, Neal D; Liu, Glenn; Alumkal, Joshi J; Higano, Celestia S; Chow Maneval, Edna; Bandekar, Rajesh; de Boer, Carla J; Yu, Margaret K; Rathkopf, Dana E

    2016-12-01

    Apalutamide is a potent androgen receptor (AR) antagonist that targets the AR ligand-binding domain and prevents AR nuclear translocation, DNA binding, and transcription of AR gene targets. To evaluate the activity and safety of apalutamide in patients with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC). We conducted a multicenter phase 2 study of nmCRPC patients with a high risk for progression (prostate-specific antigen [PSA] ≥8 ng/ml or PSA doubling time [PSA DT] ≤10 mo). Patients received 240mg/d apalutamide while continuing on androgen-deprivation therapy. Primary end point was 12-wk PSA response (Prostate Cancer Working Group 2 criteria). Secondary end points included safety, time to PSA progression (TTPP), and metastasis-free survival (MFS). A total of 51 patients were enrolled; four patients with metastatic disease were excluded from the efficacy analysis. Patient characteristics included median age, 71 yr; Eastern Cooperative Oncology Group performance status 0 (76%); Gleason score ≤7 (57%); median PSA 10.7 ng/ml; and PSA DT ≤10 mo (45%). At median follow-up of 28.0 mo, 18 patients (35%) remained in the study. Overall, 89% of patients had ≥50% PSA decline at 12 wk. Median TTPP was 24.0 mo (95% confidence interval [CI], 16.3 mo-not reached [NR]); median MFS was NR (95% CI, 33.4 mo-NR). Most of the patients discontinued study treatment (n=33) due to disease progression (n=11 [22%]) or adverse events (AEs) (n=9 [18%]). The most common AE was fatigue (any grade, n=31 [61%]) although grade ≥3 fatigue was uncommon (n=2 [4%]). These represent the first apalutamide nmCRPC patient clinical data. In high-risk nmCRPC patients, apalutamide was safe with robust activity based on durable PSA responses and disease control. Antitumor activity and the safety of apalutamide in patients with nonmetastatic castration-resistant prostate cancer support continued development in this setting. ClinicalTrials.gov identifier NCT01171898. Copyright

  18. In vitro and in vivo antitumor effects of the VO-chrysin complex on a new three-dimensional osteosarcoma spheroids model and a xenograft tumor in mice.

    PubMed

    León, Ignacio E; Cadavid-Vargas, Juan F; Resasco, Agustina; Maschi, Fabricio; Ayala, Miguel A; Carbone, Cecilia; Etcheverry, Susana B

    2016-12-01

    Osteosarcoma (OS) is the most common primary tumor of bone, occurring predominantly in the second decade of life. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for patients with localized disease. Vanadium is an ultra-trace element that after being absorbed accumulates in bone. Besides, vanadium compounds have been studied during recent years to be considered as representative of a new class of non-platinum antitumor agents. Moreover, flavonoids are a wide family of polyphenolic compounds that display many interesting biological effects. Since coordination of ligands to metals can improve the pharmacological properties, we report herein, for the first time, the in vitro and in vivo effects of an oxidovanadium(IV) complex with the flavonoid chrysin on the new 3D human osteosarcoma and xenograft osteosarcoma mice models. The pharmacological results show that VOchrys inhibited the cell viability affecting the shape and volume of the spheroids and VOchrys suppressed MG-63 tumor growth in the nude mice without inducing toxicity and side effects. As a whole, the results presented herein demonstrate that the antitumor action of the complex was very promissory on human osteosarcoma models, whereby suggesting that VOchrys is a potentially good candidate for future use in alternative antitumor treatments.

  19. Gold(I) complex of N,N'-disubstituted cyclic thiourea with in vitro and in vivo anticancer properties-potent tight-binding inhibition of thioredoxin reductase.

    PubMed

    Yan, Kun; Lok, Chun-Nam; Bierla, Katarzyna; Che, Chi-Ming

    2010-11-07

    Coinage metal complexes of an N,N'-disubstituted cyclic thiourea exert significant cytotoxicities to cancer cells and, in particular, the gold(i) thiourea complex exhibits a potent tight-binding inhibition of the anticancer drug target thioredoxin reductase with an inhibitory constant at nanomolar level.

  20. Potent DNA strand annealing activity associated with mouse Mcm2∼7 heterohexameric complex

    PubMed Central

    Masai, Hisao

    2017-01-01

    Abstract Mini-chromosome maintenance (Mcm) is a central component for DNA unwinding reaction during eukaryotic DNA replication. Mcm2∼7, each containing a conserved ATPase motif, form a six subunit-heterohexamer. Although the reconstituted Mcm2∼7–Cdc45–GINS (CMG) complex displays DNA unwinding activity, the Mcm2∼7 complex does not generally exhibit helicase activity under a normal assay condition. We detected a strong DNA strand annealing activity in the purified mouse Mcm2∼7 heterohexamer, which promotes rapid reassociation of displaced complementary single-stranded DNAs, suggesting a potential cause for its inability to exhibit DNA helicase activity. Indeed, DNA unwinding activity of Mcm2∼7 could be detected in the presence of a single-stranded DNA that is complementary to the displaced strand, which would prevent its reannealing to the template. ATPase-deficient mutations in Mcm2, 4, 5 and 6 subunits inactivated the annealing activity, while those in Mcm2 and 5 subunits alone did not. The annealing activity of Mcm2∼7 does not require Mg2+ and ATP, and is adversely inhibited by the presence of high concentration of Mg2+ and ATP while activated by similar concentrations of ADP. Our findings show that the DNA helicase activity of Mcm2∼7 may be masked by its unexpectedly strong annealing activity, and suggest potential physiological roles of strand annealing activity of Mcm during replication stress responses. PMID:28449043

  1. Crystal Structure of Checkpoint Kinase 2 in Complex with Nsc 109555, a Potent and Selective Inhibitor

    SciTech Connect

    Lountos, George T.; Tropea, Joseph E.; Zhang, Di; Jobson, Andrew G.; Pommier, Yves; Shoemaker, Robert H.; Waugh, David S.

    2009-03-05

    Checkpoint kinase 2 (Chk2), a ser/thr kinase involved in the ATM-Chk2 checkpoint pathway, is activated by genomic instability and DNA damage and results in either arrest of the cell cycle to allow DNA repair to occur or apoptosis if the DNA damage is severe. Drugs that specifically target Chk2 could be beneficial when administered in combination with current DNA-damaging agents used in cancer therapy. Recently, a novel inhibitor of Chk2, NSC 109555, was identified that exhibited high potency (IC{sub 50} = 240 nM) and selectivity. This compound represents a new chemotype and lead for the development of novel Chk2 inhibitors that could be used as therapeutic agents for the treatment of cancer. To facilitate the discovery of new analogs of NSC 109555 with even greater potency and selectivity, we have solved the crystal structure of this inhibitor in complex with the catalytic domain of Chk2. The structure confirms that the compound is an ATP-competitive inhibitor, as the electron density clearly reveals that it occupies the ATP-binding pocket. However, the mode of inhibition differs from that of the previously studied structure of Chk2 in complex with debromohymenialdisine, a compound that inhibits both Chk1 and Chk2. A unique hydrophobic pocket in Chk2, located very close to the bound inhibitor, presents an opportunity for the rational design of compounds with higher binding affinity and greater selectivity.

  2. Synthesis and reactivity of the aquation product of the antitumor complex trans-[Ru(III)Cl4(indazole)2]-.

    PubMed

    Cebrián-Losantos, Berta; Reisner, Erwin; Kowol, Christian R; Roller, Alexander; Shova, Sergiu; Arion, Vladimir B; Keppler, Bernhard K

    2008-07-21

    , cyclic voltammetry, and X-ray crystallography. Electrochemical investigations give insight into the mechanistic details of the solvolytic behavior of complex 2. The lability of the aqua ligand in 2 suggests that this complex is a potential active species responsible for the high antitumor activity of trans-[Ru(III)Cl4(Hind)2](-).

  3. Potent non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase complex.

    PubMed

    Sun, Aiming; Yoon, Jeong-Joong; Yin, Yan; Prussia, Andrew; Yang, Yutao; Min, Jaeki; Plemper, Richard K; Snyder, James P

    2008-07-10

    Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350000 deaths/year result from MV or associated complications. Antimeasles compounds could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus's RNA-dependent RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoromethyl)- N-[4-sulfonylphenyl]-1 H-pyrazole-5-carboxamide, 1 carries a critical CF 3 moiety on the 1,2-pyrazole ring. Elaborating on the preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much broader range of low nanomolar nonpeptidic MV inhibitors and speculates on the role of the CF 3 functionality.

  4. Potent antilisterial cell-free supernatants produced by complex red-smear cheese microbial consortia.

    PubMed

    Bleicher, A; Stark, T; Hofmann, T; Bogovic Matijasić, B; Rogelj, I; Scherer, S; Neuhaus, K

    2010-10-01

    The microbial surface ripening consortia of 49 soft cheeses were investigated with respect to their inhibition of Listeria monocytogenes. When L. monocytogenes EGDe (serovar 1/2a) was cultivated in cell-free supernatants obtained from consortia grown for 8 h in liquid medium, a strong bactericidal activity was observed in several cases. The cell-free supernatants of 2 of these consortia (I and II) reduced an initial L. monocytogenes inoculum of 5 × 10(7) cfu/mL to zero after 24 h of incubation. No inhibitory substances could be washed off the complex consortia when incubated for a 10-min period. A taxonomical analysis of the antilisterial consortia I and II using Fourier transform infrared spectroscopy yielded a considerable species diversity, with lactic acid bacteria increasing strongly during the 8-h cultivation. Therefore, 23 lactic acid bacteria bacteriocin genes were assayed using specific PCR primers, identifying 3 bacteriocin genes in both microbial communities. However, no transcription of these genes was found on cheese surfaces or in consortia propagated in liquid culture. Individual lactic acid bacteria isolates of consortia I and II displayed no or only weak inhibition of L. monocytogenes on solid medium. The complex cell-free supernatants I and II, in contrast, exhibited an unusually broad inhibitory spectrum, killing L. monocytogenes ssp., Bacillus spp., Staphylococcus aureus, as well as gram-negative bacteria such as Escherichia coli DH5α and Salmonella enterica serovar Typhimurium. Inhibition could not be abolished by heating to 100°C or by proteinase K treatment. Initial purification of an inhibitory substance from consortium I by solid-phase extraction and HPLC indicates the presence of rather small, extremely stable compounds, which, most probably, are not bacteriocins.

  5. Oral delivery of a potent anti-angiogenic heparin conjugate by chemical conjugation and physical complexation using deoxycholic acid.

    PubMed

    Alam, Farzana; Al-Hilal, Taslim A; Chung, Seung Woo; Seo, Donghyun; Mahmud, Foyez; Kim, Han Sung; Kim, Sang Yoon; Byun, Youngro

    2014-08-01

    Angiogenesis, the formation of new blood vessels, plays a pivotal role in tumor progression and for this reason angiogenesis inhibitors are an important class of therapeutics for cancer treatment. Heparin-based angiogenesis inhibitors have been newly developed as one of such classes of therapeutics and possess a great promise in the clinical context. Taurocholate conjugated low molecular weight heparin derivative (LHT7) has been proven to be a potent, multi-targeting angiogenesis inhibitor against broad-spectrum angiogenic tumors. However, major limitations of LHT7 are its poor oral bioavailability, short half-life, and frequent parenteral dosing schedule. Addressing these issues, we have developed an oral formulation of LHT7 by chemically conjugating LHT7 with a tetrameric deoxycholic acid named LHTD4, and then physically complexing it with deoxycholylethylamine (DCK). The resulting LHTD4/DCK complex showed significantly enhanced oral bioavailability (34.3 ± 2.89%) and prolonged the mean residence time (7.5 ± 0.5 h). The LHTD4/DCK complex was mostly absorbed in the intestine by transcellular pathway via its interaction with apical sodium bile acid transporter. In vitro, the VEGF-induced sprouting of endothelial spheroids was significantly blocked by LHTD4. LHTD4/DCK complex significantly regressed the total vessel fractions of tumor (77.2 ± 3.9%), as analyzed by X-ray microCT angiography, thereby inhibiting tumor growth in vivo. Using the oral route of administration, we showed that LHTD4/DCK complex could be effective and chronically administered as angiogenesis inhibitor.

  6. Structural characterization of more potent alternatives to HAMLET, a tumoricidal complex of α-lactalbumin and oleic acid.

    PubMed

    Nemashkalova, Ekaterina L; Kazakov, Alexei S; Khasanova, Leysan M; Permyakov, Eugene A; Permyakov, Sergei E

    2013-09-10

    HAMLET is a complex of human α-lactalbumin (hLA) with oleic acid (OA) that kills various tumor cells and strains of Streptococcus pneumoniae. More potent protein-OA complexes were previously reported for bovine α-lactalbumin (bLA) and β-lactoglobulin (bLG), and pike parvalbumin (pPA), and here we explore their structural features. The concentration dependencies of the tryptophan fluorescence of hLA, bLA, and bLG complexes with OA reveal their disintegration at protein concentrations below the micromolar level. Chemical cross-linking experiments provide evidence that association with OA shifts the distribution of oligomeric forms of hLA, bLA, bLG, and pPA toward higher-order oligomers. This effect is confirmed for bLA and bLG using the dynamic light scattering method, while pPA is shown to associate with OA vesicles. Like hLA binding, OA binding increases the affinity of bLG for small unilamellar dipalmitoylphosphatidylcholine vesicles, while pPA efficiently binds to the vesicles irrespective of OA binding. The association of OA with bLG and pPA increases their α-helix and cross-β-sheet content and resistance to enzymatic proteolysis, which is indicative of OA-induced protein structuring. The lack of excess heat sorption during melting of bLG and pPA in complex with OA and the presence of a cooperative thermal transition at the level of their secondary structure suggest that the OA-bound forms of bLG and pPA lack a fixed tertiary structure but exhibit a continuous thermal transition. Overall, despite marked differences, the HAMLET-like complexes that were studied exhibit a common feature: a tendency toward protein oligomerization. Because OA-induced oligomerization has been reported for other proteins, this phenomenon is inherent to many proteins.

  7. Potent Non-Nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase Complex

    PubMed Central

    Sun, Aiming; Yoon, Jeong-Joong; Yin, Yan; Prussia, Andrew; Yang, Yutao; Min, Jaeki; Plemper, Richard K.; Snyder, James P.

    2008-01-01

    Measles virus (MV) is one of the most infectious pathogens known. In spite of the existence of a vaccine, approximately 350,000 deaths/year result from MV or associated complications. Anti-measles compounds could conceivably diminish these statistics and provide a therapy that complements vaccine treatment. We recently described a high-throughput screening hit compound 1 (16677) against MV-infected cells with the capacity to eliminate viral reproduction at 250 nM by inhibiting the action of the virus’s RNA-dependent RNA polymerase complex (RdRp). The compound, 1-methyl-3-(trifluoromethyl)-N-[4-sulfonylphenyl]-1H-pyrazole-5-carboxamide, carries a critical CF3 moiety on the 1,2-pyrazole ring. Elaborating on the preliminary structure-activity (SAR) study, the present work presents the synthesis and SAR of a much broader range of low nanomolar non-peptidic MV inhibitors and speculates on the role of the CF3 functionality.1 PMID:18529043

  8. Conformation and recognition of DNA modified by a new antitumor dinuclear PtII complex resistant to decomposition by sulfur nucleophiles

    PubMed Central

    Zerzankova, Lenka; Suchankova, Tereza; Vrana, Oldrich; Farrell, Nicholas P.; Brabec, Viktor; Kasparkova, Jana

    2011-01-01

    Reported herein is a detailed biochemical and molecular biophysics study of the molecular mechanism of action of antitumor dinuclear PtII complex [{PtCl(DACH)}2-μ-Y]4+ [DACH = 1,2-diaminocyclohexane, Y =H2N(CH2)6NH2(CH2)2NH2(CH2)6NH2] (complex 1). This new, long-chain bifunctional dinuclear PtII complex is resistant to metabolic decomposition by sulfur-containing nucleophiles. The results show that DNA adducts of 1 can largely escape repair and yet inhibit very effectively transcription so that they should persist longer than those of conventional cisplatin. Hence, they could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. In addition, the findings of the present work make new insights into mechanisms associated with antitumor effects of dinuclear/trinuclear PtII complexes possible. PMID:19682435

  9. Optogenetic excitation of preBötzinger complex neurons potently drives inspiratory activity in vivo

    PubMed Central

    Alsahafi, Zaki; Dickson, Clayton T; Pagliardini, Silvia

    2015-01-01

    Understanding the sites and mechanisms underlying respiratory rhythmogenesis is of fundamental interest in the field of respiratory neurophysiology. Previous studies demonstrated the necessary and sufficient role of preBötzinger complex (preBötC) in generating inspiratory rhythms in vitro and in vivo. However, the influence of timed activation of the preBötC network in vivo is as yet unknown given the experimental approaches previously used. By unilaterally infecting preBötC neurons using an adeno-associated virus expressing channelrhodopsin we photo-activated the network in order to assess how excitation delivered in a spatially and temporally precise manner to the inspiratory oscillator influences ongoing breathing rhythms and related muscular activity in urethane-anaesthetized rats. We hypothesized that if an excitatory drive is necessary for rhythmogenesis and burst initiation, photo-activation of preBötC not only will increase respiratory rate, but also entrain it over a wide range of frequencies with fast onset, and have little effect on ongoing respiratory rhythm if a stimulus is delivered during inspiration. Stimulation of preBötC neurons consistently increased respiratory rate and entrained respiration up to fourfold baseline conditions. Furthermore, brief pulses of photostimulation delivered at random phases between inspiratory events robustly and consistently induced phase-independent (Type 0) respiratory reset and recruited inspiratory muscle activity at very short delays (∼100 ms). A 200 ms refractory period following inspiration was also identified. These data provide strong evidence for a fine control of inspiratory activity in the preBötC and provide further evidence that the preBötC network constitutes the fundamental oscillator of inspiratory rhythms. PMID:26010654

  10. Potent Half-Sandwich Iridium(III) Anticancer Complexes Containing C∧N-Chelated and Pyridine Ligands

    PubMed Central

    2014-01-01

    We report the synthesis and characterization of eight half-sandwich cyclopentadienyl IrIII pyridine complexes of the type [(η5-Cpxph)Ir(phpy)Z]PF6, in which Cpxph = C5Me4C6H5 (tetramethyl(phenyl)cyclopentadienyl), phpy = 2-phenylpyridine as C∧N-chelating ligand, and Z = pyridine (py) or a pyridine derivative. Three X-ray crystal structures have been determined. The monodentate py ligands blocked hydrolysis; however, antiproliferative studies showed that all the Ir compounds are highly active toward A2780, A549, and MCF-7 human cancer cells. In general the introduction of an electron-donating group (e.g., Me, NMe2) at specific positions on the pyridine ring resulted in increased antiproliferative activity, whereas electron-withdrawing groups (e.g., COMe, COOMe, CONEt2) decreased anticancer activity. Complex 5 displayed the highest anticancer activity, exhibiting submicromolar potency toward a range of cancer cell lines in the National Cancer Institute NCI-60 screen, ca. 5 times more potent than the clinical platinum(II) drug cisplatin. DNA binding appears not to be the major mechanism of action. Although complexes [(η5-Cpxph)Ir(phpy)(py)]+ (1) and [(η5-Cpxph)Ir(phpy)(4-NMe2-py)]+ (5) did not cause cell apoptosis or cell cycle arrest after 24 h drug exposure in A2780 human ovarian cancer cells at IC50 concentrations, they increased the level of reactive oxygen species (ROS) dramatically and led to a loss of mitochondrial membrane potential (ΔΨm), which appears to contribute to the anticancer activity. This class of organometallic Ir complexes has unusual features worthy of further exploration in the design of novel anticancer drugs. PMID:25328266

  11. Synthesis and antitumor activity of cis-dichloroplatinum(II) complexes of 1-(2-aminophenyl)-1,2,3,4-tetrahydroisoquinolines.

    PubMed

    Kuo, Chen-Yuan; Wu, Ming-Jung; Kuo, Yao-Haur

    2006-08-01

    Fifteen cis-dichloroplatinum complexes (5a-5o) were synthesized by treatment of 1-(2-aminophenyl)-1,2,3,4-THIQs (4a-4o) with K(2)PtCl(4). The antitumor activity of these compounds was examined against four different human tumor cell lines. Their structure-activity relationships for antitumor activity are reported. All of these compounds exhibited activity against MCF-7 cell line and showed good activity against WiDr cell line except 5c and 5f. On the other hand, compounds 5j and 5o are more active than the other compounds against Hepa59T/VGH cell line. The electron-donating group at the 6-position of isoquinoline ring seems to decrease the antitumor activity and the chloro substituent at the C-4 position of the aniline ring shown the highest potency. The "trans influence" dominates the control of the stability of [1-(2-aminophenyl)-1,2,3,4-THIQ]dichloroplatinums(II).

  12. Crystal Structure and Antitumor Activity of the Novel Zwitterionic Complex of tri-n-Butyltin(IV) with 2-Thiobarbituric Acid

    PubMed Central

    Balas, Vasilios I.; Hadjikakou, Sotiris K.; Hadjiliadis, Nick; Kourkoumelis, Nikolaos; Light, Mark E.; Hursthouse, Mike; Metsios, Apostolos K.; Karkabounas, Spyros

    2008-01-01

    A novel tri-n-butyl(IV) derivative of 2-thiobarbituric acid (HTBA) of formula [(n-Bu)3Sn(TBA) H2O] (1) has been synthesized and characterized by elemental analysis and 119Sn-NMR and FT-IR spectroscopic techniques. The crystal structure of complex 1 has been determined by single crystal X-ray diffraction analysis at 120(2) K. The geometry around Sn(IV) is trigonal bipyramidal. Three n-butyl groups and one oxygen atom from a deprotonated 2-thiobarbituric ligand are bonded to the metal center. The geometry is completed with one oxygen from a water molecule. Compound 1 exhibits potent, in vitro, cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (PAH, benzo[a]pyrene) carcinogenesis. In addition, the inhibition caused by 1, in the rate of lipoxygenase (LOX) catalyzed oxidation reaction of linoleic acid to hyperoxolinoleic acid, has been also kinetically and theoretically studied. The results are compared to that of cisplatin. PMID:18401456

  13. Effective posttransplant antitumor immunity is associated with TLR-stimulating nucleic acid–immunoglobulin complexes in humans

    PubMed Central

    Lin, Yun; Zhang, Li; Cai, Ann X.; Lee, Mark; Zhang, Wandi; Neuberg, Donna; Canning, Christine M.; Soiffer, Robert J.; Alyea, Edwin P.; Ritz, Jerome; Hacohen, Nir; Means, Terry K.; Wu, Catherine J.

    2011-01-01

    Donor lymphocyte infusion (DLI), whereby donor mononuclear cells are infused into patients, is one of the few effective immunotherapeutic strategies that generate long-lasting tumor remissions. We previously demonstrated that chronic myelogenous leukemia (CML) patients treated with DLI develop high-titer plasma antibodies specific for CML-associated antigens, the majority of which have been reported to bind nucleic acids These observations led us to predict that circulating antibody-antigen complexes in DLI-responsive patients carry nucleic acids that can engage innate immune sensors. Consistent with this, we report here that post-DLI plasma from 5 CML patients that responded to DLI treatment induced massive upregulation of MIP-1α, IP-10, and IFN-α in normal blood mononuclear cells. Importantly, this was not observed with plasma obtained before DLI and from DLI nonresponders and imatinib-treated patients. This endogenous immunostimulatory activity required nucleic acid and protein for its adjuvant effect and activated antigen-presenting cells through the RNA and DNA sensors TLR8 and TLR9. Presence of the immunoglobulin Fc receptor CD32 enhanced cellular responses, suggesting that immunoglobulins associate with this activity. Finally, a TLR-induced expression signature was detectable in post-DLI but not pre-DLI blood, consistent with an active circulating TLR8/9-stimulating factor. We have therefore demonstrated that effective tumor immunity correlates with the presence of endogenous nucleic acid–immunoglobulin complexes in patient plasma, thus providing a putative mechanism for the induction of potent antigen-specific immunity against malignant cells. PMID:21403403

  14. Crystal structures of multidrug-resistant HIV-1 protease in complex with two potent anti-malarial compounds

    SciTech Connect

    Yedidi, Ravikiran S.; Liu, Zhigang; Wang, Yong; Brunzelle, Joseph S.; Kovari, Iulia A.; Woster, Patrick M.; Kovari, Ladislau C.; Gupta, Deepak

    2012-06-19

    Two potent inhibitors (compounds 1 and 2) of malarial aspartyl protease, plasmepsin-II, were evaluated against wild type (NL4-3) and multidrug-resistant clinical isolate 769 (MDR) variants of human immunodeficiency virus type-1 (HIV-1) aspartyl protease. Enzyme inhibition assays showed that both 1 and 2 have better potency against NL4-3 than against MDR protease. Crystal structures of MDR protease in complex with 1 and 2 were solved and analyzed. Crystallographic analysis revealed that the MDR protease exhibits a typical wide-open conformation of the flaps (Gly48 to Gly52) causing an overall expansion in the active site cavity, which, in turn caused unstable binding of the inhibitors. Due to the expansion of the active site cavity, both compounds showed loss of direct contacts with the MDR protease compared to the docking models of NL4-3. Multiple water molecules showed a rich network of hydrogen bonds contributing to the stability of the ligand binding in the distorted binding pockets of the MDR protease in both crystal structures. Docking analysis of 1 and 2 showed a decrease in the binding affinity for both compounds against MDR supporting our structure-function studies. Thus, compounds 1 and 2 show promising inhibitory activity against HIV-1 protease variants and hence are good candidates for further development to enhance their potency against NL4-3 as well as MDR HIV-1 protease variants.

  15. Anticandidal cytotoxicity, antitumor activities, and purified cell wall modulation by novel Schiff base ligand and its metal (II) complexes against some pathogenic yeasts.

    PubMed

    Geweely, Neveen S

    2009-09-01

    The preparation of metal (II) complexes [CoCl(2).6H(2)O, Ni(CH(3)COO)(2).4H(2)O, Cu(CH(3)COO)(2).2H(2)O, and Zn (CH3COO)(2) .2H(2)O] with 2[N-(cinnamlidene) amino]-5-nitro phenol as a novel ligands and their biological evaluation against candida species was studied. The inhibitory effects of the tested metal complexes were tested against six pathogenic yeasts (Candida albicans, C. fructus, C. glabrata, C. oleophila, C. parapsilosis, and C. tropicalis). The effect of the most efficient metal complex (Zn(II) complex) was more pronounced at 1.25 microg/ml, while Ni(II) complex was exhibited the least suppressive effect. Co(II) and Zn(II) complexes act as potential antitumor agents, while Zn(II) complex has shown promising cytotoxic activity with slow candidal respiration rate. Addition of Zn(II) complex leading to suppression of cell wall components in all candidal cells accompanied with leaking out of amino acids. Purification of the cell wall mannoprotein of C. glabrata treated with Zn(II) complex was established, resulting one pure fissured protein peak. Cell wall protein modulation was showed by appearance of two new protein bands with molecular weights of 72 and 39 KDa in C. glabrata cells treated with Zn(II) complex compared with one pure protein band 55.6 KDa in the non treated yeast cell.

  16. Crystal structure of human secretory phospholipase A2-IIA complex with the potent indolizine inhibitor 120-1032.

    PubMed

    Kitadokoro, K; Hagishita, S; Sato, T; Ohtani, M; Miki, K

    1998-04-01

    Phospholipase A2 is a key enzyme in a number of physiologically important cellular processes including inflammation and transmembrane signaling. Human secretory phospholipase A2-IIA is present at high concentrations in synovial fluid of patients with rheumatoid arthritis and in the plasma of patients with septic shock. Inhibitors of this enzyme have been suggested to be therapeutically useful non-steroidal anti-inflammatory drugs. The crystal structure of human secretory phospholipase A2-IIA bound to a novel potent indolizine inhibitor (120-1032) has been determined. The complex crystallizes in the space group P3121, with cell dimensions of a = b = 75.8 A and c = 51.3 A. The model was refined to an R-factor of 0. 183 for the intensity data collected to a resolution of 2.2 A. It was revealed that the inhibitor is located near the active site and bound to the calcium ion. Although the binding mode of the 120-1032 inhibitor to human secretory phospholipase A2-IIA is similar to that previously determined for an indole inhibitor LY311299, the specific interactions between the enzyme and the inhibitor in the present complex include the oxycarboxylate group which was introduced in this inhibitor. The oxycarboxylate group in 120-1032 is coordinated to the calcium ion and included in the water-mediated hydrogen bonding to the catalytic Asp49. In addition, the ethyl group in 120-1032 gains hydrophobic contacts with the cavity wall of the hydrophobic channel of the enzyme.

  17. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090 .

    PubMed

    Cole, Kathryn E; Gattis, Samuel G; Angell, Heather D; Fierke, Carol A; Christianson, David W

    2011-01-18

    The first committed step of lipid A biosynthesis is catalyzed by UDP-(3-O-((R)-3-hydroxymyristoyl))-N-acetylglucosamine deacetylase, a metal-dependent deacetylase also known as LpxC. Because lipid A is essential for bacterial viability, the inhibition of LpxC is an appealing therapeutic strategy for the treatment of Gram-negative bacterial infections. Here we report the 1.79 Å resolution X-ray crystal structure of LpxC from Yersinia enterocolitica (YeLpxC) complexed with the potent hydroxamate inhibitor CHIR-090. This enzyme is a nearly identical orthologue of LpxC from Yersinia pestis (99.7% sequence identity), the pathogen that causes bubonic plague. Similar to the inhibition of LpxC from Escherichia coli, CHIR-090 inhibits YeLpxC via a two-step slow, tight-binding mechanism with an apparent K(i) of 0.54 ± 0.14 nM followed by conversion of the E·I to E·I* species with a rate constant of 0.11 ± 0.01 min(-1). The structure of the LpxC complex with CHIR-090 shows that the inhibitor hydroxamate group chelates the active site zinc ion, and the "tail" of the inhibitor binds in the hydrophobic tunnel in the active site. This hydrophobic tunnel is framed by a βαβ subdomain that exhibits significant conformational flexibility as it accommodates inhibitor binding. CHIR-090 displays a 27 mm zone of inhibition against Y. enterocolitica in a Kirby-Bauer antibiotic assay, which is comparable to its reported activity against other Gram-negative species including E. coli and Pseudomonas aeruginosa. This study demonstrates that the inhibition of LpxC should be explored as a potential therapeutic and/or prophylatic response to infection by weaponized Yersinia species.

  18. Improved systemic pharmacokinetics, biodistribution, and antitumor activity of CpG oligodeoxynucleotides complexed to endogenous antibodies in vivo

    PubMed Central

    Palma, Enzo; Cho, Moo J.

    2007-01-01

    CpG oligodeoxynucleotides (CpG-ODNs) fail to elicit antitumor immunity after intravenous administration presumably due to their rapid renal clearance and low tumor accumulation. To address this issue, we tested the hypothesis that endogenous IgG can be used as systemic drug carriers to improve the pharmacokinetics, tumor accumulation, and antitumor activity of intravenously administered CpG-ODNs. To this end, tritium-labeled CpG-ODNs conjugated with one or two dinitrophenyl (DNP) haptens (DNP- and DNP2-[3H]-CpG-ODN) were intravenously dosed into DNP-immunized Balb/c mice bearing subcutaneous CT26 colorectal tumors. Serum and tissue samples for pharmacokinetic and biodistribution profiling were collected at predetermined timepoints and analyzed by liquid scintillation. In antitumor efficacy studies, DNP-immunized, CT26 tumor-bearing mice were intravenously dosed with PBS, CpG-ODN, or DNP-CpG-ODN every five days. Tumor volumes and macroscopic and histological examination of resected solid tumors were used to quantitatively and qualitatively assess tumor growth inhibition. Relative to [3H]-CpG-ODN, dinitrophenylated [3H]-CpG-ODNs displayed substantial increases in systemic exposure (900–1650 fold) and half-life (100–300 fold), marked decreases in systemic clearance (750–1500 fold) and volume of tissue distribution (13–37 fold), as well as substantial and sustained tumor accumulation (~30% vs. <2% injected dose/g). Antitumor efficacy studies demonstrated that DNP-CpG-ODN inhibited tumor growth by up to 60% relative to PBS control whereas CpG-ODN treatment had no apparent effect. Macroscopic and histological examination of harvested tumors at various timepoints revealed the presence of regions of necrotic tissue only in tumors from mice treated with DNP-CpG-ODN. Collectively, these results show the potential of endogenous IgG to mediate the systemic delivery of CpG-ODN to solid tumors and to enhance their antitumor activity following intravenous administration

  19. Highly potent anti-proliferative effects of a gallium(III) complex with 7-chloroquinoline thiosemicarbazone as a ligand: synthesis, cytotoxic and antimalarial evaluation.

    PubMed

    Kumar, Kewal; Schniper, Sarah; González-Sarrías, Antonio; Holder, Alvin A; Sanders, Natalie; Sullivan, David; Jarrett, William L; Davis, Krystyn; Bai, Fengwei; Seeram, Navindra P; Kumar, Vipan

    2014-10-30

    A gallium(III) complex with 7-chloroquinoline thiosemicarbazone was synthesized and characterized. The complex proved to be thirty-one times more potent on colon cancer cell line, HCT-116, with considerably less cytotoxicity on non-cancerous colon fibroblast, CCD-18Co, when compared to etoposide. Its anti-malarial potential on 3D7 isolate of Plasmodium falciparum was better than lumefantrine. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. Highly Effective Non-Viral Antitumor Gene Therapy System Comprised of Biocompatible Small Plasmid Complex Particles Consisting of pDNA, Anionic Polysaccharide, and Fully Deprotected Linear Polyethylenimine

    PubMed Central

    Koyama, Yoshiyuki; Sugiura, Kikuya; Yoshihara, Chieko; Inaba, Toshio; Ito, Tomoko

    2015-01-01

    We have reported that ternary complexes of plasmid DNA with conventional linear polyethylenimine (l-PEI) and certain polyanions were very stably dispersed, and, with no cryoprotectant, they could be freeze-dried and re-hydrated without the loss of transfection ability. These properties enabled the preparation of a concentrated suspension of very small pDNA complex, by preparing the complexes at highly diluted conditions, followed by condensation via lyophilization-and-rehydration procedure. Recently, a high potency linear polyethylenimine having no residual protective groups, i.e., Polyethylenimine “Max” (PEI “Max”), is available, which has been reported to induce much higher gene expression than conventional l-PEI. We tried to prepare the small DNA/PEI “Max”/polyanion complexes by a similar freeze-drying method. Small complex particles could be obtained without apparent aggregation, but transfection activity of the rehydrated complexes was severely reduced. Complex-preparation conditions were investigated in details to achieve the freeze-dried DNA/PEI “Max”/polyanion small ternary complexes with high transfection efficiency. DNA/PEI “Max”/polyanion complexes containing cytokine-coding plasmids were then prepared, and their anti-tumor therapeutic efficacy was examined in tumor-bearing mice. PMID:26213961

  1. In vitro and in vivo anti-tumor effects of selected platinum(IV) and dinuclear platinum(II) complexes against lung cancer cells.

    PubMed

    Arsenijevic, Milos; Milovanovic, Marija; Jovanovic, Snezana; Arsenijevic, Natalija; Markovic, Bojana Simovic; Gazdic, Marina; Volarevic, Vladislav

    2017-08-01

    In the present study, cytotoxic effects of cisplatin, the most usually used chemotherapeutic agent, were compared with new designed platinum(IV) ([PtCl4(en)] (en = ethylenediamine) and [PtCl4(dach)]) (dach = (±)-trans-1,2-diaminocyclohexane) and platinum(II) complexes ([{trans-Pt(NH3)2Cl}2(μ-pyrazine)](ClO4)2 (Pt1), [{trans-Pt(NH3)2Cl}2(μ-4,4'-bipyridyl)](ClO4)2DMF(Pt2),[{trans-Pt(NH3)2Cl}2(μ-1,2-bis(4pyridyl)ethane)](ClO4)2 (Pt3)), in vitro and in vivo against human and murine lung cancer cells, to determine anti-tumor potential of newly synthesized platinum-based drugs in the therapy of lung cancer. Results obtained by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], Lactate dehydrogenase and Annexin V/Propidium Iodide assays showed that, among all tested complexes, [PtCl4(en)] had the highest cytotoxicity against human and murine lung carcinoma cells in vitro. [PtCl4(en)] showed significantly higher cytotoxicity then cisplatin in all tested concentrations, mainly by inducing apoptosis in lung cancer cells. [PtCl4(en)] was well tolerated in vivo. Clinical signs of [PtCl4(en)]-induced toxicity, such as changes in food, water consumption or body weight, nephrotoxicity or hepatotoxicity was not observed in [PtCl4(en)]-treated mice. [PtCl4(en)] managed to increase presence of CD45+ leukocytes, including F4/80+ macrophages, CD11c+ dendritic cells, CD4+ helper and CD8+ cytotoxic T cells (CTLs) in the lungs, cytotoxic NK, NKT and CTLs in the spleens of tumor bearing mice, resulting with reduction of metastatic lesions in the lungs, indicating its potential to stimulate anti-tumor immune response in vivo. Due to its anti-tumor cytotoxicity, biocompatibility, and potential for stimulation of anti-tumor immune response, [PtCl4(en)] may be a good candidate for further testing in the field of medicinal chemistry.

  2. Monofunctional platinum(II) complexes with potent tumor cell growth inhibitory activity: the effect of a hydrogen-bond donor/acceptor N-heterocyclic ligand.

    PubMed

    Margiotta, Nicola; Savino, Salvatore; Gandin, Valentina; Marzano, Christine; Natile, Giovanni

    2014-06-01

    In this paper we investigate the possibility of further increase the role of the N-donor aromatic base in antitumor Hollis-type compounds by conferring the possibility to act as a hydrogen-bond donor/acceptor. Therefore, we synthesized the Pt(II) complex cis-[PtCl(NH3 )2 (naph)]NO3 (1) containing the 1,8-naphthyridine (naph) ligand. The naphthyridine ligand is generally monodentate, and the second nitrogen atom can act as H-bond donor/acceptor depending upon its protonation state. The possibility of forming such an H-bond could be crucial in the interaction of the drug with DNA or proteins. Apart from the synthesis of the compound, in this study we evaluated its in vitro antitumor activity in a wide panel of tumor cell lines, also including cells selected for their sensitivity/resistance to oxaliplatin, which was compared with that of previously reported complex 2 ([PtI(2,9-dimethyl-1,10-phenanthroline)(1-methyl-cytosine)]I) and oxaliplatin and cisplatin as reference compounds. The cytotoxicity data were correlated with the cellular uptake and the DNA platination levels. Finally, the reactivity of 1 towards guanosine 5'-monophosphate (5'-GMP) and glutathione was investigated to provide insights into its mechanism of action.

  3. DNA interstrand cross-links of an antitumor trinuclear platinum(II) complex: thermodynamic analysis and chemical probing.

    PubMed

    Malina, Jaroslav; Farrell, Nicholas P; Brabec, Viktor

    2011-06-06

    The trinuclear platinum compound [{trans-PtCl(NH(3))(2)}(2)(μ-trans-Pt(NH(3))(2){NH(2)(CH(2))(6)NH(2)}(2))](4+) (BBR3464) belongs to the polynuclear class of platinum-based anticancer agents. These agents form in DNA long-range (Pt,Pt) interstrand cross-links, whose role in the antitumor effects of BBR3464 predominates. Our results show for the first time that the interstrand cross-links formed by BBR3464 between two guanine bases in opposite strands separated by two base pairs (1,4-interstrand cross-links) exist as two distinct conformers, which are not interconvertible, not only if these cross-links are formed in the 5'-5', but also in the less-usual 3'-3' direction. Analysis of the conformers by differential scanning calorimetry, chemical probes of DNA conformation, and minor groove binder Hoechst 33258 demonstrate that each of the four conformers affects DNA in a distinctly different way and adopts a different conformation. The results also support the thesis that the molecule of antitumor BBR3464 when forming DNA interstrand cross-links may adopt different global structures, including different configurations of the linker chain of BBR3464 in the minor groove of DNA. Our findings suggest that the multiple DNA interstrand cross-links available to BBR3464 may all contribute substantially to its cytotoxicity.

  4. New non-toxic transition metal nanocomplexes and Zn complex-silica xerogel nanohybrid: Synthesis, spectral studies, antibacterial, and antitumor activities

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy; Saif, M.; Nabeel, Asmaa I.; Shokry, R.

    2016-08-01

    A new chromone Schiff base and its complexes of Cu(II), Ni(II), Co(II), Fe(III), Zn(II), Cd(II), and UO2(VI) as well as Zn(II) complex-silica xerogel nanohybrid were successfully prepared in a nano domain with crystalline or amorphous structures. Structures of the Schiff base and its complexes were investigated by elemental and thermal analyses, IR, 1H NMR, electronic, ESR, mass spectra, XRD, and TEM, as well as conductivity and magnetic susceptibility measurements. The spectroscopic data revealed that the Schiff base ligand behaves as a monobasic tridentate ligand. The coordination sites with metal ions are γ-pyrone oxygen, azomethine nitrogen, and oxygen of the carboxylic group. The metal complexes exhibited octahedral geometry, except Cu(II) complex, which has a square planar geometry and UO2(VI) complex, in which uranium ion is hepta-coordinated. Transmission electron microscope (TEM) analysis showed that Ni(II) and Zn(II) complexes have aggregated spheres and rod morphologies, respectively. TEM images of Zn(II) complex-silica xerogel nanohybrid showed a nanosheet morphology with 46 nm average size and confirmed that the complex was uniformly distributed into the silica pores. The obtained nanocomplexes were tested as antimicrobial and antitumor agents. The results showed that Zn(II) nanocomplex and Zn(II) complex-silica xerogel nanohybrid have high activity. The toxicity test on mice showed that Zn(II) complex and Zn(II) complex-silica xerogel nanohybrid have lower toxicity than cisplatin.

  5. Structure activity-relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N,2,6-trimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminium chloride and its analogues as antitumor agents

    PubMed Central

    Gangjee, Aleem; Zhao, Ying; Raghavan, Sudhir; Rohena, Cristina; Mooberry, Susan L.; Hamel, Ernest

    2013-01-01

    A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound 1·HCl as an antimicrotubule agent. The structure-activity relationship indicates that the N-methyl and a 4′-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound 30·HCl was a 1–2 digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound 1·HCl. In addition, 30·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several antitubulin agents. In vivo efficacy of 30·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound 30·HCl is water soluble, easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent. PMID:23895532

  6. Ruthenium(II) p-cymene complex bearing 2,2'-dipyridylamine targets caspase 3 deficient MCF-7 breast cancer cells without disruption of antitumor immune response.

    PubMed

    Kaluđerović, Goran N; Krajnović, Tamara; Momcilovic, Miljana; Stosic-Grujicic, Stanislava; Mijatović, Sanja; Maksimović-Ivanić, Danijela; Hey-Hawkins, Evamarie

    2015-12-01

    [Ru(η(6)-p-cym)Cl{dpa(CH2)4COOEt}][PF6] (cym=cymene; dpa=2,2'-dipyridylamine; complex 2) was prepared and characterized by elemental analysis, IR and multinuclear NMR spectroscopy, as well as ESI-MS and X-ray structural analysis. The structural analog without a side chain [Ru(η(6)-p-cym)Cl(dpa)][PF6] (1) as well as 2 were investigated in vitro against 518A2, SW480, 8505C, A253 and MCF-7 cell lines. Complex 1 is active against all investigated tumor cell lines while the activity of compound 2 is limited only to caspase 3 deficient MCF-7 breast cancer cells, however, both are less active than cisplatin. As CD4(+)Th cells are necessary to trigger all the immune effector mechanisms required to eliminate tumor cells, besides testing the in vitro antitumor activity of 1 and 2, the effect of ruthenium(II) complexes on the cells of the adaptive immune system have also been evaluated. Importantly, complex 1 applied in concentrations which were effective against tumor cells did not affect immune cell viability, nor did exert a general immunosuppressive effect on cytokine production. Thus, beneficial characteristics of 1 might contribute to the overall therapeutic properties of the complex. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Synthesis, structural characterization, DNA binding studies and antitumor properties of tin(II)-oxydiacetate complexes containing α-diimine as auxiliary ligand.

    PubMed

    Siddiqi, Zafar A; Sharma, Prashant K; Shahid, M; Khalid, Mohd

    2013-08-05

    Metal directed supra molecular assemblies with interesting topologies have been widely used as models for metallo-enzymes and in development of metallo-pharmaceuticals. Two novel tin(II)-oxydiacetate complexes with α-diimine (1,10-phenanthroline or 2,2'-bipyridine) as auxiliary ligand were synthesized and characterized by elemental analysis, FT-IR, (1)H-, (13)C- and (119)Sn-NMR and single crystal X-ray crystallography. The spectral investigations and X-ray data show that {Sn} is hepta coordinated with pentagonal bipyramidal (pbp) geometry of the complexes. The in vitro binding and cleavage studies using CT DNA by UV-visible, fluorescence and agarose gel electrophoresis techniques revealed that both complexes bind DNA via intercalation. The observed magnitudes of Kb for complexes (1) and (2) are 2.517×10(4) and 5.35×10(3), respectively, which suggest that (1) has strong binding affinity for CT DNA as compared to (2). The complexes were tested for antitumor properties and found highly active at 10(-4)M concentration against P388, HL-60 and A-549 cell lines.

  8. Preparation of S14161 and its analogues and the discovery of 6-bromo-8-ethoxy-3-nitro-2H-chromene as a more potent antitumor agent in vitro.

    PubMed

    Yin, Shu-Qiang; Shi, Min; Kong, Ting-Ting; Zhang, Cheng-Mei; Han, Kunkun; Cao, Biyin; Zhang, Zubin; Du, Xiaolin; Tang, Long-Qian; Mao, Xinliang; Liu, Zhao-Peng

    2013-06-01

    The small chemical compound 8-ethoxy-2-(4-fluorophenyl)-3-nitro-2H-chromene (S14161) was recently identified as an inhibitor of the phosphoinositide 3-kinase (PI3K). In the present study, we designed a novel synthesis of S14161 and prepared a series of its analogues via the oxa-Michael-Henry reaction in the presence of catalytic amounts of l-proline and triethylamine. Further structural simplification led to the identification of 6-bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) that exhibited potent antiproliferative activities against a panel of 12 tumor cell lines. Compared with S14161, BENC-511 was more potent in blocking the AKT phosphorylation and inducing cancer cell apoptosis. BENC-511 also displayed more potent effects on human umbilical vein epithelial cells (HUVEC) migration, suggesting its anti-angiogenesis activity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Antitumor effects of MsurvivinT34A-CaPi complex-embedded PLGA nanoparticles in combination with Doxil in mice

    NASA Astrophysics Data System (ADS)

    Tang, Jie; He, Jinfeng; Yang, Chengli; Mao, Yi; Hu, Tingting; Zhang, Lijing; Cao, Hua; Tong, Ai-ping; Song, Xiangrong; He, Gu; Guo, Gang; Luo, Youfu; Zhang, Xiaoning; Xie, Yongmei; Zheng, Yu

    2014-11-01

    A novel calcium phosphate-pDNA complex-embedded PLGA nanoparticles have been developed for delivering therapy genes. CaPi-MsurvivinT34A-PLGA-NPs (abbreviated as ms-CaPi-PLGA-NPs) containing the MsurvivinT34A plasmid and null-CaPi-PLGA-NPs containing the empty plasmid vector as control were prepared. The nanoparticles had mean size around 130 nm and encapsulation efficiency above 85 %. What is more, the drug loading content and zeta potential of ms-CaPi-PLGA-NPs were 0.734 ± 0.007 % and -3.75 ± 1.2 mV, respectively. ms-CaPi-PLGA-NPs combined with Doxil significantly inhibited the proliferation of 4T1 breast cancer cells with IC50 of 0.2937 ± 0.02 µg/mL, which was significantly lower than those of Doxil and null-CaPi-PLGA-NPs ( p < 0.05). Morphological analysis using Hoechst 33342 and PI staining suggested that a lot of 4T1 cells in combination therapy group of ms-CaPi-PLGA-NPs + Doxil showed typical morphological characteristic of late apoptosis and necrosis. Flow cytometry analysis with PI and the apoptosis marker Annexin V-FITC staining confirmed that apoptosis fraction given by ms-CaPi-PLGA-NPs + Doxil was greater than 80 %. Both ms-CaPi-PLGA-NPs and Doxil resulted in cell cycle arrest implying that their synergistic antitumor effect was probably related to the cell cycle regulation. Then, the antitumor effect of ms-CaPi-PLGA-NPs ( i.t.) + Doxil ( i.v.) in vivo was studied using BALB/c mice inoculated with 4T1 cells. The result showed that ms-CaPi-PLGA-NPs + Doxil suppressed the tumor growth most effectively among all the treatment groups. TUNEL assay together with immunohistochemical study on CD31 and VEGF indicated that the ideal antitumor effect of ms-CaPi-PLGA-NPs + Doxil was ascribed to induction of apoptosis (apoptotic index over 90 %) and inhibition of angiogenesis. Toxicity assessment showed that no significant toxic effects were produced after treatment of ms-CaPi-PLGA-NPs + Doxil. Above all, we may conclude that the calcium phosphate-pDNA complex

  10. Antitumor activity of a polysaccharide-protein complex isolated from a wood-rotting polypore macro fungus Phellinus rimosus (Berk) Pilat.

    PubMed

    Meera, C R; Janardhanan, Kainoor K

    2012-01-01

    A protein-bound, water-soluble polysaccharide-protein complex was isolated from a medicinal mushroom, Phellinus rimosus (Berk) Pilat (PPC-Pr). The isolation was achieved by hot water extraction, filtration, solvent precipitation, dialysis, and freeze-drying. The proximate analysis showed that PPC-Pr comprised 54.8% polysaccharide and 28.6% protein. The molecular weight of the compound was determined by gel filtration using a Sephadex G 100. The molecular weight of PPC-Pr was approximately 1,200,000 D. The thin-layer chromatography analysis of PPC-Pr after acid hydrolysis with trifluroacetic acid showed that it was composed of glucose as the only monosaccharide unit. The amino acid profile analysis of PPC-Pr revealed that it contained large amounts of aspartic acid, glutamic acid, alanine, glycine, and serine. Thus, the results indicated that PPC-Pr is a glucan-protein complex. The PPC-Pr did not show in vitro cytotoxic activity against Dalton's lymphoma ascites and Ehrlich's ascites carcinoma cell lines. The PPC-Pr was found to be effective in increasing the life span of ascites tumors induced by Ehrlich's ascites carcinoma cell line in mice. PPC-Pr also was found to have significant preventive and curative effects on solid tumors induced by the Dalton's lymphoma ascites cell line. The experimental results thus indicated that protein-bound polysaccharide (PPC-Pr) isolated from P. rimosus possessed profound antitumor activity. The findings suggest the potential therapeutic use of this compound as an antitumor agent.

  11. Discovery of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine--a potent, orally active Src kinase inhibitor with anti-tumor activity in preclinical assays.

    PubMed

    Noronha, Glenn; Barrett, Kathy; Boccia, Antonio; Brodhag, Tessa; Cao, Jianguo; Chow, Chun P; Dneprovskaia, Elena; Doukas, John; Fine, Richard; Gong, Xianchang; Gritzen, Colleen; Gu, Hong; Hanna, Ehab; Hood, John D; Hu, Steven; Kang, Xinshan; Key, Jann; Klebansky, Boris; Kousba, Ahmed; Li, Ge; Lohse, Dan; Mak, Chi Ching; McPherson, Andrew; Palanki, Moorthy S S; Pathak, Ved P; Renick, Joel; Shi, Feng; Soll, Richard; Splittgerber, Ute; Stoughton, Silva; Tang, Suhan; Yee, Shiyin; Zeng, Binqi; Zhao, Ningning; Zhu, Hong

    2007-02-01

    We describe the identification of [7-(2,6-dichlorophenyl)-5-methylbenzo [1,2,4]triazin-3-yl]-[4-(2-pyrrolidin-1-ylethoxy)phenyl]amine (3), a potent, orally active Src inhibitor with desirable PK properties, demonstrated activity in human tumor cell lines and in animal models of tumor growth.

  12. A novel vanadyl complex with a polypyridyl DNA intercalator as ligand: a potential anti-protozoa and anti-tumor agent.

    PubMed

    Benítez, Julio; Guggeri, Lucía; Tomaz, Isabel; Pessoa, João Costa; Moreno, Virtudes; Lorenzo, Julia; Avilés, Francesc X; Garat, Beatriz; Gambino, Dinorah

    2009-10-01

    In the search for new metal-based drugs for the treatment of tumoral and parasitic diseases a vanadyl complex, [V(IV)O(SO(4))(H2O)(2)(dppz)].2H(2)O, that includes the bidentate polypyridyl DNA intercalator dipyrido[3,2-a:2',3'-c]phenazine (dppz), was synthesized, characterized by a combination of techniques, and in vitro evaluated on the human acute promyelocytic leukemia cell line HL-60 and against Dm28c strain epimastigotes of the parasite Trypanosoma cruzi, causative agent of Chagas' disease. EPR spectroscopy suggests a distorted octahedral geometry for the complex with the dppz ligand acting as bidentate, binding through both nitrogen donor atoms in an axial-equatorial mode. An oxo group, two water molecules and a sulphate donor occupy the remainder coordination positions. The complex, as well as the anti-trypanosomal reference drug Nifurtimox, showed IC(50) values in the muM range against T. cruzi Dm28c strain. In addition the complex exhibited excellent in vitro anti-tumor activity against leukemia (HL-60 cell line) comparable to that of cisplatin, inducing cell death by apoptosis with IC(50) values in the micromolar range. Data from gel electrophoresis and atomic force microscopy indicate that the complex interacts with DNA, suggesting that its mechanism of action may include DNA as a target. EPR and (51)V NMR experiments were also carried out with aged aerated solutions of the complex to get insight into the stability of the complex in solution and the species responsible for the in vitro activities observed.

  13. Structure of a secreted aspartic protease from C. albicans complexed with a potent inhibitor: implications for the design of antifungal agents.

    PubMed Central

    Abad-Zapatero, C.; Goldman, R.; Muchmore, S. W.; Hutchins, C.; Stewart, K.; Navaza, J.; Payne, C. D.; Ray, T. L.

    1996-01-01

    The three-dimensional structure of a secreted aspartic protease from Candida albicans complexed with a potent inhibitor reveals variations on the classical aspartic protease theme that dramatically alter the specificity of this class of enzymes. The structure presents: (1) an 8-residue insertion near the first disulfide (Cys 45-Cys 50, pepsin numbering) that results in a broad flap extending toward the active site; (2) a 7-residue deletion replacing helix hN2 (Ser 110-Tyr 114), which enlarges the S3 pocket; (3) a short polar connection between the two rigid body domains that alters their relative orientation and provides certain specificity; and (4) an ordered 11-residue addition at the carboxy terminus. The inhibitor binds in an extended conformation and presents a branched structure at the P3 position. The implications of these findings for the design of potent antifungal agents are discussed. PMID:8845753

  14. Design and optimization of (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones as potent PLK4 inhibitors with oral antitumor efficacy.

    PubMed

    Li, Sze-Wan; Liu, Yong; Sampson, Peter B; Patel, Narendra Kumar; Forrest, Bryan T; Edwards, Louise; Laufer, Radoslaw; Feher, Miklos; Ban, Fuqiang; Awrey, Donald E; Hodgson, Richard; Beletskaya, Irina; Mao, Guodong; Mason, Jacqueline M; Wei, Xin; Luo, Xunyi; Kiarash, Reza; Green, Erin; Mak, Tak W; Pan, Guohua; Pauls, Henry W

    2016-10-01

    Previous efforts from our laboratory demonstrated that (E)-3-((3-(E)-vinylaryl)-1H-indazol-6-yl)methylene)-indolin-2-ones are potent PLK4 inhibitors with in vivo anticancer efficacy upon IP dosing. As part of a continued effort to develop selective and orally efficacious inhibitors, we examined variations on this theme wherein 'directly-linked' aromatics, pendant from the indazole core, replace the arylvinyl moiety. Herein, we describe the design and optimization of this series which was ultimately superseded by (3-aryl-1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones. The latter compounds are potent and selective inhibitors of PLK4 with oral exposure in rodents and in vivo anticancer activity. Compound 13b, in particular, has a bioavailability of 22% and achieved a 96% tumor growth inhibition in an MDA-MB-468 xenograft study.

  15. Synthesis, biological and antitumor activity of a highly potent 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolate inhibitor with proton-coupled folate transporter and folate receptor selectivity over the reduced folate carrier that inhibits β-glycinamide ribonucleotide formyltransferase

    PubMed Central

    Wang, Lei; Desmoulin, Sita Kugel; Cherian, Christina; Polin, Lisa; White, Kathryn; Kushner, Juiwanna; Fulterer, Andreas; Chang, Min-Hwang; Mitchell, Shermaine; Stout, Mark; Romero, Michael F.; Hou, Zhanjun; Matherly, Larry H.; Gangjee, Aleem

    2011-01-01

    2-Amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine antifolates with a thienoyl side chain (compounds 1–3, respectively) were synthesized for comparison with compound 4, the previous lead compound of this series. Conversion of hydroxyl acetylen-thiophene carboxylic esters to thiophenyl-α-bromomethylketones and condensation with 2,4-diamino-6-hydroxypyrimidine afforded the 6-substituted pyrrolo[2,3-d]pyrimidine compounds of type 18 and 19. Coupling with L-glutamate diethyl ester, followed by saponification, afforded 1–3. Compound 3 selectively inhibited proliferation of cells expressing folate receptors (FRs) α or β, or the proton-coupled folate transporter (PCFT), including human tumor cells KB and IGROV1 much more potently than 4. Compound 3 was more inhibitory than 4 toward β-glycinamide ribonucleotide formyltransferase (GARFTase). Both 3 and 4 depleted cellular ATP pools. In SCID mice with IGROV1 tumors, 3 was more efficacious than 4. Collectively, our results show potent antitumor activity for 3 in vitro and in vivo, associated with its selective membrane transport by FRs and PCFT over RFC and inhibition of GARFTase, clearly establishing the 3-atom bridge as superior to the 1, 2 and 4-atom bridge lengths for the activity of this series. PMID:21879757

  16. A Fluorescence Polarization Assay for Binding to Macrophage Migration Inhibitory Factor and Crystal Structures for Complexes of Two Potent Inhibitors

    PubMed Central

    2016-01-01

    Human macrophage migration inhibitory factor (MIF) is both a keto–enol tautomerase and a cytokine associated with numerous inflammatory diseases and cancer. Consistent with observed correlations between inhibition of the enzymatic and biological activities, discovery of MIF inhibitors has focused on monitoring the tautomerase activity using l-dopachrome methyl ester or 4-hydroxyphenyl pyruvic acid as substrates. The accuracy of these assays is compromised by several issues including substrate instability, spectral interference, and short linear periods for product formation. In this work, we report the syntheses of fluorescently labeled MIF inhibitors and their use in the first fluorescence polarization-based assay to measure the direct binding of inhibitors to the active site. The assay allows the accurate and efficient identification of competitive, noncompetitive, and covalent inhibitors of MIF in a manner that can be scaled for high-throughput screening. The results for 22 compounds show that the most potent MIF inhibitors bind with Kd values of ca. 50 nM; two are from our laboratory, and the other is a compound from the patent literature. X-ray crystal structures for two of the most potent compounds bound to MIF are also reported here. Striking combinations of protein–ligand hydrogen bonding, aryl–aryl, and cation−π interactions are responsible for the high affinities. A new chemical series was then designed using this knowledge to yield two more strong MIF inhibitors/binders. PMID:27299179

  17. Lipophilic Cationic Cyanines Are Potent Complex I Inhibitors and Specific in Vitro Dopaminergic Toxins with Mechanistic Similarities to Both Rotenone and MPP(.).

    PubMed

    Kadigamuwa, Chamila C; Mapa, Mapa S T; Wimalasena, Kandatege

    2016-09-19

    We have recently reported that simple lipophilic cationic cyanines are specific and potent dopaminergic toxins with a mechanism of toxicity similar to that of the Parkinsonian toxin MPP(+). In the present study, a group of fluorescent lipophilic cyanines have been used to further exploit the structure-activity relationship of the specific dopaminergic toxicity of cyanines. Here, we report that all cyanines tested were highly toxic to dopaminergic MN9D cells with IC50s in the range of 60-100 nM and not toxic to non-neuronal HepG2 cells parallel to that previously reported for 2,2'- and 4,4'-cyanines. All cyanines nonspecifically accumulate in the mitochondria of both MN9D and HepG2 cells at high concentrations, inhibit the mitochondrial complex I with the inhibition potencies similar to the potent complex I inhibitor, rotenone. They increase the reactive oxygen species (ROS) production specifically in dopaminergic cells causing apoptotic cell death. These and other findings suggest that the complex I inhibition, the expression of low levels of antioxidant enzymes, and presence of high levels of oxidatively labile radical propagator, dopamine, could be responsible for the specific increase in ROS production in dopaminergic cells. Thus, the predisposition of dopaminergic cells to produce high levels of ROS in response to mitochondrial toxins together with their inherent greater demand for energy may contribute to their specific vulnerability toward these toxins. The novel findings that cyanines are an unusual class of potent mitochondrial toxins with specific dopaminergic toxicity suggest that their presence in the environment could contribute to the etiology of PD similar to that of MPP(+) and rotenone.

  18. Development of a new air-stable structure-simplified nafuredin-γ analog as a potent and selective nematode complex I inhibitor.

    PubMed

    Ohtawa, Masaki; Arima, Shiho; Shimizu, Risa; Hanatani, Naomi; Shimizu, Eri; Shiomi, Kazuro; Kita, Kiyoshi; Ōmura, Satoshi; Nagamitsu, Tohru

    2017-02-22

    Nafuredin-γ, obtained from natural nafuredin, has demonstrated a potent and selective inhibitory activity against nematode complex I. However, nafuredin-γ is unstable in air since its conjugated dienes are oxygen-labile. The instability in air was naturally solved by the synthesis of structure-simplified nafuredin-γ analogs without conjugated dienes. However, these modified analogs showed lower complex I inhibitory activities. Therefore, new air-stable structure-simplified nafuredin-γ analogs were designed and synthesized herein. Among all analogs synthesized, the one bearing a unique 1-azabicyclo[3.1.0]hexane scaffold showed the highest inhibitory activity (IC50=170 nM) while presenting high selectivity against nematode complex I.The Journal of Antibiotics advance online publication, 22 February 2017; doi:10.1038/ja.2017.16.

  19. Synthesis, Characterization, DNA Interaction, and Antitumor Activities of La (III) Complex with Schiff Base Ligand Derived from Kaempferol and Diethylenetriamine

    PubMed Central

    Wang, Qin; Huang, Yu; Zhang, Jin-Sheng; Yang, Xin-Bin

    2014-01-01

    A novel La (III) complex, [LaL(H2O)3]NO3·3H2O, with Schiff base ligand L derived from kaempferol and diethylenetriamine, has been synthesized and characterized by elemental analysis, IR, UV-visible, 1H NMR, thermogravimetric analysis, and molar conductance measurements. The fluorescence spectra, circular dichroism spectra, and viscosity measurements and gel electrophoresis experiments indicated that the ligand L and La (III) complex could bind to CT-DNA presumably via intercalative mode and the La (III) complex showed a stronger ability to bind and cleave DNA than the ligand L alone. The binding constants (Kb) were evaluated from fluorescence data and the values ranged from 0.454 to 0.659 × 105 L mol−1 and 1.71 to 17.3 × 105 L mol−1 for the ligand L and La (III) complex, respectively, in the temperature range of 298–310 K. It was also found that the fluorescence quenching mechanism of EB-DNA by ligand L and La (III) complex was a static quenching process. In comparison to free ligand L, La (III) complex exhibited enhanced cytotoxic activities against tested tumor cell lines HL-60 and HepG-2, which may correlate with the enhanced DNA binding and cleaving abilities of the La (III) complex. PMID:25371657

  20. Mononuclear dioxomolybdenum(VI) thiosemicarbazonato complexes: Synthesis, characterization, structural illustration, in vitro DNA binding, cleavage, and antitumor properties

    NASA Astrophysics Data System (ADS)

    Hussein, Mouayed A.; Guan, Teoh S.; Haque, Rosenani A.; Khadeer Ahamed, Mohamed B.; Abdul Majid, Amin M. S.

    2015-02-01

    Four dioxomolybdenum(VI) complexes were synthesized by reacting [MoO2(acac)2] with N-ethyl-2-(5-bromo-2-hydroxybenzylidene) hydrazinecarbothioamide (1), N-ethyl-2-(5-allyl-3-methoxy-2-hydroxybenzylidene) hydrazinecarbothioamide (2), N-methyl-2-(3-tert-butyl-2-hydroxybenzylidene) hydrazinecarbothioamide (3), and N-ethyl-2-(3-methyl-2-hydroxybenzylidene) hydrazinecarbothioamide (4). The molecular structures of 1, 2, and all the synthesized complexes were determined using single crystal X-ray crystallography. The binding properties of the ligand and complexes with calf thymus DNA (CT-DNA) were investigated via UV, fluorescence titrations, and viscosity measurement. Gel electrophoresis revealed that all the complexes cleave pBR 322 plasmid DNA. The cytotoxicity of the complexes were studied against the HCT 116 human colorectal cell line. All the complexes exhibited more pronounced activity than the standard reference drug 5-fluorouracil (IC50 7.3 μM). These studies show that dioxomolybdenum(VI) complexes could be potentially useful in chemotherapy.

  1. Synthesis, spectral, antitumor and antimicrobial studies on Cu(II) complexes of purine and triazole Schiff base derivatives

    NASA Astrophysics Data System (ADS)

    Amer, Said; El-Wakiel, Nadia; El-Ghamry, Hoda

    2013-10-01

    A series of copper (II) complexes of Schiff bases derived from 7H-2,6-diaminopurine and 4H-3,5-diamino-1,2,4-triazole with 2-pyridinecarbaldehyde, salicylaldehyde, 2,4-dihydroxybenzaldehyde and 2-hydroxy-1-naphthaldehyde have been prepared. The donor atoms and the possible geometry of the complexes were investigated by means of elemental and thermal analyses, molar conductance, magnetic moment, UV-Vis, IR, ESR and mass spectra. The ligands behaved as tetradentate, coordinating through the nitrogen atom of the azomethine group and the nearest nitrogen atom to it or oxygen atom of α-hydroxyl group. The results of simultaneous DTA & TGA analyses of the complexes showed the final degradation product for these complexes is CuO. The spectral studies confirmed a four coordinate environment around the metal ion. The obtained results were supported by 3D molecular modeling of complexes using molecular mechanics (MM+) and semiempirical molecular orbital calculations (PM3). These complexes were also tested for their in vitro antimicrobial activities against some bacterial and fungal strains. Complex 2 was investigated for its cyctotoxic effect against human breast cancer (MCF7), liver carcinoma (HEPG2) and colon carcinoma cell lines (HCT116). This compound exhibited a moderate activity against the tested cell lines with IC50 of 10.3, 9.8 and 8.7 μg/ml against MCF7, HCT116 and HEPG2, respectively.

  2. A silver complex with tryptophan: Synthesis, structural characterization, DFT studies and antibacterial and antitumor assays in vitro

    NASA Astrophysics Data System (ADS)

    Carvalho, Marcos A.; de Paiva, Raphael E. F.; Bergamini, Fernando R. G.; Gomes, Alexandre F.; Gozzo, Fábio C.; Lustri, Wilton R.; Formiga, André L. B.; Shishido, Silvia M.; Ferreira, Carmen V.; Corbi, Pedro P.

    2013-01-01

    The synthesis, spectroscopic characterization and biological assays of a new silver(I) complex with L-tryptophan (TRP) are presented. Elemental and thermal analyses and ESI-QTOF mass spectrometric measurements of the solid compound suggest the composition AgC11H11N2O2. Infrared and solid-state NMR analyses indicate coordination of TRP to Ag(I) ion through the nitrogen of the NH2 group and also through the oxygen of carboxylate group. Theoretical (DFT) calculations permit proposing an optimized geometry for the complex. Antibacterial assays indicated that the Ag-TRP complex is effective against Staphylococcus aureus and Enterococcus faecalis (Gram-positive), and Pseudomonas aeruginosa and Escherichia coli (Gram-negative) bacterial strains. The complex was also cytotoxic against Panc-1 (human pancreatic carcinoma) and SK-Mel 103 (human melanoma) cells.

  3. Unprecedented sugar-dependent in vivo antitumor activity of carbohydrate-pendant cis-diamminedichloroplatinum(II) complexes.

    PubMed

    Mikata, Y; Shinohara, Y; Yoneda, K; Nakamura, Y; Brudziñska, I; Tanase, T; Kitayama, T; Takagi, R; Okamoto, T; Kinoshita, I; Doe, M; Orvig, C; Yano, S

    2001-12-03

    Eight carbohydrate-pendant platinum(II) complexes have been synthesized from carbohydrate-diamine conjugates. D-Glucose, D-mannose, D-galactose, D-xylose, and L-glucose are attached to the dichloroplatinum(II) moiety by 1,3- or 1,2-diaminopropane chelates through with an O-glycoside bond. All the carbohydrate moieties reduced the toxicity inherent with platinum(II) complexes.

  4. Hydroxynaphthoquinone Metal Complexes as Antitumor Agents X: Synthesis, Structure, Spectroscopy and In Vitro Antitumor Activity of 3-Methyl-Phenylazo Lawsone Derivatives and Their Metal Complexes Against Human Breast Cancer Cell Line MCF-7

    PubMed Central

    Gokhale, Nikhil; Newton, Chris; Pritchard, Robin

    2000-01-01

    The C-3 substituted phenylazo derivatives of lawsone (2-hydroxy-l,4 p-naphthoquinone, III) were synthesized and characterized. The X-ray crystal structure was determined for the ligand 3-(3′-methyl phenylazo) lawsone. The copper complexes of these derivatives were found to possess 1:2 metal stoichiometry and square planar geometries with intermolecular stackings, resulting in antiferromagnetic exchange interactions. The in vitro activity of all the synthesized compounds was examined against human breast cancer cell-line, MCF-7, which revealed enhanced activities for the metal complexes, the highest activity being observed for the copper compound of 3-(3′-methyl phenylazo) lawsone. PMID:18475934

  5. Highly and Broad-Spectrum In Vitro Antitumor Active cis-Dichloridoplatinum(II) Complexes with 7-Azaindoles

    PubMed Central

    Štarha, Pavel; Dvořák, Zdeněk; Trávníček, Zdeněk

    2015-01-01

    The cis-[PtCl2(naza)2] complexes (1–3) containing monosubstituted 7-azaindole halogeno-derivatives (naza), showed significantly higher activity than cisplatin towards ovarian carcinoma A2780, its cisplatin-resistant variant A2780R, osteosarcoma HOS, breast carcinoma MCF7 and cervix carcinoma HeLa cell lines, with the IC50 values of 3.8, 3.5, 4.5, 2.7, and 9.2 μM, respectively, obtained for the most active complex 3. As for 4 and 5 having disubstituted 7-azaindoles in their molecule, the significant cytotoxicity was detected only for 4 against A2780 (IC50 = 4.8 μM), A2780R (IC50 = 3.8 μM) and HOS (IC50 = 4.3 μM), while 5 was evaluated as having only moderate antiproliferative effect against the mentioned cancer cell lines with IC50 = 33.4, 24.7 and 46.7 μM, respectively. All the studied complexes 1–5 effectively avoided the acquired resistance of ovarian carcinoma cell line. On the other hand, the complexes did not reveal any inhibition activity on the purified 20S proteasome from the A2780 cells. The representative complexes 3 and 5 showed low ability to be hydrolysed, but their stability was markedly lowered in the presence of physiological sulphur-containing biomolecule glutathione (GSH), as proved by the 1H NMR spectroscopy and mass spectrometry studies. A rate of interaction of the studied complexes with GSH was affected by an addition of another mechanistically relevant biomolecule guanosine monophosphate. The differences in interactions of 3 and 5 with GSH correlate well with their different cytotoxicity profiles. PMID:26309251

  6. Structural and functional effects of benzimidazole/thioether-copper complexes with antitumor activity on cell membranes and molecular models.

    PubMed

    Castillo, Ivan; Suwalsky, Mario; Gallardo, María José; Troncoso, Valentina; Sánchez-Eguía, Brenda N; Santiago-Osorio, Edelmiro; Aguiñiga, Itzen; González-Ugarte, Ana K

    2016-03-01

    Two cytotoxic copper(II) complexes with N-H and N-methylated benzimidazole-derived ligands (Cu-L(2) and Cu-L(2Me)) were synthesized and made to interact with human erythrocytes and molecular models of their plasmatic membranes. The latter consisted in lipid bilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), lipids of the types present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Initial assessment of the interaction of the complexes with DMPC and DMPE consisted of X-ray diffraction studies, which showed preferential interactions with the former. Scanning electron microscopy (SEM) of erythrocytes incubated with solutions of the Cu(II) complexes evidenced deformation of the cells to stomatocytes and knizocytes by Cu-L(2) and Cu-L(2Me) due to interactions with the inner and outer leaflets of the cell membranes, respectively. This was further confirmed by real-time observation of the dose-dependent effects of the complexes on live erythrocytes by defocusing microscopy (DM). The combined observations, including the increased antiproliferative activity of the N-methylated complex Cu-L(2Me) over that of Cu-L(2) is rationalized based on the higher lipophilicity of the former. This property would facilitate passive diffusion of Cu-L(2Me) through the cell membrane, particularly in the initial stages when the DMPC-rich outer leaflet is involved. In contrast, the benzimidazole N-H groups of Cu-L(2) may participate in hydrogen bonding with DMPE polar groups; this result is consistent with the formation of stomatocyte induced by the latter complex.

  7. Structural analysis of a holoenzyme complex of mouse dihydrofolate reductase with NADPH and a ternary complex with the potent and selective inhibitor 2, 4-diamino-6-(2′-hydroxydibenz[b, f]azepin-5-yl)methylpteridine

    SciTech Connect

    Cody, Vivian; Pace, Jim; Rosowsky, Andre

    2008-09-01

    The structures of mouse DHFR holo enzyme and a ternary complex with NADPH and a potent inhibitor are described. It has been shown that 2, 4-diamino-6-arylmethylpteridines and 2, 4-diamino-5-arylmethylpyrimidines containing an O-carboxylalkyloxy group in the aryl moiety are potent and selective inhibitors of the dihydrofolate reductase (DHFR) from opportunistic pathogens such as Pneumocystis carinii, the causative agent of Pneumocystis pneumonia in HIV/AIDS patients. In order to understand the structure–activity profile observed for a series of substituted dibenz[b, f]azepine antifolates, the crystal structures of mouse DHFR (mDHFR; a mammalian homologue) holo and ternary complexes with NADPH and the inhibitor 2, 4-diamino-6-(2′-hydroxydibenz[b, f]azepin-5-yl)methylpteridine were determined to 1.9 and 1.4 Å resolution, respectively. Structural data for the ternary complex with the potent O-(3-carboxypropyl) inhibitor PT684 revealed no electron density for the O-carboxylalkyloxy side chain. The side chain was either cleaved or completely disordered. The electron density fitted the less potent hydroxyl compound PT684a. Additionally, cocrystallization of mDHFR with NADPH and the less potent 2′-(4-carboxybenzyl) inhibitor PT682 showed no electron density for the inhibitor and resulted in the first report of a holoenzyme complex despite several attempts at crystallization of a ternary complex. Modeling data of PT682 in the active site of mDHFR and P. carinii DHFR (pcDHFR) indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit into the active site or that the inhibitor side chain would have to adopt an alternative binding mode to that observed for other carboxyalkyloxy inhibitors. These data also show that the mDHFR complexes have a decreased active-site volume as reflected in the relative shift of helix C (residues 59–64) by 0.6 Å compared with pcDHFR ternary complexes. These data are consistent with the

  8. Antitumoral, antihypertensive, antimicrobial, and antioxidant effects of an octanuclear copper(II)-telmisartan complex with an hydrophobic nanometer hole.

    PubMed

    Islas, María S; Martínez Medina, Juan J; López Tévez, Libertad L; Rojo, Teófilo; Lezama, Luis; Griera Merino, Mercedes; Calleros, Laura; Cortes, María A; Rodriguez Puyol, Manuel; Echeverría, Gustavo A; Piro, Oscar E; Ferrer, Evelina G; Williams, Patricia A M

    2014-06-02

    A new Cu(II) complex with the antihypertensive drug telmisartan, [Cu8Tlm16]·24H2O (CuTlm), was synthesized and characterized by elemental analysis and electronic, FTIR, Raman and electron paramagnetic resonance spectroscopy. The crystal structure (at 120 K) was solved by X-ray diffraction methods. The octanuclear complex is a hydrate of but otherwise isostructural to the previously reported [Cu8Tlm16] complex. [Cu8Tlm16]·24H2O crystallizes in the tetragonal P4/ncc space group with a = b = 47.335(1), c = 30.894(3) Å, Z = 4 molecules per unit cell giving a macrocyclic ring with a double helical structure. The Cu(II) ions are in a distorted bipyramidal environment with a somewhat twisted square basis, cis-coordinated at their core N2O2 basis to two carboxylate oxygen and two terminal benzimidazole nitrogen atoms. Cu8Tlm16 has a toroidal-like shape with a hydrophobic nanometer hole, and their crystal packing defines nanochannels that extend along the crystal c-axis. Several biological activities of the complex and the parent ligand were examined in vitro. The antioxidant measurements indicate that the complex behaves as a superoxide dismutase mimic with improved superoxide scavenger power as compared with native sartan. The capacity of telmisartan and its copper complex to expand human mesangial cells (previously contracted by angiotensin II treatment) is similar to each other. The antihypertensive effect of the compounds is attributed to the strongest binding affinity to angiotensin II type 1 receptor and not to the antioxidant effects. The cytotoxic activity of the complex and that of its components was determined against lung cancer cell line A549 and three prostate cancer cell lines (LNCaP, PC-3, and DU 145). The complex displays some inhibitory effect on the A549 line and a high viability decrease on the LNCaP (androgen-sensitive) line. From flow cytometric analysis, an apoptotic mechanism was established for the latter cell line. Telmisartan and CuTlm show

  9. Discovery of [4-Amino-2-(1-methanesulfonylpiperidin-4-ylamino)pyrimidin-5-yl](2,3-difluoro-6-methoxyphenyl)methanone (R547), A Potent and Selective Cyclin-Dependent Kinase Inhibitor with Significiant in Vivo Antitumor Activity

    SciTech Connect

    Chu,X.; DePinto, W.; Bartkovitz, D.; So, S.; Vu, B.; Packman, K.; Lukacs, C.; Ding, Q.; Jiang, N.; et al.

    2006-01-01

    The cyclin-dependent kinases (CDKs) and their cyclin partners are key regulators of the cell cycle. Since deregulation of CDKs is found with high frequency in many human cancer cells, pharmacological inhibition of CDKs with small molecules has the potential to provide an effective strategy for the treatment of cancer. The 2,4-diamino-5-ketopyrimidines 6 reported here represent a novel class of potent and ATP-competitive inhibitors that selectively target the cyclin-dependent kinase family. This diaminopyrimidine core with a substituted 4-piperidine moiety on the C2-amino position and 2-methoxybenzoyl at the C5 position has been identified as the critical structure responsible for the CDK inhibitory activity. Further optimization has led to a good number of analogues that show potent inhibitory activities against CDK1, CDK2, and CDK4 but are inactive against a large panel of serine/threonine and tyrosine kinases (K{sub i} > 10 {mu}M). As one of these representative analogues, compound 39 (R547) has the best CDK inhibitory activities (K{sub i} = 0.001, 0.003, and 0.001 M for CDK1, CDK2, and CDK4, respectively) and excellent in vitro cellular potency, inhibiting the growth of various human tumor cell lines including an HCT116 cell line (IC{sub 50} = 0.08 {mu}M). An X-ray crystal structure of 39 bound to CDK2 has been determined in this study, revealing a binding mode that is consistent with our SAR. Compound 39 demonstrates significant in vivo efficacy in the HCT116 human colorectal tumor xenograft model in nude mice with up to 95% tumor growth inhibition. On the basis of its superior overall profile, 39 was chosen for further evaluation and has progressed into Phase I clinical trial for the treatment of cancer.

  10. Novel thiourea derivative and its complexes: Synthesis, characterization, DFT computations, thermal and electrochemical behavior, antioxidant and antitumor activities

    NASA Astrophysics Data System (ADS)

    Yeşilkaynak, Tuncay; Muslu, Harun; Özpınar, Celal; Emen, Fatih Mehmet; Demirdöğen, Ruken Esra; Külcü, Nevzat

    2017-08-01

    A novel thiourea derivative, N-((2-chloropyridin-3-yl)carbamothioyl) thiophene-2-carboxamide,C11H8ClN3OS2 (HL) and its Co(II), Ni(II) and Cu(II) complexes (ML2 type) were prepared and characterized by elemental analysis, FT-IR,1H NMR and HR-MS methods. The crystal structure of HL was also investigated by single crystal X-ray diffraction study. The HL crystallizes in the orthorhombic crystal system with P 21 21 21 space group, Z = 4, a = 3.8875(3) Å, b = 14.6442(13) Å, c = 21.8950(19) Å. The [ML2] complex structures were optimized by using B97D/TZVP level. Molecular orbitals of HL ligand were calculated at the same level. Thermal and electrochemical behaviors of the complexes were investigated. Anticancer and antioxidant activities of the complexes were also investigated. Antioxidant activities were determined by using DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2‧-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) assays. Anticancer activities were studied via MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in MCF-7 (Michigan Cancer Foundation-7) breast cancer cells.

  11. Immunization with antigenic peptides complexed with β-glucan induces potent cytotoxic T-lymphocyte activity in combination with CpG-ODNs.

    PubMed

    Mochizuki, Shinichi; Morishita, Hiromi; Kobiyama, Kouji; Aoshi, Taiki; Ishii, Ken J; Sakurai, Kazuo

    2015-12-28

    The induction of antigen-specific immune responses requires immunization with not only antigens, but also adjuvants. CpG oligonucleotides (CpG-ODNs) are well-known ligands for Toll-like receptor 9 and a potent adjuvant that induces both Th1-type humoral and cellular immune responses including cytotoxic T-lymphocyte responses. We previously demonstrated that β-glucan schizophyllan (SPG) can form complexes with CpG-ODNs with attached dA40 (CpG-dA/SPG), which can accumulate in macrophages in the draining inguinal lymph nodes and induce strong immune responses by co-administration of antigenic proteins, namely ovalbumin (OVA). Immunization with antigenic peptides, OVA257-264, did not induce these antigen-specific immune responses even in combination with CpG-dA/SPG, indicating that peptides require a carrier to antigen presenting cells. In this study, we prepared conjugates comprising OVA257-264 and dA40, and made complexes with SPG. Immunization with OVA257-264-dA/SPG induced peptide-specific immune responses in combination with CpG-dA regardless of complexation with SPG both in vitro and in vivo. When splenocytes from immunized mice were incubated with E.G7-OVA tumor model cells presenting OVA peptides, the number of cells drastically decreased after 24h. Furthermore, mice pre-immunized with OVA257-264-dA/SPG and CpG-ODNs exhibited a long delay in tumor growth after tumor inoculation. Therefore, these peptide-dA/SPG and CpG-dA/SPG complexes could be used as a potent vaccine for the treatment of cancers and infectious diseases.

  12. Palladium(II) complexes as biologically potent metallo-drugs: Synthesis, spectral characterization, DNA interaction studies and antibacterial activity

    NASA Astrophysics Data System (ADS)

    Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Naveen Kumar, R. M.; Revanasiddappa, Hosakere D.

    2013-04-01

    Four novel mononuclear Pd(II) complexes have been synthesized with the biologically active Schiff base ligands (L1-L4) derived from 3-amino-2-methyl-4(3H)-quinazolinone. The structure of the complexes has been proposed by elemental analysis, molar conductance, IR, 1H NMR, mass, UV-Vis spectrometric and thermal studies. The investigation of interaction of the complexes with calf thymus DNA (CT-DNA) has been performed with absorption and fluorescence spectroscopic studies. The nuclease activity was done using pUC19 supercoiled DNA by gel-electrophoresis. All the ligands and their Pd(II) complexes have also been screened for their antibacterial activity by discolor diffusion technique.

  13. 3,5-Dimethyl-1-thiocarbamoylpyrazole and its Pd(II) complexes: synthesis, spectral studies and antitumor activity.

    PubMed

    Rocha, F V; Barra, C V; Netto, A V G; Mauro, A E; Carlos, I Z; Frem, R C G; Ananias, S R; Quilles, M B; Stevanato, A; da Rocha, M C

    2010-05-01

    Complexes of the type [PdX2(tdmPz)] {X=Cl-(1), Br-(2); I-(3); SCN-(4); tdmPz=1-thiocarbamoyl-3,5-dimethylpyrazole} have been synthesized and characterized. Compound 1 was formed from the reaction between [PdCl2(CH3CN)2] and 1-thiocarbamoyl-3,5-dimethylpyrazole. Complexes 2, 3 and 4 were obtained by metathesis of the chloro groups from 1 by bromide, iodide and thiocyanate ions, respectively. All the compounds and cisplatin have been tested in vitro by MTT assay for their cytotoxicity against three murine cancer cell lines: mammary adenocarcinoma (LM3 and LMM3) and lung adenocarcinoma (LP07) as well towards normal murine peritoneal exudate cells (PEC). Promising cytotoxic effect against LM3 has been found for 3 showing IC50 equal to 24.5 microM which is comparable to the value obtained for cisplatin (30.3 microM).

  14. Tricomponent complex loaded with a mosquito-stage antigen of the malaria parasite induces potent transmission-blocking immunity.

    PubMed

    Arakawa, Takeshi; Tsuboi, Takafumi; Sattabongkot, Jetsumon; Sakao, Kozue; Torii, Motomi; Miyata, Takeshi

    2014-04-01

    The development of malaria vaccines is challenging, partly because the immunogenicity of recombinant malaria parasite antigens is low. We previously demonstrated that parasite antigens integrated into a tricomponent immunopotentiating complex increase antiparasitic immunity. In this study, the B domains of a group G Streptococcus (SpG) strain and Peptostreptococcus magnus (PpL) were used to evaluate whether vaccine efficacy is influenced by the type of immunoglobulin-binding domain (IBD) in the tricomponent complex. IBDs were fused to a pentameric cartilage oligomeric matrix protein (COMP) to increase the binding avidity of the complexes for their targets. The COMP-IBD fusion proteins generated (COMP-SpG and COMP-PpL and the previously constructed COMP-Z) bound a large fraction of splenic B lymphocytes but not T lymphocytes. These carrier molecules were then loaded with an ookinete surface protein of Plasmodium vivax, Pvs25, by chemical conjugation. The administration of the tricomponent complexes to mice induced more Pvs25-specific serum IgG than did the unloaded antigen. The PpL complex, which exhibited a broad Ig-binding spectrum, conferred higher vaccine efficacy than did the Z or SpG complexes when evaluated with a membrane feed assay. This study demonstrates that this tricomponent immunopotentiating system, incorporating IBDs as the B-lymphocyte-targeting ligands, is a promising technology for the delivery of malaria vaccines, particularly when combined with an aluminum salt adjuvant.

  15. A quantitative structure-activity approach for lipophilicity estimation of antitumor complexes of different metals using microemulsion electrokinetic chromatography.

    PubMed

    Foteeva, Lidia S; Trofimov, Denis A; Kuznetsova, Olga V; Kowol, Christian R; Arion, Vladimir B; Keppler, Bernhard K; Timerbaev, Andrei R

    2011-06-01

    Microemulsion electrokinetic chromatography (MEEKC) offers a valuable tool for the rapid and highly productive determination of lipophilicity for metal-based anticancer agents. In this investigation, the MEEKC technique was applied for estimation of n-octanol-water partition coefficient (logP(oct)) of a series of antiproliferative complexes of gallium(III) and iron(III) with (4)N-substituted α-N-heterocyclic thiosemicarbazones. Analysis of relationships between the experimental logP(oct) and the retention factors of compounds showed their satisfactory consistency in the case of single metal sets, as well as for both metals. Since none of available calculation programs allows for evaluating the contribution of central metal ion into logP(oct) (i.e. ΔlogP(oct)) of complexes of different metals, this parameter was measured experimentally, by the standard 'shake-flask' method. Extension of the logP(oct) programs by adding ΔlogP(oct) data resulted in good lipophilicity predictions for the complexes of gallium(III) and iron(III) included in one regression set. Comparison of metal-thiosemicarbazonates under examination in terms of logP(oct) vs. antiproliferative activities (i.e. 50% inhibitory concentration in cancer cells) provided evidence that their cytotoxic potency is associated with the ability to cross the lipid bilayer of the cell-membrane via passive diffusion. Copyright © 2011 Elsevier B.V. All rights reserved.

  16. Antigenic Characterization of the HCMV gH/gL/gO and Pentamer Cell Entry Complexes Reveals Binding Sites for Potently Neutralizing Human Antibodies

    PubMed Central

    Ciferri, Claudio; Chandramouli, Sumana; Leitner, Alexander; Donnarumma, Danilo; Cianfrocco, Michael A.; Gerrein, Rachel; Friedrich, Kristian; Aggarwal, Yukti; Palladino, Giuseppe; Aebersold, Ruedi; Norais, Nathalie; Settembre, Ethan C.; Carfi, Andrea

    2015-01-01

    Human Cytomegalovirus (HCMV) is a major cause of morbidity and mortality in transplant patients and in fetuses following congenital infection. The glycoprotein complexes gH/gL/gO and gH/gL/UL128/UL130/UL131A (Pentamer) are required for HCMV entry in fibroblasts and endothelial/epithelial cells, respectively, and are targeted by potently neutralizing antibodies in the infected host. Using purified soluble forms of gH/gL/gO and Pentamer as well as a panel of naturally elicited human monoclonal antibodies, we determined the location of key neutralizing epitopes on the gH/gL/gO and Pentamer surfaces. Mass Spectrometry (MS) coupled to Chemical Crosslinking or to Hydrogen Deuterium Exchange was used to define residues that are either in proximity or part of neutralizing epitopes on the glycoprotein complexes. We also determined the molecular architecture of the gH/gL/gO- and Pentamer-antibody complexes by Electron Microscopy (EM) and 3D reconstructions. The EM analysis revealed that the Pentamer specific neutralizing antibodies bind to two opposite surfaces of the complex, suggesting that they may neutralize infection by different mechanisms. Together, our data identify the location of neutralizing antibodies binding sites on the gH/gL/gO and Pentamer complexes and provide a framework for the development of antibodies and vaccines against HCMV. PMID:26485028

  17. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells.

    PubMed

    Demir, Ummuhan; Koehler, Andrea; Schneider, Rainer; Schweiger, Susann; Klocker, Helmut

    2014-01-31

    Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin.

  18. Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells

    PubMed Central

    2014-01-01

    Background Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. Methods The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. Results Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-α4/PP2A protein complex by siRNA knockdown of MID1 or α4 whereas AMPK activation was not required. Conclusions Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naïve and castration-resistant prostate cancer and suggest AR is an important indirect target of metformin. PMID:24484909

  19. Behavior of the potential antitumor V(IV)O complexes formed by flavonoid ligands. 3. Antioxidant properties and radical production capability.

    PubMed

    Sanna, Daniele; Ugone, Valeria; Fadda, Angela; Micera, Giovanni; Garribba, Eugenio

    2016-08-01

    The radical production capability and the antioxidant properties of some V(IV)O complexes formed by flavonoid ligands were examined. In particular, the bis-chelated species of quercetin (que), [VO(que)2](2-), and morin (mor), [VO(mor)2], were evaluated for their capability to reduce the stable radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) and produce the hydroxyl radical (•)OH by Fenton-like reactions, where the reducing agent is V(IV)O(2+). The results were compared with those displayed by other V(IV)O complexes, such as [VO(H2O)5](2+), [VO(acac)2] (acac=acetylacetonate) and [VO(cat)2](2-) (cat=catecholate). The capability of the V(IV)O flavonoids complexes to reduce DPPH is much larger than that of the V(IV)O species formed by non-antioxidant ligands and it is due mainly to the flavonoid molecule. Through the 5,5-dimethyl-1-pyrroline N-oxide (DMPO) spin trapping assay of the hydroxyl radical it was possible to demonstrate that in acidic solution V(IV)O(2+) has an effectiveness in producing (•)OH radicals comparable to that of Fe(2+). When V(IV)O complexes of flavonoids were taken into account, the amount of hydroxyl radicals produced in Fenton-like reactions depends on the specific structure of the ligand and on their capability to reduce H2O2 to give (•)OH. Both the formation of reactive oxygen species (ROS) under physiological conditions by V(IV)O complexes of flavonoid ligands and their radical scavenging capability can be put in relationship with their antitumor effectiveness and it could be possible to modulate these actions by changing the features of the flavonoid coordinated to the V(IV)O(2+) ion, such as the entity, nature and position of the substituents and the number of phenolic groups. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Characterization of nineteen antimony(III) complexes as potent inhibitors of photosystem II, carbonic anhydrase, and glutathione reductase.

    PubMed

    Karacan, Mehmet Sayım; Rodionova, Margarita V; Tunç, Turgay; Venedik, Kübra Begüm; Mamaş, Serhat; Shitov, Alexandr V; Zharmukhamedov, Sergei K; Klimov, Vyacheslav V; Karacan, Nurcan; Allakhverdiev, Suleyman I

    2016-12-01

    Nineteen antimony(III) complexes were obtained and examined as possible herbicides. Six of these were synthesized for the first time, and their structures were identified using elemental analyses, (1)H-NMR, (13)C-NMR, FTIR, LCMS, magnetic susceptibility, and conductivity measurement techniques. For the nineteen examined antimony(III) complexes their most-stable forms were determined by DFT/B3LYP/LanL2DZ calculation method. These compounds were examined for effects on photosynthetic electron transfer and carbonic anhydrase activity of photosystem II, and glutathione reductase from chloroplast as well were investigated. Our results indicated that all antimony(III) complexes inhibited glutathione reductase activity of chloroplast. A number of these also exhibited good inhibitory efficiency of the photosynthetic and carbonic anhydrase activity of Photosystem II.

  1. Synthesis, characterization, toxicity, cytogenetic and in vivo antitumor studies of 1,1-dithiolate Cu(II) complexes with di-, tri-, tetra- amines and 1,3-thiazoles. Structure-activity correlation.

    PubMed

    Bolos, C A; Chaviara, A T; Mourelatos, D; Iakovidou, Z; Mioglou, E; Chrysogelou, E; Papageorgiou, A

    2009-04-15

    A series of new mixed-ligand neutral copper(II) complexes of the general type [Cu(amine)(i-MNT)] and [Cu(tz)(i-MNT)] was prepared and characterized by elemental, spectroscopic methods, mu(eff), Lambda(mu) measurements and molecular modeling studies. The acute toxicity, the cytogenetic and the in vivo antitumor activity of the new complexes, is related to their chemical and physicochemical properties. Among the Cu(II) compounds tested the complex with 2-amino-5-methyl thiazole increases significantly the life span of leukemia P388 bearing mice in vivo.

  2. Solution studies of the antitumor complex dichloro 1,2-propylendiaminetetraacetate ruthenium (III) and of its interactions with proteins.

    PubMed

    Gonzalez Vilchez, F; Vilaplana, R; Blasco, G; Messori, L

    1998-08-01

    A mixed complex of ruthenium (III) with 1,2-propylendiaminetetraacetate (PDTA) and chloride--RAP hereafter--has been found to exhibit favorable anticancer properties in vivo. To get some insight into the possible mechanism of action of this ruthenium (III) complex, its solution behavior and reactivity with proteins were investigated through absorption, circular dichroism and 1H NMR spectroscopies. Under physiological conditions RAP slowly looses the two coordinated chlorine atoms to produce a number of ruthenium (III) reactive species; a description of the distribution of these species on the dependence of pH has been obtained through 1H NMR studies of the hyperfine shifted signals. Remarkably, through the different solution conditions employed in this study, the ruthenium ion always remains in the 3+ oxidation state and the PDTA ligand is always bound to the metal. Upon reaction with albumin, apotransferrin or diferric transferrin, at a 1:1 ratio, RAP rapidly binds to these proteins to produce substantially equivalent and relatively stable adducts. This behavior is tentatively interpreted in terms of a tight interaction between RAP and surface residues of these proteins. The implications of these findings for the biological action of this novel ruthenium (III) compound are discussed.

  3. Imino-phosphine palladium(II) and platinum(II) complexes: synthesis, molecular structures and evaluation as antitumor agents.

    PubMed

    Motswainyana, William M; Onani, Martin O; Madiehe, Abram M; Saibu, Morounke; Thovhogi, Ntevheleni; Lalancette, Roger A

    2013-12-01

    The imino-phosphine ligands L1 and L2 were prepared via condensation reaction of 2-(diphenylphosphino)benzaldehyde with substituted anilines and obtained in very good yields. An equimolar reaction of L1 and L2 with either PdCl2(cod) or PtCl2(cod) gave new palladium(II) and platinum(II) complexes 1-4. The compounds were characterized by elemental analysis, IR, (1)H and (31)P NMR spectroscopy. The molecular structures of 2, 3 and 4 were confirmed by X-ray crystallography. All the three molecular structures crystallized in monoclinic C2/c space system. The coordination geometry around the palladium and platinum atoms in respective structures exhibited distorted square planar geometry at the metal centers. The complexes were evaluated in vitro for their cytotoxic activity against human breast (MCF-7) and human colon (HT-29) cancer cells, and they exhibited growth inhibitory activities and selectivity that were superior to the standard compound cisplatin.

  4. 1,4,7,10-tetraazacyclododecane metal complexes as potent promoters of phosphodiester hydrolysis under physiological conditions.

    PubMed

    Subat, Michael; Woinaroschy, Kristina; Gerstl, Corinna; Sarkar, Biprajit; Kaim, Wolfgang; König, Burkhard

    2008-06-02

    Previously reported mono- and dinuclear Zn(II), Cu(II), and Ni(II) complexes of 1,4,7,10-tetrazacyclododecane ([12]aneN4 or cyclen) with different heterocyclic spacers (triazine, pyridine) of various lengths (bi- and tripyridine) or an azacrown-pendant have been tested for the hydrolysis of bis(4-nitrophenyl)phosphate (BNPP) under physiological conditions (pH 7-9, 25 degrees C). All Zn(II) complexes promote the hydrolysis of BNPP under physiological conditions, while those of Cu(II) and Ni(II) do not have a significant effect on the hydrolysis reaction. The hydrolysis kinetics in buffered solutions (0.05 M Bis/Tris, TRIS, HEPES, or CHES, I=0.1 M, NaCl) at 25 degrees C were determined by the initial slope method (product conversion<5%). Comparison of the second-order pH-independent rate constants (kBNPP, M(-1) s(-1)) for the mononuclear complexes ZnL1, ZnL3, and ZnL6, which are 6.1x10 (-5), 5.1x10(-5), and 5.7x10(-5), respectively, indicate that the heterocyclic moiety improves the rate of hydrolysis up to six times over the parent Zn([12]aneN4) complex (kBNPP=1.1x10(-5) M(-1) s(-1)). The reactive species is the Zn(II)-OH- complex, in which the Zn(II)-bound OH- acts as a nucleophile. For dinuclear complexes Zn2L2, Zn2L4, and Zn2L5, the rate of reaction is defined by the degree of cooperation between the metal centers, which is determined by the spacer length. Zn2L2 and Zn2L4 possessing shorter spacers are able to hydrolyze BNPP 1 to 2 orders of magnitudes faster than Zn2L5. The second-order rate constants k of Zn2L4 and Zn2L2 at pH 7, 8, and 9 are significantly higher than those of previously reported related complexes. The high BNPP hydrolytic activity may be related to pi-stacking and hydrophobic interactions between the aromatic spacer moieties and the substrate. Complexes Zn2L4 and Zn2L2 show hydrolytic activity at pH 7 and 8, which allows for the hydrolysis of activated phosphate esters under physiological conditions.

  5. Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.

    PubMed

    Zhou, Ting; Shi, Qian; Bastow, Kenneth F; Lee, Kuo-Hsiung

    2010-12-23

    In this study, various 3'R,4'R-disubstituted-2',2'-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI₅₀ value of VCR by 12-349-fold. At a concentration of 1 μg/mL, three compounds, 11, 14, and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a 2-fold increase compared to verapamil, a first-generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3' and 4' substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.

  6. The antitumor agent doxorubicin binds to Fanconi anemia group F protein.

    PubMed

    Kusayanagi, Tomoe; Tsukuda, Senko; Shimura, Satomi; Manita, Daisuke; Iwakiri, Kanako; Kamisuki, Shinji; Takakusagi, Yoichi; Takeuchi, Toshifumi; Kuramochi, Kouji; Nakazaki, Atsuo; Sakaguchi, Kengo; Kobayashi, Susumu; Sugawara, Fumio

    2012-11-01

    Doxorubicin, a commonly used cancer chemotherapy agent, elicits several potent biological effects, including synergistic-antitumor activity in combination with cisplatin. However, the mechanism of this synergism remains obscure. Here, we employed an improved T7 phage display screening method to identify Fanconi anemia group F protein (FANCF) as a doxorubicin-binding protein. The FANCF-doxorubicin interaction was confirmed by pull-down assay and SPR analysis. FANCF is a component of the Fanconi anemia complex, which monoubiquitinates D2 protein of Fanconi anemia group as a cellular response against DNA cross-linkers such as cisplatin. We observed that the monoubiquitination was inhibited by doxorubicin treatment.

  7. Anti-tumor activity of lipophilic imidazolium salts on select NSCLC cell lines.

    PubMed

    Wright, Brian D; Deblock, Michael C; Wagers, Patrick O; Duah, Ernest; Robishaw, Nikki K; Shelton, Kerri L; Southerland, Marie R; DeBord, Michael A; Kersten, Kortney M; McDonald, Lucas J; Stiel, Jason A; Panzner, Matthew J; Tessier, Claire A; Paruchuri, Sailaja; Youngs, Wiley J

    2015-07-01

    The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

  8. Iron-Targeting Antitumor Activity of Gallium Compounds and Novel Insights Into Triapine®-Metal Complexes

    PubMed Central

    Antholine, William E.

    2013-01-01

    Abstract Significance: Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Recent Advances: Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine® has demonstrated activity against other tumors. Critical Issues: Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed. Future Directions: The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it. Antioxid. Redox Signal. 00, 000–000. PMID:22900955

  9. Iron-targeting antitumor activity of gallium compounds and novel insights into triapine(®)-metal complexes.

    PubMed

    Chitambar, Christopher R; Antholine, William E

    2013-03-10

    Despite advances made in the treatment of cancer, a significant number of patients succumb to this disease every year. Hence, there is a great need to develop new anticancer agents. Emerging data show that malignant cells have a greater requirement for iron than normal cells do and that proteins involved in iron import, export, and storage may be altered in cancer cells. Therefore, strategies to perturb these iron-dependent steps in malignant cells hold promise for the treatment of cancer. Recent studies show that gallium compounds and metal-thiosemicarbazone complexes inhibit tumor cell growth by targeting iron homeostasis, including iron-dependent ribonucleotide reductase. Chemical similarities of gallium(III) with iron(III) enable the former to mimic the latter and interpose itself in critical iron-dependent steps in cellular proliferation. Newer gallium compounds have emerged with additional mechanisms of action. In clinical trials, the first-generation-compound gallium nitrate has exhibited activity against bladder cancer and non-Hodgkin's lymphoma, while the thiosemicarbazone Triapine(®) has demonstrated activity against other tumors. Novel gallium compounds with greater cytotoxicity and a broader spectrum of antineoplastic activity than gallium nitrate should continue to be developed. The antineoplastic activity and toxicity of the existing novel gallium compounds and thiosemicarbazone-metal complexes should be tested in animal tumor models and advanced to Phase I and II clinical trials. Future research should identify biologic markers that predict tumor sensitivity to gallium compounds. This will help direct gallium-based therapy to cancer patients who are most likely to benefit from it.

  10. Novel octahedral Pt(IV) complex with di-n-propyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoato ligand exerts potent immunomodulatory effects.

    PubMed

    Miljković, Djordje; Poljarević, Jelena M; Petković, Filip; Blaževski, Jana; Momčilović, Miljana; Nikolić, Ivana; Saksida, Tamara; Stošić-Grujičić, Stanislava; Grgurić-Šipka, Sanja; Sabo, Tibor J

    2012-01-01

    We have recently reported that a novel octahedral Pt(IV) complex with di-n-propyl-(S,S)-ethylenediamine-N,N'-di-2-(3-cyclohexyl)propanoato ligand has a potent cytotoxic effect on glioma, melanoma and fibrosarcoma cell lines. In this work, we investigated the influence of the Pt(IV) compound on immune cells. We determined its effect on the viability of spleen cells and lymph node cells and on their capability to produce interferon (IFN)-γ and interleukin (IL)-17. Also, we researched the compound's impact on peritoneal macrophages and generation of NO in these cells. Our results show that the complex has limited influence on cell viability of immune cells, but profound inhibitory effect on the production of examined immune mediators. These results are valuable as they show that the novel Pt(IV) complex applied in concentrations which are effective against tumor cells do not affect immune cell viability. Moreover, they also imply that the complex has immunomodulatory properties.

  11. The Potent Inhibitory Effect of a Naproxen-Appended Cobalt(III)-Cyclam Complex on Cancer Stem Cells.

    PubMed

    Cressey, Paul B; Eskandari, Arvin; Bruno, Peter M; Lu, Chunxin; Hemann, Michael T; Suntharalingam, Kogularamanan

    2016-09-15

    We report the potency against cancer stem cells (CSCs) of a new cobalt(III)-cyclam complex (1) that bears the nonsteroidal anti-inflammatory drug, naproxen. The complex displays selective potency for breast CSC-enriched HMLER-shEcad cells over breast CSC-depleted HMLER cells. Additionally, it inhibited the formation of three-dimensional tumour-like mammospheres, and reduced their viability to a greater extent than clinically used breast cancer drugs (vinorelbine, cisplatin and paclitaxel). The anti-mammosphere potency of 1 was enhanced under hypoxia-mimicking conditions. Detailed mechanistic studies revealed that DNA damage and cyclooxygenase-2 (COX-2) inhibition contribute to the cytotoxic mechanism of 1. To the best of our knowledge, 1 is the first cobalt-containing compound to show selective potency for CSCs over bulk cancer cells. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. In vitro evaluation of Zn-norfloxacin complex as a potent cytotoxic and antibacterial agent, proposed model for DNA binding.

    PubMed

    Ahmadi, F; Saberkari, M; Abiri, R; Motlagh, H Mohammadi; Saberkari, H

    2013-06-01

    A tetrahedral Zn(II) complex with the second generation fluoroquinolone, norfloxacin, was prepared and characterized (NOR-Zn complex, NZC). The antibacterial efficiency of the NZC was tested on two Gram-positive and four Gram-negative bacteria by minimum inhibitory concentration method. The cytotoxic potential of NZC on MDA (human breast adenocarcinoma), Caco-2 (human colon adenocarcinoma), and Hela (human cervix carcinoma) cell lines was studied. The DNA interaction property of the NZC has been investigated using UV-vis, fluorescence, Fourier transform infrared, as well as cyclic voltammetry methods. Intrinsic binding constant (K(b)), thermodynamic, and other spectroscopic and voltammetric data indicate that the NZC has more affinity for DNA than for norfloxacin and interacted with DNA via two modes: electrostatic and outside hydrogen binding. The proposed DNA binding mode supports the large enhancement in the cytotoxicity and antibacterial activity of NZC.

  13. β-Cyclodextrin duplexes that are connected through two disulfide bonds: potent hosts for the complexation of organic molecules.

    PubMed

    Grishina, Anastasia; Stanchev, Stancho; Kumprecht, Lukáš; Buděšínský, Miloš; Pojarová, Michaela; Dušek, Michal; Rumlová, Michaela; Křížová, Ivana; Rulíšek, Lubomír; Kraus, Tomáš

    2012-09-24

    New tubular host molecules, which are composed of two β-cyclodextrin macrocycles that are connected through two disulfide bonds, have been prepared by the air-promoted oxidation of 6(I),6(IV)-dideoxy-6(I),6(IV)-disulfanyl-β-cyclodextrin in aqueous solution. This reaction leads to three products: monomeric intramolecular disulfide and two dimeric species, which are termed as "non-eclipsed" and "eclipsed" cyclodextrin duplexes. Oxidation at a concentration of the starting thiol of 0.1 mM gave the intramolecular disulfide as the major product whereas a concentration in the millimolar range afforded the dimeric species as the dominant products. The tubular structure of the "non-eclipsed" isomer was unequivocally determined by X-ray analysis. The binding affinities of the duplexes to a wide range of compounds, including fluorescent dyes and clinically used drugs Imatinib and Esomeprazol, were studied in water by ITC. For most guest compounds, the experimentally determined K(a) values were in the range 10(7)-10(8) M(-1). These binding affinities are significantly higher than those found in the literature for analogous complexes with native cyclodextrins. In cases of binding of neutral or anionic guest molecules cyclodextrin duplexes outperformed cucurbiturils. A complex between a duplex and Nile blue was used to investigate its ability to penetrate the cytoplasmic membrane of HeLa cells. We found that the complex accumulated in the cell membrane but did not pass into cytosol. Importantly, the complex did not decompose to a significant extent under high dilution in the cellular environment. Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

    PubMed Central

    2016-01-01

    The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer. PMID:26796641

  15. Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses

    PubMed Central

    Tijsma, Aloys; Neyts, Johan; Spyrou, John A. B.; Ren, Jingshan; Grimes, Jonathan M.; Puerstinger, Gerhard; Leyssen, Pieter; Fry, Elizabeth E.; Rao, Zihe; Stuart, David I.

    2015-01-01

    The replication of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), which are the major cause of hand, foot and mouth disease (HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta-analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity. PMID:26485389

  16. Structural Analysis of a Holoenzyme Complex of Mouse Dihydrofolate Reductase With NADPH And a Ternary Complex With the Potent And Selective Inhibitor 2,4-Diamino-6-(2'-Hydroxydibenz[b,F]azepin-5-YI)

    SciTech Connect

    Cody, V.; Pace, J.; Rosowsky, A.

    2009-05-12

    It has been shown that 2,4-diamino-6-arylmethylpteridines and 2,4-diamino-5-arylmethylpyrimidines containing an O-carboxylalkyloxy group in the aryl moiety are potent and selective inhibitors of the dihydrofolate reductase (DHFR) from opportunistic pathogens such as Pneumocystis carinii, the causative agent of Pneumocystis pneumonia in HIV/AIDS patients. In order to understand the structure-activity profile observed for a series of substituted dibenz[b,f]azepine antifolates, the crystal structures of mouse DHFR (mDHFR; a mammalian homologue) holo and ternary complexes with NADPH and the inhibitor 2,4-diamino-6-(2{prime}-hydroxydibenz[b,f]azepin-5-yl)methylpteridine were determined to 1.9 and 1.4 A resolution, respectively. Structural data for the ternary complex with the potent O-(3-carboxypropyl) inhibitor PT684 revealed no electron density for the O-carboxylalkyloxy side chain. The side chain was either cleaved or completely disordered. The electron density fitted the less potent hydroxyl compound PT684a. Additionally, cocrystallization of mDHFR with NADPH and the less potent 2{prime}-(4-carboxybenzyl) inhibitor PT682 showed no electron density for the inhibitor and resulted in the first report of a holoenzyme complex despite several attempts at crystallization of a ternary complex. Modeling data of PT682 in the active site of mDHFR and P. carinii DHFR (pcDHFR) indicate that binding would require ligand-induced conformational changes to the enzyme for the inhibitor to fit into the active site or that the inhibitor side chain would have to adopt an alternative binding mode to that observed for other carboxyalkyloxy inhibitors. These data also show that the mDHFR complexes have a decreased active-site volume as reflected in the relative shift of helix C (residues 59-64) by 0.6 A compared with pcDHFR ternary complexes. These data are consistent with the greater inhibitory potency against pcDHFR.

  17. Antitumoral cyclic peptide analogues of chlamydocin.

    PubMed

    Bernardi, E; Fauchere, J L; Atassi, G; Viallefont, P; Lazaro, R

    1993-01-01

    A series of cyclic tetrapeptides bearing the bioactive alkylating group on an epsilon-amino-lysyl function have been examined for their antitumoral activity on L1210 and P388 murine leukemia cell lines. One analogue belonging to the chlamydocin family and bearing a beta-chloroethylnitrosourea group was found to be potent at inhibiting L1210 cell proliferation and had a higher therapeutic index than the reference compound bis-beta-chloroethylnitrosourea (BCNU) on the in vivo P388-induced leukemia model.

  18. Modelling, Simulation & Analysis (MS&A): Potent Enabling Tools for Planning and Executing Complex Major National Events

    DTIC Science & Technology

    2011-10-01

    événements complexes d’envergure nationale et des besoins croissants d’évaluation et de validation des plans de gestion des mesures d’urgence et de...événements tels que les Jeux olympiques de 2012 à Londres, les Jeux du Commonwealth de 2015 à Toronto et la gestion des cas d’urgence transfrontaliers...tels que les Jeux olympiques. La gestion de la sécurité lors d’événements comme Vancouver 2010 et les sommets du G8 et du G20 est un enjeu

  19. Therapeutic administration of IL-15 superagonist complex ALT-803 leads to long-term survival and durable antitumor immune response in a murine glioblastoma model.

    PubMed

    Mathios, Dimitrios; Park, Chul-Kee; Marcus, Warren D; Alter, Sarah; Rhode, Peter R; Jeng, Emily K; Wong, Hing C; Pardoll, Drew M; Lim, Michael

    2016-01-01

    Glioblastoma is the most aggressive primary central nervous system malignancy with a poor prognosis in patients. Despite the need for better treatments against glioblastoma, very little progress has been made in discovering new therapies that exhibit superior survival benefit than the standard of care. Immunotherapy has been shown to be a promising treatment modality that could help improve clinical outcomes of glioblastoma patients by assisting the immune system to overcome the immunosuppressive tumor environment. Interleukin-15 (IL-15), a cytokine shown to activate several effector components of the immune system, may serve as an excellent immunotherapeutic candidate for the treatment of glioblastoma. Thus, we evaluated the efficacy of an IL-15 superagonist complex (IL-15N72D:IL-15RαSu-Fc; also known as ALT-803) in a murine GL261-luc glioblastoma model. We show that ALT-803, as a single treatment as well as in combination with anti-PD-1 antibody or stereotactic radiosurgery, exhibits a robust antitumor immune response resulting in a prolonged survival including complete remission in tumor bearing mice. In addition, ALT-803 treatment results in long-term immune memory against glioblastoma tumor rechallenge. Flow cytometric analysis of tumor infiltrating immune cells shows that ALT-803 leads to increased percentage of CD8+-cell infiltration, but not the NK cells, and IFN-γ production into the tumor microenvironment. Cell depletion studies, in accordance with the flow cytometric results, show that the ALT-803 therapeutic effect is dependent on CD4+ and CD8+ cells. These results provide a rationale for evaluating the therapeutic activity of ALT-803 against glioblastoma in the clinical setting.

  20. The antitumor mechanism of di-2-pyridylketone 2-pyridine carboxylic acid hydrazone and its copper complex in ROS generation and topoisomerase inhibition, and hydrazone involvement in oxygen-catalytic iron mobilization.

    PubMed

    Huang, Tengfei; Li, Cuiping; Sun, Xingzhi; Zhu, Zhenfu; Fu, Yun; Liu, Youxun; Yuan, Yanbin; Li, Shaoshan; Li, Changzheng

    2015-11-01

    Iron depletion and stimulation of iron-dependent free radical damage is a rapidly developing field for chelation therapy, but the iron mobilization from ferritin by chelators has received less attention. In this study, the di-2-pyridylketone 2-pyridine carboxylic acid hydrazone (DPPCAH) and its copper complex was prepared and characterized by NMR and MS spectra. The proliferation inhibition assay showed that both DPPCAH and its copper complex exhibited selectively proliferation inhibition for HepG2 (IC50, 4.6 ± 0.2 µM for DPPACH and 1.3 ± 0.2 µM for its copper complex), but less inhibition for HCT-116 cell line (IC50, >100 µM for DPPACH and 7.8 ± 0.4 µM for its copper complex). The mechanistic studies revealed that DPPACH could remove iron from ferritin in a oxygen-catalytic manner, and contributed to redox activity of labile iron pool (LIP), that is less reported for the chelators that possess significant biological activity. The reactive oxygen species (ROS) generation and DNA cleavage assay in vitro and in vivo showed that both DPPACH-Fe(II) and DPPACH-Cu were redox-active species, indicating that ROS may mediate their antitumor activity. Further study revealed that both DPPACH and its copper complex displayed certain degree of inhibition of type II topoisomerase (Top) which contributed to their antitumor activity. Thus, the mechanism that iron mobilization by DPPACH from ferritin contributed to LIP was proposed, and both DPPACH and its copper complex were involved in ROS generation and Top II inhibition for their antitumor activities.

  1. Synthesis, characterization and antitumoral activity of new cobalt(II)complexes: Effect of the ligand isomerism on the biological activity of the complexes.

    PubMed

    Morcelli, Samila R; Bull, Érika S; Terra, Wagner S; Moreira, Rafaela O; Borges, Franz V; Kanashiro, Milton M; Bortoluzzi, Adailton J; Maciel, Leide L F; de A Almeida, João Carlos; Júnior, Adolfo Horn; Fernandes, Christiane

    2016-08-01

    The synthesis, physico-chemical characterization and cytotoxicity against five human tumoral cell lines (THP-1, U937, Molt-4, Colo205 and H460) of three new cobalt(II) coordination compounds are reported (i.e. Co(HL1)Cl (1), Co(HL2)Cl (2) and [Co(HL3)Cl]0.0.5 (CH3)2CHOH (3)). H2L2 (2-{[[2-hydroxy-3-(1-naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) and H2L3 (2-{[[2-hydroxy-3-(2-naphthyloxy)propyl](pyridin-2-ylmethyl)amino]methyl}phenol) present α and β-naphthyl groups respectively, which is absent in H2L1 (N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)]propylamine. These compounds were characterized by a range of physico-chemical methods. X-ray diffraction studies were performed for complex (3), indicating the formation of a mononuclear complex. Complexes (2) and (3), which contain α and β-naphthyl groups respectively, have presented lower IC50 values than those exhibited by complex (1). Complex (3) presents IC50 values lower than cisplatin against Colo205 (90 and 196μmolL(-1), respectively) and H460 (147 and 197μmolL(-1), respectively). These human neoplastic cells under investigation were also more susceptible toward complex (3) than peripheral blood mononuclear cells. Transmission electron microscopy investigations are in agreement with the loss of mitochondrial membrane potential (ΔΨm) observed by JC-1 mitochondrial potential sensor and indicate that the activity of complex (3) against leukemic cell line (U937) is mediated by an apoptotic mechanism associated with mitochondrial dysfunction (intrinsic pathway).

  2. Structural comparison of chromosomal and exogenous dihydrofolate reductase from Staphylococcus aureus in complex with the potent inhibitor trimethoprim

    SciTech Connect

    Heaslet, Holly; Harris, Melissa; Fahnoe, Kelly; Sarver, Ronald; Putz, Henry; Chang, Jeanne; Subramanyam, Chakrapani; Barreiro, Gabriela; Miller, J. Richard; Pfizer

    2010-09-02

    Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites. Because of its importance in multiple cellular functions, DHFR has been the subject of much research targeting the enzyme with anticancer, antibacterial, and antimicrobial agents. Clinically used compounds targeting DHFR include methotrexate for the treatment of cancer and diaminopyrimidines (DAPs) such as trimethoprim (TMP) for the treatment of bacterial infections. DAP inhibitors of DHFR have been used clinically for >30 years and resistance to these agents has become widespread. Methicillin-resistant Staphylococcus aureus (MRSA), the causative agent of many serious nosocomial and community acquired infections, and other gram-positive organisms can show resistance to DAPs through mutation of the chromosomal gene or acquisition of an alternative DHFR termed 'S1 DHFR.' To develop new therapies for health threats such as MRSA, it is important to understand the molecular basis of DAP resistance. Here, we report the crystal structure of the wild-type chromosomal DHFR from S. aureus in complex with NADPH and TMP. We have also solved the structure of the exogenous, TMP resistant S1 DHFR, apo and in complex with TMP. The structural and thermodynamic data point to important molecular differences between the two enzymes that lead to dramatically reduced affinity of DAPs to S1 DHFR. These differences in enzyme binding affinity translate into reduced antibacterial activity against strains of S. aureus that express S1 DHFR.

  3. Complex Consisting of β-Glucan and Antigenic Peptides with Cleavage Site for Glutathione and Aminopeptidases Induces Potent Cytotoxic T Lymphocytes.

    PubMed

    Mochizuki, Shinichi; Morishita, Hiromi; Sakurai, Kazuo

    2017-09-20

    The efficient induction of antigen-specific immune responses requires not only promotion of the uptake of antigens and adjuvant molecules into antigen-presenting cells but also control of their intracellular behavior. We previously demonstrated that the β-glucan schizophyllan (SPG) can form complexes with CpG oligonucleotides with attached dA40 (CpG-dA/SPG), which can accumulate in macrophages in the draining inguinal lymph nodes and induce strong immune responses. In this study, we prepared various conjugates composed of antigenic peptide (OVA257-264) and dA40 and made complexes with SPG. The conjugates with a disulfide bond between OVA257-264 and dA40 were easily cleaved by glutathione. The resultant peptides with a hydrophobic amino acid at the C-terminal end was recognized by puromycin-insensitive leucine aminopeptidase (PILS-AP), which trims antigenic peptide precursors and prepares peptides of eight or nine amino acids in length, which is the optimal length for binding to major histocompatibility complex (MHC)-I. The conjugate exposed to such enzymes induced a high antigen presentation level. The antigen presentation level was almost the same before and after the complexation with SPG. Immunization with a mixture of dA-OVA257-264/SPG and CpG-dA/SPG induced high antigen-specific cytotoxic T-lymphocyte activity at a much lower peptide dose than in previous studies. These results can be strongly ascribed to not only the cell-specific delivery by SPG but also the control of the intracellular behavior by the introduction of cleavage sites. Therefore, peptide-dA/SPG complexes could be used as potent vaccine antigens for the treatment of cancers and infectious diseases.

  4. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes.

    PubMed

    Cloutier, Nathalie; Tan, Sisareuth; Boudreau, Luc H; Cramb, Catriona; Subbaiah, Roopashree; Lahey, Lauren; Albert, Alexandra; Shnayder, Ruslan; Gobezie, Reuben; Nigrovic, Peter A; Farndale, Richard W; Robinson, William H; Brisson, Alain; Lee, David M; Boilard, Eric

    2013-02-01

    Immunoglobulins, antigens and complement can assemble to form immune complexes (IC). ICs can be detrimental as they propagate inflammation in autoimmune diseases. Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis. We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy. We find that the MPs in RA synovial fluid are highly heterogeneous in size. The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs. These mpICs frequently express the integrin CD41, consistent with platelet origin. Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor. Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs. Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils. Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.

  5. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes

    PubMed Central

    Cloutier, Nathalie; Tan, Sisareuth; Boudreau, Luc H; Cramb, Catriona; Subbaiah, Roopashree; Lahey, Lauren; Albert, Alexandra; Shnayder, Ruslan; Gobezie, Reuben; Nigrovic, Peter A; Farndale, Richard W; Robinson, William H; Brisson, Alain; Lee, David M; Boilard, Eric

    2013-01-01

    Immunoglobulins, antigens and complement can assemble to form immune complexes (IC). ICs can be detrimental as they propagate inflammation in autoimmune diseases. Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis. We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy. We find that the MPs in RA synovial fluid are highly heterogeneous in size. The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs. These mpICs frequently express the integrin CD41, consistent with platelet origin. Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor. Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs. Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils. Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs. PMID:23165896

  6. DNA strand scission by the novel antitumor antibiotic leinamycin

    SciTech Connect

    Hara, Mitsunobu; Saitoh, Yutaka; Nakano, Hirofumi )

    1990-06-19

    Leinamycin is a recently discovered antitumor antibiotic with an unusual 1,3-dioxo-1,2-dithiolane structure. It preferentially inhibits the incorporation of ({sup 3}H)thymidine into the acid-insoluble fraction of Bacillus subtilis. In vitro, leinamycin causes single-strand cleavage of supercoiled double-helical pBR322 DNA in the presence of thiol cofactors. Scavengers of oxygen radical did not suppress the DNA-cleaving activity. Thiol-activated leinamycin binds calf thymus DNA at 4{degree}C and thermal treatment of the leinamycin-DNA adduct released a chemically modified leinamycin from the complex. The lack of cytotoxicity and DNA-cleaving activity for S-deoxyleinamycin indicates that the 1,3-dioxo-1,2-dithiolane moiety is essential for the activity of leinamycin. Thus, the primary cellular target of leinamycin appears to be DNA. It binds DNA and causes single-strand break at low concentrations, which may account for the potent antitumor activity.

  7. Antitumor and antiparasitic activity of novel ruthenium compounds with polycyclic aromatic ligands.

    PubMed

    Miserachs, Helena Guiset; Cipriani, Micaella; Grau, Jordi; Vilaseca, Marta; Lorenzo, Julia; Medeiros, Andrea; Comini, Marcelo A; Gambino, Dinorah; Otero, Lucía; Moreno, Virtudes

    2015-09-01

    Five novel ruthenium(II)-arene complexes with polycyclic aromatic ligands were synthesized, comprising three compounds of the formula [RuCl(η(6)-p-cym)(L)][PF6], where p-cym = 1-isopropyl-4-methylbenzene and L are the bidentate aromatic ligands 1,10-phenanthroline-5,6-dione, 1, 5-amine-1,10-phenanthroline, 4, or 5,6-epoxy-5,6-dihydro-phenanthroline, 5. In the other two complexes [RuCl2(η(6)-p-cym)(L')], the metal is coordinated to a monodentate ligand L', where L' is phenanthridine, 2, or 9-carbonylanthracene, 3. All compounds were fully characterized by mass spectrometry and elemental analysis, as well as NMR and IR spectroscopic techniques. Obtained ruthenium compounds as well as their respective ligands were tested for their antiparasitic and antitumoral activities. Even though all compounds showed lower Trypanosoma brucei activity than the free ligands, they also resulted less toxic on mammalian cells. Cytotoxicity assays on HL60 cells showed a moderate antitumoral activity for all ruthenium compounds. Compound 1 was the most potent antitumoral (IC50 = 1.26±0.78 μM) and antiparasitic (IC50 = 0.19 ± 0.05 μM) agent, showing high selectivity towards the parasites (selectivity index >100). As complex 1 was the most promising antitumoral compound, its interaction with ubiquitin as potential target was also studied. In addition, obtained ruthenium compounds were found to bind DNA, and they are thought to interact with this macromolecule mainly through intercalation of the aromatic ligand. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Synthesis, Characterization And Antitumor Activity Of Copper(II) Complexes, [CuL2] [HL1-3=N,N-Diethyl-N'-(R-Benzoyl)Thiourea (R=H, o-Cl and p-NO2)

    PubMed Central

    Hernández, Wilfredo; Beyer, Lothar; Schröder, Uwe; Richter, Rainer; Ferreira, Jorge; Pavani, Mario

    2005-01-01

    The copper (II) complexes (CuL2) were prepared by reaction of Cu(CH3COO)2 with the corresponding derivatives of acylthioureas in a Cu:HL molar ratio of 1:2. Acylthiourea ligands, N,N-diethyl-N'-(R-benzoyl) thiourea (HL1-3) [R=H, o-Cl and p-NO2] were synthesized in high yield (78-83%) and characterized by elemental analysis, infrared spectroscopy, 1H and 13C NMR spectroscopy. The complexes CuL2 were characterized by elemental analysis, IR, FAB(+)-MS, magnetic susceptibility measurements, EPR and cyclic voltammetry. The crystal structure of the complex Cu(L2)2 shows a nearly square-planar geometry with two deprotonated ligands (L) coordinated to CuII through the oxygen and sulfur atoms in a cis arrangement. The antitumor activity of the copper(II) complexes with acylthiourea ligands was evaluated in vitro against the mouse mammary adenocarcinoma TA3 cell line. These complexes exhibited much higher cytotoxic activity (IC50 values in the range of 3.9-6.9 μM) than their corresponding ligands (40-240 μM), which indicates that the coordination of the chelate ligands around the CuII enhances the antitumor activity and, furthermore, this result confirmed that the participation of the nitro and chloro substituent groups in the complex activities is slightly relevant. The high accumulation of the complexes Cu(L2)2 and Cu(L3)2 in TA3 tumor cells and the much faster binding to cellular DNA than Cu(L1)2 are consistent with the in vitro cytotoxic activities found for these copper complexes. PMID:18365106

  9. Potent dual anti-HIV and spermicidal activities of novel oxovanadium(V) complexes with thiourea non-nucleoside inhibitors of HIV-1 reverse transcriptase.

    PubMed

    D'Cruz, Osmond J; Dong, Yanhong; Uckun, Fatih M

    2003-03-07

    We have previously demonstrated that tetrahedral bis(cyclopentadienyl)vanadium(IV) complexes and square pyramidal oxovanadium(IV) complexes of vanadium are rapid and selective spermicidal agents at low micromolar concentrations. This study investigated the potential utility of oxovanadium in combination with thiourea non-nucleoside inhibitors (NNIs) of HIV-1 reverse transcriptase (RT) for the development of an effective dual-function anti-HIV spermicide. Two rationally designed substituted phenyl-ring containing pyridyl thiourea NNIs, N-[2-(2-chlorophenethyl)]-N(')-[2-(5-bromopyridyl)-thiourea) [1] and N-[2-(2-methoxyphenethyl)]-N(')-[2-(pyridyl)-thiourea [2] that exhibited subnanomolar IC(50) values against the drug-sensitive, drug-resistant, and multidrug-resistant strains of HIV-1, were complexed with oxovanadium. The oxovanadium-thiourea [OVT] NNIs, C(29)H(27)Br(2)Cl(2)N(6)O(2)S(2)V [3], and C(31)H(35)N(6)O(4)S(2)V [4], were synthesized by reacting VOSO(4), a V(IV) compound, with the corresponding deprotonated thiourea NNI compounds as ligands. Elemental analysis showed that each OVT-NNI used two thiourea molecules as ligands. The existence of the Vz.dbnd6;O bond (968cm(-1)) was confirmed by IR spectroscopy. No d-d bands were observed in the visible spectra of OVT-NNIs and their EPR spectra were featureless, indicating that the vanadium centers were oxidized to V(V). The new OVT-NNIs as well as their thiourea NNI ligands were evaluated for (i) anti-HIV activity using the cell-free recombinant RT inhibition assays, (ii) cellular HIV replication assays, (iii) spermicidal activity against human sperm by computer-assisted sperm analysis (CASA), and (iv) cytotoxicity against normal human female genital tract epithelial cell using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) dye-reduction assays. Similar to thiourea NNIs 1 and 2, the OVT-NNIs 3 and 4, exhibited potent anti-HIV activity with submicromolar IC(50[p24]) values (0.08 and 0.128 micro

  10. Treatment with targeted Vesicular Stomatitis Virus generates therapeutic multifunctional anti-tumor memory CD4 T-cells

    PubMed Central

    Gao, Yanhua; Whitaker-Dowling, Patricia; Griffin, Judith A.; Bergman, Ira

    2011-01-01

    A generally applicable, easy-to-use method of focusing a patient's immune system to eradicate or prevent cancer has been elusive. We are attempting to develop a targeted virus to accomplish these aims. We previously created a recombinant replicating Vesicular Stomatitis Virus that preferentially infected Her2/neu expressing breast cancer cells and showed therapeutic efficacy in an implanted Balb/c mouse tumor model. The current work shows that this therapy generated therapeutic anti-tumor CD4 T-cells against multiple tumor antigens. CD4 T-cells transferred directly from cured donor mice could eradicate established tumors in host mice. T-cells were transferred directly from donor mice and were not stimulated ex vivo. Both tumors that expressed Her2/neu and those that did not were cured by transferred T-cells. Analysis of cytokines secreted by anti-tumor memory CD4 T-cells displayed a multifunctional pattern with high levels of IFNγ, IL-4 and IL-17. Anti-tumor memory CD4 T-cells traveled to the mesenteric lymph nodes and were activated there. Treatment with targeted rrVSV is a potent immune adjuvant that generates therapeutic, multifunctional anti-tumor memory CD4 T-cells that recognize multiple tumor antigens. Immunity elicited by viral therapy is independent of host major histocompatibility complex (MHC) or knowledge of tumor antigens. Virus-induced tumor immunity could have great benefit in the prevention and treatment of tumor metastases. PMID:22240921

  11. Cobalt(II), Nickel(II) and Copper(II) complexes of a tetradentate Schiff base as photosensitizers: Quantum yield of 1O2 generation and its promising role in anti-tumor activity.

    PubMed

    Pradeepa, S M; Bhojya Naik, H S; Vinay Kumar, B; Indira Priyadarsini, K; Barik, Atanu; Ravikumar Naik, T R

    2013-01-15

    In the present investigation, a Schiff base N'1,N'3-bis[(E)-(5-bromo-2-hydroxyphenyl)methylidene]benzene-1,3-dicarbohydrazide and its metal complexes have been synthesized and characterized. The DNA-binding studies were performed using absorption spectroscopy, emission spectra, viscosity measurements and thermal denatuaration studies. The experimental evidence indicated that, the Co(II), Ni(II) and Cu(II) complexes interact with calf thymus DNA through intercalation with an intrinsic binding constant Kb of 2.6×10(4) M(-1), 5.7×10(4) M(-1) and 4.5×10(4) M(-1), respectively and they exhibited potent photodamage abilities on pUC19 DNA, through singlet oxygen generation with quantum yields of 0.32, 0.27 and 0.30 respectively. The cytotoxic activity of the complexes resulted that they act as a potent photosensitizers for photochemical reactions.

  12. Cobalt(II), Nickel(II) and Copper(II) complexes of a tetradentate Schiff base as photosensitizers: Quantum yield of 1O2 generation and its promising role in anti-tumor activity

    NASA Astrophysics Data System (ADS)

    Pradeepa, S. M.; Bhojya Naik, H. S.; Vinay Kumar, B.; Indira Priyadarsini, K.; Barik, Atanu; Ravikumar Naik, T. R.

    2013-01-01

    In the present investigation, a Schiff base N'1,N'3-bis[(E)-(5-bromo-2-hydroxyphenyl)methylidene]benzene-1,3-dicarbohydrazide and its metal complexes have been synthesized and characterized. The DNA-binding studies were performed using absorption spectroscopy, emission spectra, viscosity measurements and thermal denatuaration studies. The experimental evidence indicated that, the Co(II), Ni(II) and Cu(II) complexes interact with calf thymus DNA through intercalation with an intrinsic binding constant Kb of 2.6 × 104 M-1, 5.7 × 104 M-1 and 4.5 × 104 M-1, respectively and they exhibited potent photodamage abilities on pUC19 DNA, through singlet oxygen generation with quantum yields of 0.32, 0.27 and 0.30 respectively. The cytotoxic activity of the complexes resulted that they act as a potent photosensitizers for photochemical reactions.

  13. Synthesis, Characterization and Solution Chemistry of trans-Indazoliumtetrachlorobis(Indazole)Ruthenate(III), a New Anticancer Ruthenium Complex. IR, UV, NMR, HPLC Investigations and Antitumor Activity. Crystal Structures of trans-1-Methyl-Indazoliumtetrachlorobis-(1-Methylindazole)Ruthenate(III) and its Hydrolysis Product trans-Monoaquatrichlorobis-(1-Methylindazole)-Ruthenate(III)

    PubMed Central

    Lipponer, Kari-Georg; Vogel, Ellen

    1996-01-01

    Besides intensive studies into the synthesis of the complex trans-Hlnd[RuCl4(ind)2] (Ind = indazole) 1, which differs remarkably from the usual method for the complexes of the HL[RuCl4L2] - type, competitive products and hydrolysis of this species are described. Stability and pseudo-first-order rate constant under physiological conditions of complex 1 in comparison with the analogous imidazole complex trans-Hlm[RuCl4im2] (Im = imidaZole) ICR were examined by means of HPLC, UV and conductivity measurements (Kobs.(1) = 1.55 × 10-4 s-1; Kobs.(ICR) = 9.10 × 10-4 s-1). An attempt was made to elucidate the bonding conditions in 1 by studying the reactions of Ru(lll) and the two N-methyl isomers of indazole. It can be expected that bonding in the unsubstituted ligand should occur via the N2 nitrogen. The molecular structures of the complex trans-H(1-Melnd)[RuCl4(1-Melnd)2] × 1H2O (1-Melnd = 1-methylindazole) 6 and its hydrolysis product in aqueous solution [RuCl4(H2O)(1-Melnd)2] 7 were determined crystallographically. After anisotropic refinement of F values by least squares, R is 0.053 for 6 and 0.059 for 7. Both complexes crystallize with four molecules in a unit cell of monoclinic symmetry. The space group is P2.1/n for 6 with cell dimensions a = 10.511Å, b = 13.87Å, c = 19.93Å, and β = 98.17° and C2/c for 7 with a = 19.90Å, b = 10.94Å, c = 8.490Å and β = 96.74 ° The fact that the aqua species 7 could be isolated after dissolving 6 in a water/acetone solution confirmed the theory of many Ru(lll) complexes being initially transformed, under physiological conditions, into aqua complexes in a first and often rate-determining hydrolysis step. Compounds 1 and ICR are potent antitumor agents which exhibit activity against a variety of tumor cells and experimental tumor models in animals, including autochthonous colorectal tumors. Clinical studies with 1 are in preparation. PMID:18472901

  14. Antitumor Trans Platinum DNA Adducts: NMR and HPLC Study of the Interaction Between a trans-Pt Iminoether Complex and the Deoxy Decamer d(CCTCGCTCTC)·d(GAGAGCGAGG)

    PubMed Central

    Andersen, Bjørn; Margiotta, Nicola; Coluccia, Mauro; Natile, Giovanni

    2000-01-01

    The single-stranded oligonucleotide 5′-d(CCTCGCTCTC) (I) was reacted with the antitumor trans platinum iminoderivative trans-[PtCl2{E-HN = C(OMe)Me}2] (trans-EE) and subsequently annealed with its complementary strand 5′-d(GAGAGCGAGG) (II). The platinated duplex was characterized by 1D and 2D proton NMR spectroscopy at 600 MHz. In agreement with previous studies by different techniques trans-EE was found to form a monofunctional adduct with the duplex involving the guanine residue. The modification by trans-EE has been found to induce only minor local distortion in the duplex geometry. Two key crosspeaks observed in the NOESY map corresponding to a close contact between G5-H8 and the methoxy and the methyl group, respectively, enabled us to dock the trans-EE complex with the duplex by geometry optimization. The results support the idea that the antitumor activity of trans-EE is related to lesion of DNA fundamentally different from that of cisplatin. Unexpectedly, the NOESY spectra indicated that at the high NaCl concentration used (0.2 M) the duplex was found to undergo slow deplatination. This was subsequently proved by HPLC. In a separate experiment on platination of the single strand in a salt free environment the HPLC analysis showed that the monofunctional adduct was not deplatinated, however, after 24 hours, additidnal minor isomers were detected. PMID:18475920

  15. Binary and ternary copper(II) complexes of a new Schiff base ligand derived from 4-acetyl-5,6-diphenyl-3(2H)-pyridazinone: Synthesis, spectral, thermal, antimicrobial and antitumor studies

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy; Adly, Omima M. I.; Abdelrhman, Ebtesam M.; El-Shetary, B. A.

    2017-10-01

    A new Schiff base ligand was synthesized by the reaction of 4-acetyl-5,6-diphenyl-3(2H)-pyridazinone with ethylenediamine. A series of binary copper(II) Schiff base complexes have been synthesized by using various copper(II) salts; AcO-, NO3-, ClO4-, Cl- and Br-. Ternary complexes were synthesized by using auxiliary ligands (L‧) [N,O-donor; 8-hydroxyquinoline and glycine or N,N-donor; 1,10-phenanthroline, bipyridyl and 2-aminopyridine]. The structures of the Schiff base and its complexes were characterized by elemental and thermal analyses, IR, electronic, mass, 1H NMR and ESR spectra in addition to conductivity and magnetic susceptibility measurements. The obtained complexes include neutral binuclear complexes as well as neutral and cationic mononuclear complexes according to the anion used and the experimental conditions. The ESR spin Hamiltonian parameters of some complexes were calculated and discussed. The metal complexes exhibited octahedral and square planar geometrical arrangements depending on the nature of the anion. Kinetic parameters (Ea, A, ΔH, ΔS and ΔG) of the thermal decomposition stages were evaluated using Coats-Redfern equations. The antimicrobial activity of the Schiff base and its complexes was screened against Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), Gram-negative bacteria (Salmonella typhimurium and Escherichia coli), yeast (Candida albicans) and fungus (Aspergillus fumigatus). The antitumor activity of the Schiff base and some of its Cu(II) complexes was investigated against HepG-2 cell line.

  16. Discovery of potent and efficacious cyanoguanidine-containing nicotinamide phosphoribosyltransferase (Nampt) inhibitors.

    PubMed

    Zheng, Xiaozhang; Baumeister, Timm; Buckmelter, Alexandre J; Caligiuri, Maureen; Clodfelter, Karl H; Han, Bingsong; Ho, Yen-Ching; Kley, Nikolai; Lin, Jian; Reynolds, Dominic J; Sharma, Geeta; Smith, Chase C; Wang, Zhongguo; Dragovich, Peter S; Oh, Angela; Wang, Weiru; Zak, Mark; Wang, Yunli; Yuen, Po-Wai; Bair, Kenneth W

    2014-01-01

    A co-crystal structure of amide-containing compound (4) in complex with the nicotinamide phosphoribosyltransferase (Nampt) protein and molecular modeling were utilized to design and discover a potent novel cyanoguanidine-containing inhibitor bearing a sulfone moiety (5, Nampt Biochemical IC50=2.5nM, A2780 cell proliferation IC50=9.7nM). Further SAR exploration identified several additional cyanoguanidine-containing compounds with high potency and good microsomal stability. Among these, compound 15 was selected for in vivo profiling and demonstrated good oral exposure in mice. It also exhibited excellent in vivo antitumor efficacy when dosed orally in an A2780 ovarian tumor xenograft model. The co-crystal structure of this compound in complex with the NAMPT protein was also determined.

  17. Structural variety of mono- and binuclear transition metal complexes of 3-[(2-hydroxy-benzylidene)-hydrazono]-1-(2-hydroxyphenyl)-butan-1-one: Synthesis, spectral, thermal, molecular modeling, antimicrobial and antitumor studies

    NASA Astrophysics Data System (ADS)

    Shebl, Magdy; Adly, Omima M. I.; El-Shafiy, Hoda F.; Khalil, Saied M. E.; Taha, A.; Mahdi, Mohammed A. N.

    2017-04-01

    A new polydentate Schiff base ligand and its metal complexes were synthesized and characterized by elemental analyses, IR, 1H NMR, electronic, ESR and mass spectra, conductivity and magnetic susceptibility measurements as well as thermal analyses. The free ligand was synthesized by condensation of o-acetoacetylphenol with salicylaldehyde hydrazone. The analytical and spectroscopic tools showed that the obtained complexes are mono- and binuclear complexes, which can be generally formulated as: [(L)M2X2(H2O)m]·nZ; M = Cr, Fe, Ni or Cu, X = OAc or NO3, m = 5 or nil and n = 3, 1.5 or 0.5 and Z = EtOH or H2O, [(H2L)2M(X)m].nH2O; M = Mn, Zn, or Cd, X = EtOH, H2O or nil, m = 2 or nil and n = 3.5 or 0, [(HL)2Co2]·0.5H2O and [(H2L)2UO2(H2O)]. The metal complexes displayed octahedral, tetrahedral and square-planar geometrical arrangements, while uranium complex displayed seven-coordinate. Kinetic parameters (Ea, A, ΔH, ΔS and ΔG) of the thermal decomposition stages have been evaluated using Coats-Redfern equations. The molecular structural parameters of the ligand and its metal complexes have been calculated and correlated with the experimental data such as IR. The antimicrobial activity of the ligand and its complexes was screened against some kinds of bacteria and fungi. The antitumor activity of the ligand and its Ni(II) and Cu(II) complexes was investigated against HepG2 cell line.

  18. N-heterocyclic carbenes (NHC) with 1,2,4-oxadiazole-substituents related to natural products: synthesis, structure and potential antitumor activity of some corresponding gold(I) and silver(I) complexes.

    PubMed

    Maftei, Catalin V; Fodor, Elena; Jones, Peter G; Freytag, Matthias; Franz, M Heiko; Kelter, Gerhard; Fiebig, Heinz-Herbert; Tamm, Matthias; Neda, Ion

    2015-08-28

    This work presents the synthesis, characterization and application of eleven new gold (I) complexes 13-23 with 1,2,4-oxadiazole-containing N-heterocyclic carbene (NHC) ligands and of the NHC silver(I) complex 24. The 1,2,4-oxadiazole unit, which can be found in a variety of biologically active natural products such as phidianidines or quisqualic acid, was incorporated, along with a variety of other biologically active moieties (anthracene, indole, 2-pyridine, 2,3,4,5-tetra-O-acetyl-D-glucopyranose, quincorine and quincoridine), in order to change the lipophilicity of the complexes, so that the transport of the active units (M-NHC) though the cell wall barrier is facilitated. The biological activity of the complexes was investigated. In vitro assessment of anti-tumor activity in a panel of 12 human tumor cell lines by a monolayer assay revealed impressive potency (mean IC50 < 0.1 μM) and tumor selectivity for 6 compounds, with individual IC50 values in the low nanomolar range. The solid state structures of compounds 13, 14, 15, 17, 18, 19 and 24 were determined by X-ray diffraction analyses.

  19. Synthesis, spectroscopic, molecular structure, antioxidant, antimicrobial and antitumor behavior of Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes of O2N type tridentate chromone-2-carboxaldehyde Schiff's base ligand

    NASA Astrophysics Data System (ADS)

    Ammar, Reda A.; Alaghaz, Abdel-Nasser M. A.; Zayed, Mohamed E.; Al-Bedair, Lamia A.

    2017-08-01

    Tridentate Schiff's base (HL) ligand was synthesized via condensation of salicylaldehyde and 3-hydroxypyridin-2-yliminomethyl-4H-chromen-4-one and their corresponding Mn(II), Co(II), Ni(II), Cu(II) and Zn(II) complexes have been synthesized. The isolated solid complexes were characterized by elemental analyses, molar conductance, spectral (IR, UV-Vis, 1H NMR), magnetic moment, EPR, and thermal measurements. The IR spectra showed that HL was coordinated to the metal ions in tridentate manner with O2N donor sites of the azomethine N, deprotonated phenolic-OH and carbonyl-O. The activation of thermodynamic parameters are calculated using Coast-Redfern and Horowitz-Metzger (HM). The octahedral geometry of the complexes is confirmed using DFT method from DMOL3 calculations, UV-Vis and magnetic moment measurements, ESR and ligand field parameters. Antioxidant activities have also been performed for all the compounds. The investigated ligand and metal complexes were screened for their in-vitro antimicrobial activities against different types of fungal and bacterial strains. The resulting data assert on the inspected compounds as a highly promising bactericides and fungicides. The antitumor activities of all inspected compounds were evaluated towards human liver Carcinoma (HepG2) cell line.

  20. Structure of aldehyde reductase in ternary complex with coenzyme and the potent 20alpha-hydroxysteroid dehydrogenase inhibitor 3,5-dichlorosalicylic acid: implications for inhibitor binding and selectivity.

    PubMed

    Carbone, Vincenzo; Chung, Roland; Endo, Satoshi; Hara, Akira; El-Kabbani, Ossama

    2008-11-01

    The structure of aldehyde reductase (ALR1) in ternary complex with the coenzyme NADPH and 3,5-dichlorosalicylic acid (DCL), a potent inhibitor of human 20alpha-hydroxysteroid dehydrogenase (AKR1C1), was determined at a resolution of 2.41A. The inhibitor formed a network of hydrogen bonds with the active site residues Trp22, Tyr50, His113, Trp114 and Arg312. Molecular modelling calculations together with inhibitory activity measurements indicated that DCL was a less potent inhibitor of ALR1 (256-fold) when compared to AKR1C1. In AKR1C1, the inhibitor formed a 10-fold stronger binding interaction with the catalytic residue (Tyr55), non-conserved hydrogen bonding interaction with His222, and additional van der Waals contacts with the non-conserved C-terminal residues Leu306, Leu308 and Phe311 that contribute to the inhibitor's selectivity advantage for AKR1C1 over ALR1.

  1. Intracellular molecular interactions of antitumor drug amsacrine (m-AMSA) as revealed by surface-enhanced Raman spectroscopy.

    PubMed

    Chourpa, I; Morjani, H; Riou, J F; Manfait, M

    1996-11-11

    Cytotoxicity of several classes of antitumor DNA intercalators is thought to result from disturbance of DNA metabolism following trapping of the nuclear enzyme DNA topoisomerase II as a covalent complex on DNA. Here, molecular interactions of the potent antitumor drug amsacrine (m-AMSA), an inhibitor of topoisomerase II, within living K562 cancer cells have been studied using surface-enhanced Raman (SER) spectroscopy. The work is based on data of the previously performed model SER experiments dealing with amsacrine/DNA, drug/topoisomerase II and drug/DNA/topoisomerase II complexes in aqueous buffer solutions. The SER data indicated two kinds of amsacrine interactions in the model complexes with topoisomerase II alone or within ternary complex: non-specific (via the acridine moiety) and specific to the enzyme conformation (via the side chain of the drug). These two types of interactions have been both revealed by the micro-SER spectra of amsacrine within living K562 cancer cells. Our data suppose the specific interactions of amsacrine with topoisomerase II via the side chain of the drug (particular feature of the drug/topoisomerase II and ternary complexes) to be crucial for its inhibitory activity.

  2. Fibrinogen facilitates the anti-tumor effect of nonnative endostatin

    PubMed Central

    Tang, Huadong; Fu, Yan; Lei, Qingxin; Han, Qing; Ploplis, Victoria A.; Castellino, Francis J.; Li, Ling; Luo, Yongzhang

    2009-01-01

    Endostatin is a potent inhibitor of tumor angiogenesis. Interestingly, nonnative endostatin also exhibits an anti-tumor effect, which remains a mystery so far. Here we show that intravenous injection of nonnative endostatin results in tumor inhibition effect. Soluble and active endostatin is isolated from human blood after the addition of nonnative endostatin in vitro. By fractionation of the whole blood, we surprisingly identify fibrinogen specifically binding to and inhibiting the aggregation of nonnative endostatin. Moreover, the anti-tumor activity of nonnative endostatin is substantially impaired in fibrinogen-deficient mice. Our studies demonstrate that fibrinogen facilitates the anti-tumor effect of nonnative endostatin, which also provides new insights into the novel physiological function of fibrinogen. PMID:19167351

  3. Low-dimensional compounds containing bioactive ligands. Part VIII: DNA interaction, antimicrobial and antitumor activities of ionic 5,7-dihalo-8-quinolinolato palladium(II) complexes with K(+) and Cs(+) cations.

    PubMed

    Farkasová, Veronika; Drweesh, Sayed Ali; Lüköová, Andrea; Sabolová, Danica; Radojević, Ivana D; Čomić, Ljiljana R; Vasić, Sava M; Paulíková, Helena; Fečko, Stanislav; Balašková, Tatiana; Vilková, Mária; Imrich, Ján; Potočňák, Ivan

    2017-02-01

    Starting from well-defined NH2(CH3)2[PdCl2(XQ)] complexes, coordination compounds of general formula Cat[PdCl2(XQ)] have been prepared by cationic exchange of NH2(CH3)2(+) and Cat cations, where XQ are biologically active halogen derivatives of quinolin-8-ol (5-chloro-7-iodo-quinolin-8-ol (CQ), 5,7-dibromo-quinolin-8-ol (dBrQ) and 5,7-dichloro-quinolin-8-ol (dClQ)) and Cat is K(+) or Cs(+). The cation exchange of all prepared complexes, K[PdCl2(CQ)] (1), K[PdCl2(dClQ)] (2), K[PdCl2(dBrQ)] (3), Cs[PdCl2(CQ)] (4), Cs[PdCl2(dClQ)] (5) and Cs[PdCl2(dBrQ)] (6) was approved using IR spectroscopy, their structures in DMSO solution were elucidated by one- and two-dimensional NMR experiments, whereas their stability in solution was verified by UV-VIS spectroscopy. Interaction of complexes to ctDNA was investigated using UV-VIS and fluorescence emission spectroscopy. The minimum inhibitory concentration and the minimum microbicidal concentration values were detected against 15 bacterial strains and 4 yeast strains to examine the antimicrobial activity for the complexes. The in vitro antitumor properties of the complexes were studied by testing the complexes on leukemic cell line L1210, ovarian cancer cell line A2780 and non-cancerous cell line HEK293. The majority of the prepared compounds exhibited moderate antimicrobial and very high cytotoxic activity.

  4. Design, synthesis and in vitro and in vivo antitumor activities of novel bivalent β-carbolines.

    PubMed

    Shi, Buxi; Cao, Rihui; Fan, Wenxi; Guo, Liang; Ma, Qin; Chen, Xuemei; Zhang, Guoxian; Qiu, Liqin; Song, Huacan

    2013-02-01

    A series of bivalent β-carbolines with a spacer of three to ten methylene units between the indole nitrogen was synthesized and evaluated as antitumor agents. The results demonstrated that compounds 18c, 21b, 25a and 31b exhibited strong cytotoxic activities with IC(50) value of lower than 20 μM against four tumor cell lines. Acute toxicities and antitumor efficacies of the selected compounds in mice were also evaluated, compounds 18b, 21b, 26a and 31b exhibited potent antitumor activities with tumor inhibition rate of over 40% in animal models. Preliminary structure-activity relationships analysis indicated that (1) the spacer length affected antitumor potencies, and four to six methylene units were more favorable; (2) the introduction of appropriate substituent into position-1 of β-carboline facilitated antitumor potencies.

  5. Utility of Clostridium difficile toxin B for inducing anti-tumor immunity.

    PubMed

    Huang, Tuxiong; Li, Shan; Li, Guangchao; Tian, Yuan; Wang, Haiying; Shi, Lianfa; Perez-Cordon, Gregorio; Mao, Li; Wang, Xiaoning; Wang, Jufang; Feng, Hanping

    2014-01-01

    Clostridium difficile toxin B (TcdB) is a key virulence factor of bacterium and induces intestinal inflammatory disease. Because of its potent cytotoxic and proinflammatory activities, we investigated the utility of TcdB in developing anti-tumor immunity. TcdB induced cell death in mouse colorectal cancer CT26 cells, and the intoxicated cells stimulated the activation of mouse bone marrow-derived dendritic cells and subsequent T cell activation in vitro. Immunization of BALB/c mice with toxin-treated CT26 cells elicited potent anti-tumor immunity that protected mice from a lethal challenge of the same tumor cells and rejected pre-injected tumors. The anti-tumor immunity generated was cell-mediated, long-term, and tumor-specific. Further experiments demonstrated that the intact cell bodies were important for the immunogenicity since lysing the toxin-treated tumor cells reduced their ability to induce antitumor immunity. Finally, we showed that TcdB is able to induce potent anti-tumor immunity in B16-F10 melanoma model. Taken together, these data demonstrate the utility of C. difficile toxin B for developing anti-tumor immunity.

  6. Antitumor vaccination: where we stand.

    PubMed

    Bocchia, M; Bronte, V; Colombo, M P; De Vincentiis, A; Di Nicola, M; Forni, G; Lanata, L; Lemoli, R M; Massaia, M; Rondelli, D; Zanon, P; Tura, S

    2000-11-01

    , recombinant viruses or bacteria as TAA genes vectors, DNA injection, tumor cells genetically modified to express co-stimulatory molecules and/or cytokines. The use of professional antigen-presenting cells, namely dendritic cells, either pulsed with TAA or transduced with tumor-specific genes, provides a useful alternative for inducing antitumor cytotoxic activity. Some of these approaches have been tested in phase I/II clinical trials in hematologic malignancies, such as lymphoproliferative diseases or chronic myeloid leukemia, and in solid tumors, such as melanoma, colon cancer, prostate cancer and renal cell carcinoma. Different types of vaccines, use of adjuvants, timing of vaccination as well as selection of patients eligible for this procedure are discussed in this review. Experimental models demonstrate the possibility of curing cancer through the active induction of a specific immune response to TAA. However, while pre-clinical research has identified several possible targets and strategies for tumor vaccination the clinical scenario is far more complex for a number of possible reasons. Since experimental data suggest that vaccination is more likely to be effective on small tumor burden, such as a minimal residual disease after conventional treatments, or tumors at an early stage of disease, better selection of patients will allow more reliable clinical results to be obtained. Moreover, a poor correlation is frequently observed between the ability of TAA to induce a T-cell response in vitro and clinical responses. Controversial findings may also be due to the techniques used for monitoring the immune status. Therefore, the development of reliable assays for efficient monitoring of the state of immunization of cancer patients against TAA is an important goal that will markedly improve the progress of antitumor vaccines. (ABSTRACT TRUNCATED)

  7. Antitumor compounds from tunicates.

    PubMed

    Rinehart, K L

    2000-01-01

    Of the six marine-derived compounds that have reached clinical trials as antitumor agents three-didemnin B, Aplidine, and ecteinascidin 743-are derived from tunicates. Di-demnin B (DB), a cyclic depsipeptide from the compound tunicate Trididemnum solidum, was the first marine-derived compound to enter Phases I and II clinical trials. The Phase II studies, sponsored by the U. S. National Cancer Institute, indicated complete or partial remissions with non-Hodgkins lymphoma, but cardiotoxicity caused didemnin B to be dropped from further study. The closely related dehydrodidemnin B (DDB, Aplidine) was isolated in 1988 from a second colonial tunicate, Aplidium albicans, and spectroscopic studies assigned a structural formula in which a pyruvyl group in DDB replaced the lactyl group in DB and syntheses of DDB have been achieved. Aplidine is more active than DB and lacks DB's cardiotoxicity. It was introduced by PharmaMar into Phase I clinical trials in January 1999. The second family of tunicate-derived antitumor agents are the ecteinascidins (ETs), from the mangrove tunicate Ecteinascidia turbinata. The antitumor extracts of E. turbinata were first described in 1969, but the small amount of ETs in E. turbinata prevented their isolation for over a decade. The structures of ETs have been assigned mainly by spectroscopy. Phase II clinical trials with ET 743 are underway. Future supplies of ET's should be available from aquaculture or synthesis. Copyright 2000 John Wiley & Sons, Inc. Med Res Rev, 20, No. 1, 1-27, 2000

  8. Non-covalent assembly of meso-tetra-4-pyridyl porphine with single-stranded DNA to form nano-sized complexes with hydrophobicity-dependent DNA release and anti-tumor activity

    PubMed Central

    Ghosh, Supratim; Ucer, Kamil B.; D’Agostino, Ralph; Grant, Ken; Sirintrapun, Joseph; Thomas, Michael J.; Hantgan, Roy; Bharadwaj, Manish; Gmeiner, William H.

    2013-01-01

    DNA and porphyrin based therapeutics are important for anti-cancer treatment. The present studies demonstrate single-stranded DNA (ssDNA) assembles with meso-tetra-4-pyridyl porphine (MTP) forming porphyrin:DNA nano-complexes (PDN) that are stable in aqueous solution under physiologically relevant conditions and undergo dissociation with DNA release in hydrophobic environments, including cell membranes. PDN formation is DNA-dependent with the ratio of porphyrin:DNA being approximately two DNA nucleobases per porphyrin. PDN produce reactive oxygen species (ROS) in a light-dependent manner under conditions that favor nano-complex dissociation in the presence of hydrophobic solvents. PDN induce light-dependent cytotoxicity in vitro and anti-tumor activity towards bladder cancer xenografts in vivo. Light-dependent, PDN-mediated cell death results from ROS-mediated localized membrane damage due to lipid peroxidation with mass spectrometry indicating the generation of the lipid peroxidation products 9- and 13-hydroxy octadecanoic acid. Our results demonstrate that PDN have properties useful for therapeutic applications, including cancer treatment. PMID:23988714

  9. Preexisting antitumor immunity augments the antitumor effects of chemotherapy.

    PubMed

    Zhang, Lingbing; Feng, Dongdong; Yu, Lynda X; Tsung, Kangla; Norton, Jeffrey A

    2013-06-01

    Efficacy of cancer chemotherapy is generally believed to be the result of direct drug killing of tumor cells. However, increased tumor cell killing does not always lead to improved efficacy. Herein, we demonstrate that the status of antitumor immunity at the time of chemotherapy treatment is a critical factor affecting the therapeutic outcome in that tumor-bearing mice that possess preexisting antitumor immunity respond to chemotherapy much better than those that do not. Enhancing antitumor immunity before or at the time of chemotherapy-induced antigen release increases subsequent response to chemotherapy significantly. By in vitro and in vivo measurements of antitumor immunity, we found a close correlation between the intensity of antitumor immunity activated by chemotherapy and the efficacy of treatment. Immune intervention with interleukin-12 during the early phase of chemotherapy-induced immune activation greatly amplifies the antitumor response, often resulting in complete tumor eradication not only at the chemo-treated local site, but also systemically. These findings provide additional evidence for an immune-mediated antitumor response to chemotherapy. Further, our results show that timely immune modification of chemotherapy-activated antitumor immunity can result in enhanced antitumor-immune response and complete tumor eradication.

  10. Synthesis and Evaluation of In Vitro DNA/Protein Binding Affinity, Antimicrobial, Antioxidant and Antitumor Activity of Mononuclear Ru(II) Mixed Polypyridyl Complexes.

    PubMed

    Putta, Venkat Reddy; Chintakuntla, Nagamani; Mallepally, Rajender Reddy; Avudoddi, Srishailam; K, Nagasuryaprasad; Nancherla, Deepika; V V N, Yaswanth; R S, Prakasham; Surya, Satyanarayana Singh; Sirasani, Satyanarayana

    2016-01-01

    The four novel Ru(II) complexes [Ru(phen)2MAFIP](2+) (1) [MAFIP = 2-(5-(methylacetate)furan-2-yl)-1 H-imidazo[4,5-f] [1, 10]phenanthroline, phen = 1,10-Phenanthroline], [Ru(bpy)2MAFIP](2+) (2) (bpy = 2,2'-bipyridine) and [Ru(dmb)2MAFIP](2+) (3) (dmb = 4,4'-dimethyl-2,2'-bipyridine) and [Ru(hdpa)2MAFIP](2+) (4) (hdpa = 2,2-dipyridylamine) have been synthesized and fully characterized via elemental analysis, NMR spectroscopy, EI-MS and FT-IR spectroscopy. In addition, the DNA-binding behaviors of the complexes 1-4 with calf thymus DNA were investigated by UV-Vis absorption, fluorescence studies and viscosity measurement. The DNA-binding experiments showed that the complexes 1-4 interact with CT-DNA through an intercalative mode. BSA protein binding affinity of synthesized complexes was determined by UV/Vis absorption and fluorescence emission titrations. The binding affinity of ruthenium complexes was supported by molecular docking. The photoactivated cleavage of plasmid pBR322 DNA by ruthenium complexes 1-4 was investigated. All the synthesized compounds were tested for antimicrobial activity by using three Gram-negative (Escherichia coli, Salmonella typhi and Pseudomonas aeruginosa) and three Gram-positive (Micrococcus luteus, Bacillus subtilis and Bacillus megaterium) organisms, these results indicated that complex 3 was more activity compared to other complexes against all tested microbial strains while moderate antimicrobial activity profile was noticed for complex 4. The antioxidant activity experiments show that the complexes exhibit moderate antioxidant activity. The cytotoxicity of synthesized complexes on HeLa cell lines has been examined by MTT assay. The apoptosis assay was carried out with Acridine Orange (AO) staining methods and the results indicate that complexes can induce the apoptosis of HeLa cells. The cell cycle arrest investigated by flow cytometry and these results indicate that complexes 1-4 induce the cell cycle arrest at G0/G1

  11. Investigation of antitumor potential of Ni(II) complexes with tridentate PNO acylhydrazones of 2-(diphenylphosphino)benzaldehyde and monodentate pseudohalides.

    PubMed

    Čobeljić, Božidar; Milenković, Milica; Pevec, Andrej; Turel, Iztok; Vujčić, Miroslava; Janović, Barbara; Gligorijević, Nevenka; Sladić, Dušan; Radulović, Siniša; Jovanović, Katarina; Anđelković, Katarina

    2016-04-01

    Square-planar azido Ni(II) complex with condensation product of 2-(diphenylphosphino)benzaldehyde and Girard's T reagent was synthesized and its crystal structure was determined. Cytotoxic activity of the azido complex and previously synthesized isothiocyanato, cyanato and chlorido Ni(II) complexes with this ligand was examined on six tumor cell lines (HeLa, A549, K562, MDA-MB-453, MDA-MB-361 and LS-174) and two normal cell line (MRC-5 and BEAS-2B). All the investigated nickel(II) complexes were cytotoxic against all tumor cell lines. The newly synthesized azido complex showed selectivity to HeLa and A549 tumor cell lines compared to the normal cells (for A549 IC50 was similar to that of cisplatin). Azido complex interferes with cell cycle phase distribution of A549 and HeLa cells and possesses nuclease activity towards supercoiled DNA. The observed selectivity of the azido complex for some tumor cell lines can be connected with its strong DNA damaging activity.

  12. Mononuclear copper(II) complexes with 3,5-substituted-4-salicylidene-amino-3,5-dimethyl-1,2,4-triazole: synthesis, structure and potent inhibition of protein tyrosine phosphatases.

    PubMed

    Ma, Ling; Lu, Liping; Zhu, Miaoli; Wang, Qingming; Li, Ying; Xing, Shu; Fu, Xueqi; Gao, Zengqiang; Dong, Yuhui

    2011-06-28

    Six copper complexes of Schiff base ligands containing 3,5-substituted-4-salicylideneamino-3,5-dimethyl-1,2,4-triazole have been synthesized and well characterized. The structures of complexes 1 and 2 were determined by X-ray crystal analysis. Fluorescence and potentiometric study indicated that in the physiological pH range, one ligand was dissociated from the complexes to form 1:1 mononucleus copper complexes. The complexes potently inhibit protein tyrosine phosphatase 1B (PTP1B), T-cell protein tyrosine phosphatase (TCPTP), megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) and Src homology phosphatase 1 (SHP-1) with 3-4 fold selectivity against PTP1B over TCPTP and PTP-MEG2, and 3-9 fold over SHP-1, but display almost no inhibition against Src homology phosphatase 2 (SHP-2). Complex 1 inhibits PTP1B with a competitive model with K(i) of 30 nM. Substitution with small groups at the phenyl of the ligand does not obviously influence the inhibitory ability of the complexes.

  13. Synthesis, characterization, in vitro antitumoral investigations and interaction with plasmid pBR322 DNA of R2eddp-platinum(IV) complexes (R = Et, n-Pr).

    PubMed

    Kaluderović, Goran N; Kommera, Harish; Schwieger, Sebastian; Paethanom, Anchan; Kunze, Michael; Schmidt, Harry; Paschke, Reinhard; Steinborn, Dirk

    2009-12-28

    The studies on synthetic, spectroscopic and biological properties of platinum(IV) complexes, [PtCl(4)(R(2)eddp)] (R = Et, 1; n-Pr, 2), containing kappa(2)N,N' bidentate ligands, esters of ethylenediamine-N,N'-di-3-propionic acid (HOOCCH(2)CH(2)NHCH(2)CH(2)NHCH(2)CH(2)COOH, H(2)eddp), are reported. Complexes have been characterized by infrared, (1)H and (13)C NMR spectroscopy and elemental analysis and it was concluded that the coordination of the ligands occurs via nitrogen donor atoms of the ester ligands (R(2)eddp). Cytotoxicity studies were performed for ligand precursors and corresponding platinum(IV) complexes. Although the n-Pr(2)eddp.2HCl itself showed no activity (IC(50) values > 125 microM) in selected cell lines, the activity of complex 2, via apoptotic mode of cell death, has increased significantly for a broad range of cancer cell lines tested in vitro (IC(50) = 8.6-49 microM). As it was found that complexes 1 and 2 are able to interact with pBR322 plasmid DNA, platinum(IV) complexes of this type may act as drugs and pro-drugs.

  14. Env-2dCD4 S60C complexes act as super immunogens and elicit potent, broadly neutralizing antibodies against clinically relevant human immunodeficiency virus type 1 (HIV-1).

    PubMed

    Killick, Mark A; Grant, Michelle L; Cerutti, Nichole M; Capovilla, Alexio; Papathanasopoulos, Maria A

    2015-11-17

    The ability to induce a broadly neutralizing antibody (bNAb) response following vaccination is regarded as a crucial aspect in developing an effective vaccine against human immunodeficiency virus type 1 (HIV-1). The bNAbs target the HIV-1 envelope glycoprotein (Env) which is exposed on the virus surface, thereby preventing cell entry. To date, conventional vaccine approaches such as the use of Env-based immunogens have been unsuccessful. We expressed, purified, characterized and evaluated the immunogenicity of several unique HIV-1 subtype C Env immunogens in small animals. Here we report that vaccine immunogens based on Env liganded to a two domain CD4 variant, 2dCD4(S60C) are capable of consistently eliciting potent, broadly neutralizing antibody responses in New Zealand white rabbits against a panel of clinically relevant HIV-1 pseudoviruses. This was irrespective of the Env protein subtype and context. Importantly, depletion of the anti-CD4 antibodies appeared to abrogate the neutralization activity in the rabbit sera. Taken together, this data suggests that the Env-2dCD4(S60C) complexes described here are "super" immunogens, and potentially immunofocus antibody responses to a unique epitope spanning the 2dCD4(60C). Recent data from the two available anti-CD4 monoclonal antibodies, Ibalizumab and CD4-Ig (and bispecific variants thereof) have highlighted that the use of these broad and potent entry inhibitors could circumvent the need for a conventional vaccine targeting HIV-1. Overall, the ability of the unique Env-2dCD4(S60C) complexes to elicit potent bNAb responses has not been described previously, reinforcing that further investigation for their utility in preventing and controlling HIV-1/SIV infection is warranted.

  15. Hydroxyquinoline derived vanadium(IV and V) and copper(II) complexes as potential anti-tuberculosis and anti-tumor agents.

    PubMed

    Correia, Isabel; Adão, Pedro; Roy, Somnath; Wahba, Mohamed; Matos, Cristina; Maurya, Mannar R; Marques, Fernanda; Pavan, Fernando R; Leite, Clarice Q F; Avecilla, Fernando; Costa Pessoa, João

    2014-12-01

    Several mixed ligand vanadium and copper complexes were synthesized containing 8-hydroxyquinoline (8HQ) and a ligand such as picolinato (pic(-)), dipicolinato (dipic(2-)) or a Schiff base. The complexes were characterized by spectroscopic techniques and by single-crystal X-ray diffraction in the case of [V(V)O(L-pheolnaph-im)(5-Cl-8HQ)] and [V(V)O(OMe)(8HQ)2], which evidenced the distorted octahedral geometry of the complexes. The electronic absorption data showed the presence of strong ligand to metal charge transfer bands, significant solvent effects, and methoxido species in methanol, which was further confirmed by (51)V-NMR spectroscopy. The structures of [Cu(II)(dipic)(8HQ)]Na and [V(IV)O(pic)(8HQ)] were confirmed by EPR spectroscopy, showing only one species in solution. The biological activity of the compounds was assessed through the minimal inhibitory concentration (MIC) of the compounds against Mycobacterium tuberculosis (Mtb) and the cytotoxic activity against the cisplatin sensitive/resistant ovarian cells A2780/A2780cisR and the non-tumorigenic HEK cells (IC50 values). Almost all tested vanadium complexes were very active against Mtb and the MICs were comparable to, or better than, the MICs of drugs, such as streptomycin. The activity of the complexes against the A2780 cell line was dependent on incubation time presenting IC50 values in the 3-14 μM (at 48 h) range. In these conditions, the complexes were significantly (*P<0.05-**P<0.001) more active than cisplatin (22 μM), in the A2780 cells and even surpassing its activity in the cisplatin-resistant cells A2780cisR (2.4-8 μM vs. 75.4; **P<0.001). In the non-tumorigenic HEK cells poor selectivity toward cancer cells for most of the complexes was observed, as well as for cisplatin.

  16. Synthesis, Structure, Electrochemistry, and Spectral Characterization of Bis-Isatin Thiocarbohydrazone Metal Complexes and Their Antitumor Activity Against Ehrlich Ascites Carcinoma in Swiss Albino Mice

    PubMed Central

    Sathisha, M. P.; Revankar, V. K.; Pai, K. S. R.

    2008-01-01

    The synthesis, structure, electrochemistry, and biological studies of Co(II), Ni(II), Cu(II), and Zn(II) complexes of thiocarbohydrazone ligand are described. The ligand is synthesized starting from thiocarbohydrazide and isatin. It is evident from the IR data that in all the complexes, only one part of the ligand is coordinated to the metal ion resulting mononuclear complexes. The ligand coordinates essentially through the carbonyl oxygen of the isatin fragment, the nitrogen atom of the azomethine group, and sulfur atom after deprotonation to give five membered rings. H1 NMR spectrum of the ligand shows only one set of signals for the aromatic protons, while the NH of isatin and NH of hydrazone give rise to two different singlets in the 11–14 ppm range. The formulations, [Cu(L)Cl]·2H2O, [Cu(L)(CH3COO)]·2H2O, [Ni(L)Cl], [Ni(L)(CH3COO)], [Co(L2)], and [Zn(L2)]·2H2O are in accordance with elemental analyses, physical, and spectroscopic measurements. The complexes are soluble in organic solvents. Molar conductance values in DMF indicate the nonelectrolytic nature of the complexes. Copper complex displays quasireversible cyclic voltametric responses with Ep near −0.659 v and 0.504 v Vs Ag/AgCl at the scan rate of 0.1 V/s. Copper(II) complexes show a single line EPR signals. For the observed magnetic moment and electronic spectral data possible explanation has been discussed. From all the available data, the probable structures for the complexes have been proposed. The compounds synthesized in present study have shown promising cytotoxic activity when screened using the in vitro method and at the same time were shown to have good activity when tested using the Ehrlich ascites carcinoma (EAC) model. The antimicrobial screening showed that the cobalt complex possesses enhanced antimicrobial activity towards fungi. PMID:18320020

  17. Synthesis of 1-Substituted Carbazolyl-1,2,3,4-tetrahydro- and Carbazolyl-3,4-dihydro-β-carboline Analogs as Potential Antitumor Agents

    PubMed Central

    Shen, Ya-Ching; Chang, Yao-To; Lin, Chun-Ling; Liaw, Chia-Ching; Kuo, Yao Haur; Tu, Lan-Chun; Yeh, Sheau Farn; Chern, Ji-Wang

    2011-01-01

    A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-β-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1–14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR) study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed. PMID:21566798

  18. Complexes of the antitumoral drugs Doxorubicin and Sabarubicin with telomeric G-quadruplex in basket conformation: ground and excited state properties.

    PubMed

    Manet, Ilse; Manoli, Francesco; Zambelli, Barbara; Andreano, Giuseppina; Masi, Annalisa; Cellai, Luciano; Ottani, Stefano; Marconi, Giancarlo; Monti, Sandra

    2011-08-01

    We studied the binding of two anthracycline drugs, Doxorubicin and Sabarubicin, to a model telomeric sequence 5'-d[GGG(TTAGGG)(3)]-3' (21-mer), assuming the basket G-quadruplex (G4) conformation in Na(+)-rich aqueous solution. We used an approach that combines spectroscopic and microcalorimetric techniques to obtain information about ground and excited state properties of the most stable complexes. Both drugs bind to the 21-mer in basket conformation and complexes of 1:1 and 2:1 drug : 21-mer stoichiometry coexist in solution. Binding constants were determined from fluorescence and isothermal titration calorimetry experiments. For both drugs association is driven by enthalpy and disfavoured by entropy in the case of two sequential binding events to different sites. The drug fluorescence is completely quenched in the 1:1 complex, most likely by electron transfer from the guanine system to the anthraquinone moiety, while part of the emission survives in the 2:1 complex. Circular dichroism (CD) of the individual complexes is dominated by the G-quadruplex signal in the UV and by the anthracycline signal in the near-UV and Vis region. The experimental CD spectra combined with conformational calculations at MM level and quantum mechanical calculation of the rotational strength of the electronic transitions afforded information on the binding geometries. This journal is © The Royal Society of Chemistry and Owner Societies 2011

  19. Synthesis, characterization and potent superoxide dismutase like activity of novel bis(pyrazole) – 2,2′-bipyridyl mixed ligand copper(II) complexes

    PubMed Central

    Potapov, Andrei S.; Nudnova, Evgenia A.; Domina, Galina A.; Kirpotina, Liliya N.; Quinn, Mark T.; Khlebnikov, Andrei I.; Schepetkin, Igor A.

    2010-01-01

    Eleven new complexes of Cu(II) chloride and nitrate with bis(pyrazol-1-yl)propane and bis[2-(pyrazol-1-yl)ethyl]ether ligands were prepared and characterized by spectral and electrochemical methods. X-ray crystal structure determination of bis[2-(3,5-dimethylpyrazol-1-yl)ethyl]etherdinitratocopper revealed a hepta-coordinated structure with the bis(pyrazole) ligand coordinated in a tridentate NNO-fashion and both of the nitrate ions in a bidentate fashion. Reaction of Cu(II) nitrate complexes with 2,2′-bipyridyl led to the displacement of one of the nitrate ions into the outer sphere and the formation of mixed-ligand complexes. Mixed-ligand bipyridyl Cu(II) complexes demonstrated the highest superoxide dismutase (SOD)-like activity in a chemical superoxide anion-generating system, with IC50 values in the low micromolar range. Density functional theory calculations showed that introduction of a bipypidyl ligand into the complexes dramatically lowered the lowest unoccupied molecular orbital (LUMO) energy level, which explains the increased SOD-like activity of these complexes compared to non-bipy species. These bipy complexes were also effective scavengers of reactive oxygen species generated by phagocytes (human neutrophils and murine bone marrow leukocytes) ex vivo. Thus, these bipy mixed-ligand complexes represent a promising class of SOD mimetics for future development. PMID:19488447

  20. Preparation of 6/8/11-Amino/Chloro-Oxoisoaporphine and Group-10 Metal Complexes and Evaluation of Their in Vitro and in Vivo Antitumor Activity

    PubMed Central

    Qin, Qi-Pin; Qin, Jiao-Lan; Meng, Ting; Yang, Gui-Ai; Wei, Zu-Zhuang; Liu, Yan-Cheng; Liang, Hong; Chen, Zhen-Feng

    2016-01-01

    A series of group-10 metal complexes 1–14 of oxoisoaporphine derivatives were designed and synthesized. 1–14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1–6, 7, 8, 10 and 11, especially 3, were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1–6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand La exhibited less side effects than 6 with 8-amino substituted ligand Lb and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent. PMID:27898051

  1. Copper(II/I) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline: synthesis, crystal structure, antitumor activity and DNA interaction.

    PubMed

    Huang, Ke-Bin; Chen, Zhen-Feng; Liu, Yan-Cheng; Wang, Meng; Wei, Jian-Hua; Xie, Xiao-Li; Zhang, Jian-Lian; Hu, Kun; Liang, Hong

    2013-01-01

    Three new copper(II) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline (PYP), i.e. [Cu₂(PYP)₂Cl₄] (1), [Cu₄(PYP)₄(ClO₄)₂(H₂O)₂](ClO₄)₂·2H₂O (2), and [Cu₂(PYP)2Cl4]n (3), were synthesized and fully characterized. In comparison to free PYP, complexes 1-3 exhibited enhanced cytotoxicity against tested human tumor cell lines BEL-7404, SK-OV-3, A549, A375, MGC-803 and NCI-H460, with IC₅₀ values ranging from 0.31 to 30.76 μM. Complexes 1-3 exhibited lower cytotoxicity to HL-7702 than them to cancer cells. Complex 1 induced apoptotic death of BEL-7404, which involved mitochondria in the process. Caspase-3 activation assay indicated that 1 could be an efficient activator of caspase-3. DNA binding studies by UV-vis, DNA-melting, competitive binding, CD, viscosity measurement and agarose gel electrophoresis, revealed that intercalation might be the most likely binding mode of 1 with DNA.

  2. Novel C,N-Cyclometalated Benzimidazole Ruthenium(II) and Iridium(III) Complexes as Antitumor and Antiangiogenic Agents: A Structure-Activity Relationship Study.

    PubMed

    Yellol, Jyoti; Pérez, Sergio A; Buceta, Alicia; Yellol, Gorakh; Donaire, Antonio; Szumlas, Piotr; Bednarski, Patrick J; Makhloufi, Gamall; Janiak, Christoph; Espinosa, Arturo; Ruiz, José

    2015-09-24

    A series of novel C,N-cyclometalated benzimidazole ruthenium(II) and iridium(III) complexes of the types [(η(6)-p-cymene)RuCl(κ(2)-N,C-L)] and [(η(5)-C5Me5)IrCl(κ(2)-N,C-L)] (HL = methyl 1-butyl-2-arylbenzimidazolecarboxylate) with varying substituents (H, Me, F, CF3, MeO, NO2, and Ph) in the R4 position of the phenyl ring of 2-phenylbenzimidazole chelating ligand of the ruthenium (3a-g) and iridium complexes (4a-g) have been prepared. The cytotoxic activity of the new ruthenium(II) and iridium(III) compounds has been evaluated in a panel of cell lines (A2780, A2780cisR, A427, 5637, LCLC, SISO, and HT29) in order to investigate structure-activity relationships. Phenyl substitution at the R4 position shows increased potency in both Ru and Ir complexes (3g and 4g, respectively) as compared to their parent compounds (3a and 4a) in all cell lines. In general, ruthenium complexes are more active than the corresponding iridium complexes. The new ruthenium and iridium compounds increased caspase-3 activity in A2780 cells, as shown for 3a,d and 4a,d. Compound 4g is able to increase the production of ROS in A2780 cells. Furthermore, all the new compounds are able to overcome the cisplatin resistance in A2780cisR cells. In addition, some of the metal complexes effectively inhibit angiogenesis in the human umbilical vein endothelial cell line EA.hy926 at 0.5 μM, the ruthenium derivatives 3g (Ph) and 3d (CF3) being the best performers. QC calculations performed on some ruthenium model complexes showed only moderate or slight electron depletion at the phenyl ring of the C,N-cyclometalated ligand and the chlorine atom on increasing the electron withdrawing effect of the R substituent.

  3. Allogeneic IgG combined with dendritic cell stimuli induces anti-tumor T cell immunity

    PubMed Central

    Carmi, Yaron; Spitzer, Matthew H.; Linde, Ian L.; Burt, Bryan M; Prestwood, Tyler R.; Perlman, Nikola; Davidson, Matthew G.; Kenkel, Justin A.; Segal, Ehud; Pusapati, Ganesh V.; Bhattacharya, Nupur; Engleman, Edgar G.

    2015-01-01

    While cancers grow in their hosts and evade host immunity through immunoediting and immunosuppression1–5, tumors are rarely transmissible between individuals. Much like transplanted allogeneic organs, allogeneic tumors are reliably rejected by host T cells, even when the tumor and host share the same major histocompatibility complex (MHC) alleles, the most potent determinants of transplant rejection6–10. How such tumor-eradicating immunity is initiated remains unknown, though elucidating this process could provide a roadmap for inducing similar responses against naturally arising tumors. We found that allogeneic tumor rejection is initiated by naturally occurring tumor-binding IgG antibodies, which enable dendritic cells (DC) to internalize tumor antigens and subsequently activate tumor-reactive T cells. We exploited this mechanism to successfully treat autologous and autochthonous tumors. Either systemic administration of DC loaded with allogeneic IgG (alloIgG)-coated tumor cells or intratumoral injection of alloIgG in combination with DC stimuli induced potent T cell mediated anti-tumor immune responses, resulting in tumor eradication in mouse models of melanoma, pancreas, lung and breast cancer. Moreover, this strategy led to eradication of distant tumors and metastases, as well as the injected primary tumors. To assess the clinical relevance of these findings, we studied antibodies and cells from patients with lung cancer. T cells from these patients responded vigorously to autologous tumor antigens after culture with alloIgG-loaded DC, recapitulating our findings in mice. These results reveal that tumor-binding alloIgG can induce powerful anti-tumor immunity that can be exploited for cancer immunotherapy. PMID:25924063

  4. Synthesis of N-diisopropyl phosphoryl benzyltetrahydroisoquinoline, a new class of mitochondrial complexes I and III inhibitors.

    PubMed

    Andreu, I; Cabedo, N; Tormo, J R; Bermejo, A; Mello, R; Cortes, D

    2000-07-03

    The synthesis of N-(O,O-diisopropylphosphoryl)-benzyltetrahydroisoquinoline (3) has been achieved in a 'one pot' procedure from imine (2) and diisopropyl-phosphorochloridate (1) generated in situ (POCl3 + iPrOH). Compound 3 is the first benzyltetrahydroisoquinoline derivative found to be a potent inhibitor of mitochondrial complexes I and III, and therefore it opens a new perspective with this series of compounds as they can be considered as new class of antitumor agents.

  5. The Antitumor Effect of Singlet Oxygen.

    PubMed

    Bauer, Georg

    2016-11-01

    Tumor cells are protected against intercellular apoptosis-inducing signaling through expression of membrane-associated catalase and superoxide dismutase. Exogenous singlet oxygen derived from activated photosensitizers or from cold atmospheric plasma causes local inactivation of protective catalase which is followed by the generation of secondary extracellular singlet oxygen. This process is specific for tumor cells and is driven by a complex interaction between H2O2 and peroxynitrite. Secondary singlet oxygen has the potential for autoamplification of its generation, resulting in optimal inactivation of protective catalase and reactivation of intercellular apoptosis-inducing signaling. An increase in the endogenous NO concentration also causes inactivation of catalase and autoamplificatory generation of secondary singlet oxygen. This principle is essential for the antitumor activity of secondary plant products, such as cyanidins and other inhibitors of NO dioxygenase. It seems that the action of the established chemotherapeutic taxol and the recently established antitumor effect of certain azoles are based on the same principles.

  6. Recent advances in understanding antitumor immunity

    PubMed Central

    Munhoz, Rodrigo Ramella; Postow, Michael Andrew

    2016-01-01

    The term “antitumor immunity” refers to innate and adaptive immune responses which lead to tumor control. Turning the immune system into a destructive force against tumors has been achieved in a broad range of human cancers with the use of non-specific immunotherapies, vaccines, adoptive-cell therapy, and, more recently with significant success, through blockade of immune checkpoints. Nevertheless, the efficacy of these approaches is not universal, and tools to identify long-term responders and primarily refractory patients are warranted. In this article, we review recent advances in understanding the complex mechanisms of antitumor immunity and how these developments can be used to address open questions in a setting of growing clinical indications for the use of immunotherapy. PMID:27803807

  7. Synthesis and in vitro antitumor activity of water soluble sulfonate- and ester-functionalized silver(I) N-heterocyclic carbene complexes.

    PubMed

    Gandin, Valentina; Pellei, Maura; Marinelli, Marika; Marzano, Cristina; Dolmella, Alessandro; Giorgetti, Marco; Santini, Carlo

    2013-12-01

    The novel N-heterocyclic carbene ligand precursor NaHIm(PrSO3) (sodium 3,3'-(1H-imidazole-3-ium-1,3-diyl)dipropane-1-sulfonate) and the related silver carbene complex [Na4(Im(PrSO3))2]AgCl have been synthesized and characterized. Recrystallization of the analogous [Im(AcEt)]AgCl complex allowed the development of X-ray analysis which led to achieve relevant structural information concerning this silver(I) derivative. Both sulfonate- and ester-functionalized silver(I) N-heterocyclic carbenes (NHCs) were evaluated for their antiproliferative activities in a wide panel of human cancer cells. Complex [Na4(Im(PrSO3))2]AgCl showed a significant in vitro antiproliferative activity that was correlated with its strong ability to inhibit thioredoxin reductase. The inhibition of this selenoenzyme determined an alteration of the cellular redox environment thus leading to the induction of the apoptotic cell death through the activation of the ASK-1 pathway. © 2013.

  8. Transition metal complexes of buparvaquone as potent new antimalarial agents. 1. Synthesis, X-ray crystal-structures, electrochemistry and antimalarial activity against Plasmodium falciparum.

    PubMed

    Gokhale, Nikhil H; Padhye, Subhash B; Croft, Simon L; Kendrick, Howard D; Davies, Wendy; Anson, Christopher E; Powell, Annie K

    2003-07-01

    New Cu(II), Ni(II), Co(II), Fe(II), and Mn(II) metal complexes of buparvaquone [3-trans(4-tert.-butylcyclohexyl)methyl-2-hydroxy-1,4-naphthoquione] (L1H) have been synthesized and characterized using IR, electron paramagnetic resonance (EPR) spectroscopy, microanalytical methods and single crystal X-ray diffraction methods. The single crystal structures were determined for ligand L1H [space group P-1 with a=6.2072(14) A, b=10.379 (2) A, c=13.840 (3) A, V=878.7(3) A(3), Z=2, D(calcd.)=1.234 mg/m(3)] and copper complex [Cu(L1)(2)(C(2)H(5)OH)(2)] C1 [space group I2/a with a=17.149(14) A, b=9.4492(8) A, c=26.946(3) A, V=4335.3(7)A(3), Z=4, D(calcd.)=1.233 mg/m(3)]. All the metal complexes along with the parent ligand have been studied for their electrochemical properties using cyclic voltammetric techniques. The compounds were tested for their in vitro antimalarial activity against Plasmodium falciparum strains. A correlation between the antimalarial activity and the redox property of these complexes is presented. The copper complex C1 exhibits significantly higher growth inhibitory activity both in vitro and in vivo than the parent ligand.

  9. DFT Simulation of Structural and Optical Properties of 9-Aminoacridine Half-Sandwich Ru(II), Rh(III), and Ir(III) Antitumoral Complexes and Their Interaction with DNA.

    PubMed

    Cerón-Carrasco, José Pedro; Ruiz, José; Vicente, Consuelo; de Haro, Concepción; Bautista, Delia; Zúñiga, José; Requena, Alberto

    2017-08-08

    In this work, we use DFT-based methods to simulate the chemical structures, optical properties, and interaction with DNA of a recently synthesized chelated C^N 9-aminoacridine arene Ru(II) anticancer agent and two new closely related Rh(III) and Ir(III) complexes using DFT-based methods. Four chemical models and a number of theoretical approaches, which representatively include the PBE0, B97D, ωB97X, ωB97X-D, M06, and M06-L density functionals and the LANL2DZ, def2-SVP, and def2-TZVP basis sets, are tested. The best overall accuracy/cost performance for the optimization process is reached at the ωB97X-D/def2-SVP and M06/def2-SVP levels of theory. Inclusion of explicit solvent molecules (CHCl3) further refines the geometry, while taking into account the crystal network gives no significant improvements of the computed bond distances and angles. The analysis of the excited states reveals that the M06 level matches better the experimental absorption spectra, compared to ωB97X-D. The use of the M06/def2-SVP approach is therefore a well-balanced method to study theoretically the bioactivity of this type of antitumoral complexes, so we couple this TD-DFT approach to molecular dynamics simulations in order to assess their reactivity with DNA. The reported results demonstrate that these drugs could be used to inject electrons into DNA, which might broaden their applications in photoactivated chemotherapy and as new materials for DNA-based electrochemical nanodevices.

  10. Synthesis and characterization of water-insoluble and water-soluble dibutyltin(IV) porphinate complexes based on the tris(pyridinyl)porphyrin moiety, their anti-tumor activity in vitro and interaction with DNA.

    PubMed

    Han, Gaoyi; Yang, Pin

    2002-07-25

    The water-insoluble and water-soluble organotin(IV)porphinate complexes based on the tris-(4-pyridinyl)porphyrin and tris(N-methyl-4-pyridiniumyl)porphyrin moieties were synthesized and characterized by elemental analysis, (1)H NMR, IR and electrospray ionization mass spectra. The in vitro activity of the compounds against P388 leukemia and A-549 was determined. The results show that the anti-tumor activities of organotin(IV)porphinate is related to the water solubility of the compounds and the central ion in the porphyrin ring. The interaction between the water-soluble dibutyltin(IV) porphinate (7 and 10) complexes and DNA has been investigated. The result shows that compounds 7 and 10 cause DNA hypochromism measured by A(260), a slight increase in the viscosity of the DNA, and an increase in the melting point of DNA by 2.9 and 1.6 degrees C, respectively at DNA(base)/Drug(Por) ratios of 60. The binding constants to DNA were 1.35+/-0.16 x 10(7) M(-1) (7) and 1.45+/-0.12 x 10(6) M(-1) (10) determined using EB competition method based on the porphyrin concentration, which is 20 and five times greater than that of precursor porphyrins [5-p,o-(carboxy)methoxyphenyl-10,15,20-tris(N-methyl-4-pyridiniumyl)] porphyrin (p,o-tMPyPac) to DNA. Electrophoresis test shows that the compounds cannot cleave the DNA. According to the electrophoresis test result and all the above results, the cytotoxic activity against P388 and A-549 tumor cells appears not to come from the cleavage of DNA caused by the compounds but from the high affinity of compounds to DNA.

  11. Structure and dynamics of the antitumor drugs nogalamycin and disnogalamycin complexed to d(CGTACG)2: comparison of crystal and solution structures.

    PubMed

    Robinson, H; Yang, D; Wang, A H

    1994-11-04

    The nuclear magnetic resonance (NMR) solution structures of the 2:1 complexes of nogalamycin-d(CGTACG)2 (Ng-CGTACG) and disnogalamycin-d(CGTACG)2 (DNg-CGTACG) have been determined by a quantitative treatment of two-dimensional nuclear Overhauser effect (2D-NOE) crosspeak intensities. The 1.3 A resolution crystal structure of the 2:1 complex of Ng-CGTACG was used as a starting model for refinement using the procedure, SPEDREF [Robinson and Wang, Biochemistry 31 (1992) 3524-3533], which incorporates full matrix relaxation theory and simulated annealing minimization. The refined solution structures have R-factors of 16.1 and 19.6% between the observed and simulated NOEs for Ng-CGTACG and DNg-CGTACG, respectively. The refined NMR structures retain major features of the crystal structure in which the elongated aglycone chromophore is intercalated between the CpG steps with its nogalose and aminoglucose lying in the minor and major grooves, respectively. The root mean square deviation between the solution and crystal structure for the complexes is 1.01 A (Ng-CGTACG) and 1.20 A (DNg-CGTACG) for the drug, plus the three base pairs surrounding the drug, indicating a very similar local structure at the intercalation site. In the NMR structure, the two G:C Watson-Crick base pairs (C1:G12 and G2:C11) that wrap around the aglycone have large buckles, as do those seen in the crystal structure. There is a 22 degree bend at the T3-A4 step in the refined solution structure. This rearrangement of the solution conformation is likely due to the absence of crystal packing. Specific hydrogen bonds between the drug and G:C bases in both grooves of the helix are preserved in the solution structure. A separate study of the 2:1 complex at low pH showed that the terminal G-C base pairing is destabilized.

  12. Pd(II) and Pt(II) complexes with a thio-aza macrocycle ligand containing an intercalating fragment: Structural and antitumor activity studies.

    PubMed

    Amatori, Stefano; Ambrosi, Gianluca; Errico Provenzano, Alfredo; Fanelli, Mirco; Formica, Mauro; Fusi, Vieri; Giorgi, Luca; Macedi, Eleonora; Micheloni, Mauro; Paoli, Paola; Rossi, Patrizia

    2016-09-01

    Two new Pt(II) and Pd(II) complexes of formula [LMCl2] (M=Pt, Pd) were synthesized and characterized both in solution and solid state. They were obtained using the thio-aza macrocycle 9,18-dimethyl-12,17dithia-9,18,27,28-tetraaaza-29-oxatetracyclo[24.2.1.0(2,7).0(20,25)]enneicosa-2,4,6,20,22,24,26,28(1)-octaene (L) containing the 2,5-diphenyl [1, 3, 4]oxadiazole as intercalating fragment. M(II) is coordinated in cis-position by the two S atoms of L. The two crystal structures of [LPtCl2] and [LPdCl2] complexes showed that the M(II) ion is located outside the macrocyclic cavity. The square planar coordination sphere is fulfilled by two chloride anions in a cisplatin-like arrangement with the chloride leaving groups exposed to the environment. The biological activity of both [LPtCl2] and [LPdCl2], monitored towards a leukemic cellular model (U937), is coherent with their ability to interfere, at different levels, with the DNA structure. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Chromatin folding and DNA replication inhibition mediated by a highly antitumor-active tetrazolato-bridged dinuclear platinum(II) complex

    PubMed Central

    Imai, Ryosuke; Komeda, Seiji; Shimura, Mari; Tamura, Sachiko; Matsuyama, Satoshi; Nishimura, Kohei; Rogge, Ryan; Matsunaga, Akihiro; Hiratani, Ichiro; Takata, Hideaki; Uemura, Masako; Iida, Yutaka; Yoshikawa, Yuko; Hansen, Jeffrey C.; Yamauchi, Kazuto; Kanemaki, Masato T.; Maeshima, Kazuhiro

    2016-01-01

    Chromatin DNA must be read out for various cellular functions, and copied for the next cell division. These processes are targets of many anticancer agents. Platinum-based drugs, such as cisplatin, have been used extensively in cancer chemotherapy. The drug–DNA interaction causes DNA crosslinks and subsequent cytotoxicity. Recently, it was reported that an azolato-bridged dinuclear platinum(II) complex, 5-H-Y, exhibits a different anticancer spectrum from cisplatin. Here, using an interdisciplinary approach, we reveal that the cytotoxic mechanism of 5-H-Y is distinct from that of cisplatin. 5-H-Y inhibits DNA replication and also RNA transcription, arresting cells in the S/G2 phase, and are effective against cisplatin-resistant cancer cells. Moreover, it causes much less DNA crosslinking than cisplatin, and induces chromatin folding. 5-H-Y will expand the clinical applications for the treatment of chemotherapy-insensitive cancers. PMID:27094881

  14. Intracellular uptake of an antitumor-active azole-bridged dinuclear platinum(II) complex in cisplatin-resistant tumor cells.

    PubMed

    Kishimoto, Shuichi; Yasuda, Megumi; Suzuki, Ryosuke; Fukushima, Shoji

    2016-12-01

    A cationic azolato-bridged dinuclear platinum(II) complex, [{cis-Pt(NH3)2}2(μ-OH)(μ-methyl-pyrazolate)](2+) (4M-PzPt), was developed to overcome resistance to cisplatin (CDDP). This study aimed to assess the cytotoxicity of 4M-PzPt against a CDDP-resistant cell line, H4-II-E/CDDP, and compare the intracellular accumulation of CDDP and 4M-PzPt. H4-II-E and H4-II-E/CDDP displayed similar sensitivity to 4M-PzPt; however, the sensitivity of H4-II-E/CDDP to CDDP was approximately 19-fold lower than that of H4-II-E. The difference in the sensitivity to both platinum complexes corresponded with the difference in the amount of intracellular platinum accumulation after exposure to CDDP or 4M-PzPt in both cell lines. In H4-II-E, HepG2, and HuH-7 cells, the intracellular uptake of CDDP and 4M-PzPt occurred via active transport and passive transport. Results of co-exposure with the transport inhibitors ouabain, tetraethylammonium, and cimetidine indicated that the intracellular uptake of CDDP was dependent on Na(+)/K(+)-ATPase and that of 4M-PzPt was dependent on organic cation transporters (OCTs), probably OCT1. This study suggested that 4M-PzPt could inhibit the growth of a CDDP-resistant tumor via an intracellular uptake mechanism different from that of CDDP.

  15. Behavior of the potential antitumor V(IV)O complexes formed by flavonoid ligands. 2. Characterization of sulfonate derivatives of quercetin and morin, interaction with the bioligands of the plasma and preliminary biotransformation studies.

    PubMed

    Sanna, Daniele; Ugone, Valeria; Pisano, Luisa; Serra, Maria; Micera, Giovanni; Garribba, Eugenio

    2015-12-01

    The biotransformation in the plasma and red blood cells of two potential antitumor V(IV)O complexes formed by flavonoid ligands (quercetin or que and morin or mor) and their sulfonic derivatives (quercetin-5'-sulfonic acid or que(S) and morin-5'-sulfonic acid or mor(S)) was studied by spectroscopic (EPR, Electron Paramagnetic Resonance) and computational (DFT, Density Functional Theory) methods. Que and que(S) form with V(IV)O stable complexes, and in the systems with apo-transferrin (apo-hTf) and albumin (HSA) VO(que)2 and VO(que(S))2 remain unchanged. VO(mor)2 and VO(mor(S))2 undergo displacement reactions to give the partial formation of (VO)x(HSA) and (VO)(apo-hTf)/(VO)2(apo-hTf); moreover, mor(S) forms with apo-transferrin and albumin mixed species VO-mor(S)-apo-hTf and VO-mor(S)-HSA. In the systems with apo-hTf and HSA anisotropic EPR spectra at room temperature are detected in which the protein is not directly coordinated to V(IV)O(2+) ion. This is explained assuming that the bis-chelated complexes interact strongly with the proteins through a network of hydrogen bonds with the polar groups present on the protein surface. It is suggested that this "indirect" transport of V(IV)O species could be common to all the species containing ligands which can interact with the blood proteins. Uptake experiments by red blood cells were also carried out, using vanadium concentration of 5.0×10(-4)M and incubation time in the range 0-160min. VO(que)2/VO(que(S))2 and VO(mor)2/VO(mor(S))2 cross the erythrocytes membrane and in the cytosol VO(que)2/VO(que(S))2 do not transform, whereas VO(mor)2/VO(mor(S))2 give the partial formation of mixed species with hemoglobin (Hb) and other V(IV)O complexes. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Novel natural-product-like caged xanthones with improved druglike properties and in vivo antitumor potency.

    PubMed

    Wu, Yue; Hu, Mingyang; Yang, Li; Li, Xiang; Bian, Jinlei; Jiang, Fen; Sun, Haopeng; You, Qidong; Zhang, Xiaojin

    2015-06-15

    DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.

  17. Mycalamides, pederin and psymberin as natural carbohydrates and potential antitumor agents: past and future perspectives.

    PubMed

    Witczak, Zbigniew J; Rampulla, Ricky M; Bommareddy, Ajay

    2012-12-01

    The mycalamide class of potent antiviral and antitumor natural compounds originally isolated from marine sponges in 1988 is a new interdisciplinary approach to molecular recognition. We review new synthetic approaches to this new family of natural products with remarkable biological activity. Some biological evaluation data are compiled and compared to other structurally similar molecular targets.

  18. Antitumor effects of naturally occurring oligomeric resveratrol derivatives.

    PubMed

    Qiao, Haishi; Chen, Xiaoqing; Xu, Lanfang; Wang, Jingjing; Zhao, Guoyan; Hou, Yayi; Ge, Hui Ming; Tan, Ren-Xiang; Li, Erguang

    2013-11-01

    This study was designed to evaluate and characterize the molecular basis of antitumor activity of naturally occurring resveratrol (RES; 3,5,4'-trihydroxy-trans-stilbene) derivatives. The compounds were isolated from plants in previous studies and characterized spectroscopically. The antitumor activities of 31 RES derivatives, including dimers, trimers, and tetramers of RES, were evaluated using cell-based assays and validated on a murine model. Several trimeric and a tetrameric stilbenoids induced tumor cell apoptosis or growth arrest of several tumor cell lines with IC50 values (2.8-19.7 μM), significantly lower than that of RES (IC50>70 μM). Using pauciflorol B (PauB) as an example, we showed that the compound induced apoptosis p53 dependently, inducing p53 accumulation and p53-modulated gene expression in cells with wild-type p53, but not in those with nonfunctional p53. Reexpression of p53 in p53-null cells rescued cell death response. In parallel, the MAPK/p38 was activated and critical for PauB-induced killing. Interestingly, activation of p38 in p53 deficient cells was sufficient to drive cells into senescence via the p16-pRb pathway. Finally, PauB dose-dependently inhibited tumor growth on nude mice. Naturally occurring trimeric and tetrameric stilbenoids are potent antitumor agents. Those compounds exert antitumor effect through p53-dependent induction of apoptosis or senescence.

  19. Synthesis, X-ray diffraction structures, spectroscopic properties, and in vitro antitumor activity of isomeric (1H-1,2,4-triazole)Ru(III) complexes.

    PubMed

    Arion, Vladimir B; Reisner, Erwin; Fremuth, Madeleine; Jakupec, Michael A; Keppler, Bernhard K; Kukushkin, Vadim Yu; Pombeiro, Armando J L

    2003-09-22

    Three ruthenium(III) complexes containing 1H-1,2,4-triazole (Htrz), viz., (H(2)trz)[cis-RuCl(4)(Htrz)(2)], 1, (H(2)trz)[trans-RuCl(4)(Htrz)(2)], 2, and (Ph(3)PCH(2)Ph)[trans-RuCl(4)(Htrz)(2)], 3, have been synthesized by reaction between RuCl(3) and excess of the triazole in 2.38 M HCl (1 and 2), while 3 was obtained by metathesis of 2 and [Ph(3)PCH(2)Ph]Cl in water. The products were characterized by IR, UV-vis, electrospray mass spectrometry, cyclic voltammetry, and X-ray crystallography (1 and 3). X-ray diffraction study revealed cis and trans arrangements of the triazole ligands in 1 and 3, correspondingly, and unprecedented monodentate coordination of the triazole through N2 and stabilization of its 4H tautomeric form, which is the disfavored one for the free triazole. The cytotoxicity of 1 and 2 has been assayed in three human carcinoma cell lines SW480, HT29 (colon carcinoma), and SK-BR-3 (mammary carcinoma). Both compounds exhibit antiproliferative activity in vitro. Time-dependent response of all three lines to 1 and 2 and a structure-activity relationship, i.e., higher activity of the trans-isomer 2 than that of cis-species 1, have been observed.

  20. Antitumor Peptides from Marine Organisms

    PubMed Central

    Zheng, Lan-Hong; Wang, Yue-Jun; Sheng, Jun; Wang, Fang; Zheng, Yuan; Lin, Xiu-Kun; Sun, Mi

    2011-01-01

    The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides. PMID:22072999

  1. Antitumor peptides from marine organisms.

    PubMed

    Zheng, Lan-Hong; Wang, Yue-Jun; Sheng, Jun; Wang, Fang; Zheng, Yuan; Lin, Xiu-Kun; Sun, Mi

    2011-01-01

    The biodiversity of the marine environment and the associated chemical diversity constitute a practically unlimited resource of new antitumor agents in the field of the development of marine bioactive substances. In this review, the progress on studies of antitumor peptides from marine sources is provided. The biological properties and mechanisms of action of different marine peptides are described; information about their molecular diversity is also presented. Novel peptides that induce apoptosis signal pathway, affect the tubulin-microtubule equilibrium and inhibit angiogenesis are presented in association with their pharmacological properties. It is intended to provide useful information for further research in the fields of marine antitumor peptides.

  2. Immunologic mechanisms of antitumor activity.

    PubMed

    Foss, Francine M

    2002-06-01

    The growth and metastatic spread of tumors, to a large extent, depends on their capacity to evade host immune surveillance and overcome host defenses. All tumors express antigens that are recognized to a variable extent by the immune system, but in many cases an inadequate immune response is elicited because of partial antigen masking or ineffective activation of effector cells. Tumor antigens presented in the context of major histocompatability antigen (MHC) class I complexes on either the tumor cell itself or on antigen-presenting cells are capable of inducing tumor-specific cytotoxic T lymphocytes. The presence of costimulatory molecules, such as B7-1 and B7-2, on antigen-presenting cells and the secretion of IL-2 promote the differentiation of recruited CD8+ lymphocytes into cytotoxic T lymphocytes. Tumor escape from immune effectors is most often caused by weak immunogenicity of tumor antigens, antigen masking, or overall immunosuppression, a characteristic of advanced cancer. Failure of antigen processing or binding to MHC molecules, inadequate or low-affinity binding of MHC complexes to T-cell receptors, or inadequate expression of costimulatory adhesion molecules in conjunction with the antigen-presenting MHC complex may all lead to poor immunogenicity of tumor-associated peptides and impaired antitumor response. Therapeutic interventions to augment tumor antigenicity include vaccination with immunogenic peptides, administration of in vitro expanded and activated immune effector cells, in vivo effector cell expansion with cytokine therapies, or genetic modification of either immune effectors or tumor cells with cytokine genes or genes encoding costimulatory molecules to effectively activate the immune response. Copyright 2002, Elsevier Science (USA). All rights reserved.

  3. Targeting oxidative injury and cytokines' activity in the treatment with anti-tumor necrosis factor-α antibody for complex regional pain syndrome 1.

    PubMed

    Miclescu, Adriana A; Nordquist, Lena; Hysing, Eva-Britt; Butler, Stephen; Basu, Samar; Lind, Anne-Li; Gordh, Torsten

    2013-11-01

    Cytokines and oxygen free radicals have been implicated in the potential pathogenic development of complex regional pain syndrome (CRPS). We aimed to analyze the relationship between clinical status, circulating levels of cytokines, and markers of oxidative damage during the treatment with anti-TNFα antibodies. The patient chosen for treatment had not had improvement through a number of conventional therapies and fulfilled the current diagnostic criteria for CRPS-1. We investigated the clinical variables before and after systemic administration of 1.4 mg/kg anti-TNFα antibody (infliximab), repeated after 1 month in a dose of 3 mg/kg. Blood samples were collected before and after anti-TNFα antibodies administration, and plasma was analyzed for 8-isoprostane-prostaglandin F2α (8-iso-PGF2α, a marker of oxidative injury) and cytokines (TNF-α, IL-4, IL-6, IL-7, IL-8, IL-10, IL-17A). Plasma concentrations of 8-iso-PGF2α were measured with radioimmunoassay (RIA), and the kinetics of cytokines were detected in plasma by antibody-based proximity ligation (PLA). Pathologically high levels of 8-iso-PGF2α were found in the patient. Immediately after each administration of infliximab, the levels of 8-iso-PGF2α decreased. Although the patient showed an improvement of the cutaneous dystrophic symptoms and diminished pain associated with these lesions, the levels of circulating TNFα increased after the administration of anti-TNFα antibodies. In a patient with CRPS-1 treated with anti-TNFα antibodies, we report increased levels of circulating TNFα and a temporary mitigation of oxidative stress as measured by plasma F2 -isoprostane. This case report provides evidence 2 supporting the indication of monitoring the oxidative stress biomarkers during treatment with anti-TNFα antibodies in CRPS 1.

  4. Characterization of the complex formed between a potent neutralizing ovine-derived polyclonal anti-TNFα Fab fragment and human TNFα

    PubMed Central

    Abbott, W. Mark; Snow, Melanie; Eckersley, Sonia; Renshaw, Jonathan; Davies, Gareth; Norman, Richard A.; Ceuppens, Peter; Slootstra, Jerry; Benschop, Joris J.; Hamuro, Yoshitomo; Lee, Jessica E.; Newham, Peter

    2013-01-01

    TNFα (tumour necrosis factor α) is an early mediator in the systemic inflammatory response to infection and is therefore a therapeutic target in sepsis. AZD9773 is an ovine-derived, polyclonal anti-TNFα Fab fragment derived from a pool of serum and currently being developed as a treatment for severe sepsis and septic shock. In the present study, we show that although AZD9773 has a modest affinity for TNFα in a binding assay, the Ki in a cell-based assay is approximately four orders of magnitude lower. We show using SEC (size exclusion chromatography) that the maximum size of the complex between AZD9773 and TNFα is consistent with approximately 12 Fabs binding to one TNFα trimer. A number of approaches were taken to map the epitopes recognized by AZD9773. These revealed that a number of different regions on TNFα are involved in binding to the polyclonal Fab. The data suggest that there are probably three epitopes per monomer that are responsible for most of the inhibition by AZD9773 and that all three can be occupied at the same time in the complex. We conclude that AZD9773 is clearly demonstrated to bind to multiple epitopes on TNFα and suggest that the polyclonal nature may account, at least in part, for the very high potency observed in cell-based assays. PMID:23863106

  5. New bipyridine gold(III) dithiocarbamate-containing complexes exerted a potent anticancer activity against cisplatin-resistant cancer cells independent of p53 status

    PubMed Central

    Altaf, Muhammad; Monim-ul-Mehboob, Muhammad; Kawde, Abdel-Nasser; Corona, Giuseppe; Larcher, Roberto; Ogasawara, Marcia; Casagrande, Naike; Celegato, Marta; Borghese, Cinzia; Siddik, Zahid H.; Aldinucci, Donatella; Isab, Anvarhusein A.

    2017-01-01

    We synthesized, characterized and tested in a panel of cancer cell lines, nine new bipyridine gold(III) dithiocarbamate-containing complexes. In vitro studies demonstrated that compounds 1, 2, 4, 5, 7 and 8 were the most cytotoxic in prostate, breast, ovarian cancer cell lines and in Hodgkin lymphoma cells with IC50 values lower than the reference drug cisplatin. The most active compound 1 was more active than cisplatin in ovarian (A2780cis and 2780CP-16) and breast cancer cisplatin-resistant cells. Compound 1 determined an alteration of the cellular redox homeostasis leading to increased ROS levels, a decrease in the mitochondrial membrane potential, cytochrome-c release from the mitochondria and activation of caspases 9 and 3. The ROS scavenger NAC suppressed ROS generation and rescued cells from damage. Compound 1 resulted more active in tumor cells than in normal human Mesenchymal stromal cells. Gold compounds were active independent of p53 status: exerted cytotoxic effects on a panel of non-small cell lung cancer cell lines with different p53 status and in the ovarian A2780 model where the p53 was knocked out. In conclusion, these promising results strongly indicate the need for further preclinical evaluation to test the clinical potential of these new gold(III) complexes. PMID:27888799

  6. A potent mitogenic lectin from the mycelia of a phytopathogenic fungus, Rhizoctonia bataticola, with complex sugar specificity and cytotoxic effect on human ovarian cancer cells.

    PubMed

    Nagre, Nagaraja N; Chachadi, Vishwanath B; Sundaram, Palaniswamy M; Naik, Ramachandra S; Pujari, Radha; Shastry, Padma; Swamy, Bale M; Inamdar, Shashikala R

    2010-04-01

    A lectin with strong mitogenic activity towards human peripheral blood mononuclear cells (PBMCs) and cytotoxic effect on human ovarian cancer cells has been purified from the mycelium of a phytopathogenic fungus, Rhizoctonia bataticola, using ion exchange chromatography and affinity chromatography on asialofetuin-Sepharose. The lectin, termed RBL, is a tetramer of 11-kDa subunits and has unique amino acid sequence at its blocked N-terminus. The purified RBL was blood group nonspecific and its hemagglutination activity was inhibited by mucin (porcine stomach), fetuin (fetal calf serum) and asialofetuin. Glycan array analysis revealed high affinity binding of RBL towards N-glycans and also the glycoproteins containing complex N-glycan chains. Interestingly, the lectin showed high affinity for glycans which are part of ovarian cancer marker CA125, a high molecular weight mucin containing high mannose and complex bisecting type N-linked glycans as well core 1 and 2 type O-glycans. RBL bound to human PBMCs eliciting strong mitogenic response, which could be blocked by mucin, fetuin and asialofetuin demonstrating the carbohydrate-mediated interaction with the cells. Analysis of the kinetics of binding of RBL to PBMCs revealed a delayed mitogenic response indicating a different signaling pathway compared to phytohemagglutinin-L. RBL had a significant cytotoxic effect on human ovarian cancer cell line, PA-1.

  7. Antitumor effects of electrochemical treatment

    PubMed Central

    González, Maraelys Morales; Zamora, Lisset Ortíz; Cabrales, Luis Enrique Bergues; Sierra González, Gustavo Victoriano; de Oliveira, Luciana Oliveira; Zanella, Rodrigo; Buzaid, Antonio Carlos; Parise, Orlando; Brito, Luciana Macedo; Teixeira, Cesar Augusto Antunes; Gomes, Marina das Neves; Moreno, Gleyce; Feo da Veiga, Venicio; Telló, Marcos; Holandino, Carla

    2013-01-01

    Electrochemical treatment is an alternative modality for tumor treatment based on the application of a low intensity direct electric current to the tumor tissue through two or more platinum electrodes placed within the tumor zone or in the surrounding areas. This treatment is noted for its great effectiveness, minimal invasiveness and local effect. Several studies have been conducted worldwide to evaluate the antitumoral effect of this therapy. In all these studies a variety of biochemical and physiological responses of tumors to the applied treatment have been obtained. By this reason, researchers have suggested various mechanisms to explain how direct electric current destroys tumor cells. Although, it is generally accepted this treatment induces electrolysis, electroosmosis and electroporation in tumoral tissues. However, action mechanism of this alternative modality on the tumor tissue is not well understood. Although the principle of Electrochemical treatment is simple, a standardized method is not yet available. The mechanism by which Electrochemical treatment affects tumor growth and survival may represent more complex process. The present work analyzes the latest and most important research done on the electrochemical treatment of tumors. We conclude with our point of view about the destruction mechanism features of this alternative therapy. Also, we suggest some mechanisms and strategies from the thermodynamic point of view for this therapy. In the area of Electrochemical treatment of cancer this tool has been exploited very little and much work remains to be done. Electrochemical treatment constitutes a good therapeutic option for patients that have failed the conventional oncology methods. PMID:23592904

  8. Diorganotin(IV) complexes of biologically potent 4(3H)-quinazolinone derived Schiff bases: synthesis, spectroscopic characterization, DNA interaction studies and antimicrobial activity.

    PubMed

    Prasad, Kollur Shiva; Kumar, Linganna Shiva; Chandan, Shivamallu; Jayalakshmi, Basvegowda; Revanasiddappa, Hosakere D

    2011-10-15

    Four Schiff base ligands and their corresponding organotin(IV) complexes have been synthesized and characterized by elemental analyses, IR, (1)H NMR, MS and thermal studies. The Schiff bases are obtained by the condensation of 3-amino-2-methyl-4(3H)-quinazolinone with different substituted aldehydes. The elemental analysis data suggest the stoichiometry to be 1:1 ratio formation. Infrared spectral data agreed with the coordination to the central metal ion through imine nitrogen, lactam oxygen and deprotonated phenolic oxygen atoms. All the synthesized compounds have been evaluated for antimicrobial activity against selected species of microorganisms. In addition, DNA binding/cleavage capacity of the compounds was analyzed by absorption spectroscopy, viscosity measurements and gel electrophoresis methods.

  9. Optimization of Potent and Selective Quinazolinediones: Inhibitors of Respiratory Syncytial Virus That Block RNA-Dependent RNA-Polymerase Complex Activity

    PubMed Central

    2015-01-01

    A quinazolinedione-derived screening hit 2 was discovered with cellular antiviral activity against respiratory syncytial virus (CPE EC50 = 2.1 μM), moderate efficacy in reducing viral progeny (4.2 log at 10 μM), and marginal cytotoxic liability (selectivity index, SI ∼ 24). Scaffold optimization delivered analogs with improved potency and selectivity profiles. Most notable were compounds 15 and 19 (EC50 = 300–500 nM, CC50 > 50 μM, SI > 100), which significantly reduced viral titer (>400,000-fold), and several analogs were shown to block the activity of the RNA-dependent RNA-polymerase complex of RSV. PMID:25399509

  10. Antitumor Activity of the Methanol Extract of Hypericum hookerianum Stem Against Ehrlich Ascites Carcinoma in Swiss Albino Mice.

    PubMed

    Dongre, Santoshkumar H; Badami, Shrishailappa; Natesan, Senthilkumar; H, Raghu Chandrashekhar

    2007-04-01

    A large number of plants belonging to the Hypericum family are known to possess strong antitumor properties. The methanol extract of H. hookerianum Wight and Arnott stem (MEHH) exhibited potent in vitro cytotoxic activity against various cancerous cell lines. In the present study, the high performance liquid chromatography (HPLC) standardized MEHH was tested for in vivo antitumor properties against Ehrlich ascites carcinoma (EAC) tumor bearing mice at 100, 200, and 400 mg/kg body weight doses given orally once daily for 14 days. The results indicate that administration of the extract not only increased the survival of animals with ascites tumor, decreased the body weight induced by the tumor burden, and reduced packed cell volume and viable tissue cell count, but also altered many hematological parameters changed during tumor progression, indicating the potent antitumor nature of the extract. Among the three doses tested, the 200 mg/kg body weight dose was found to be the most potent.

  11. The discovery of Polo-like kinase 4 inhibitors: identification of (1R,2S).2-(3-((E).4-(((cis).2,6-dimethylmorpholino)methyl)styryl). 1H.indazol-6-yl)-5'-methoxyspiro[cyclopropane-1,3'-indolin]-2'-one (CFI-400945) as a potent, orally active antitumor agent.

    PubMed

    Sampson, Peter B; Liu, Yong; Forrest, Bryan; Cumming, Graham; Li, Sze-Wan; Patel, Narendra Kumar; Edwards, Louise; Laufer, Radoslaw; Feher, Miklos; Ban, Fuqiang; Awrey, Donald E; Mao, Guodong; Plotnikova, Olga; Hodgson, Richard; Beletskaya, Irina; Mason, Jacqueline M; Luo, Xunyi; Nadeem, Vincent; Wei, Xin; Kiarash, Reza; Madeira, Brian; Huang, Ping; Mak, Tak W; Pan, Guohua; Pauls, Henry W

    2015-01-08

    Previous publications from our laboratory have introduced novel inhibitors of Polo-like kinase 4 (PLK4), a mitotic kinase identified as a potential target for cancer therapy. The search for potent and selective PLK4 inhibitors yielded (E)-3-((1Hindazol-6-yl)methylene)indolin-2-ones, which were superseded by the bioisosteric 2-(1H-indazol-6-yl)spiro[cyclopropane-1,3'-indolin]-2'-ones, e.g., 3. The later scaffold confers improved drug-like properties and incorporates two stereogenic centers. This work reports the discovery of a novel one-pot double SN2 displacement reaction for the stereoselective installation of the desired asymmetric centers and confirms the stereochemistry of the most potent stereoisomer, e.g., 44. Subsequent work keys on the optimization of the oral exposure of nanomolar PLK4 inhibitors with potent cancer cell growth inhibitory activity. A short list of compounds with superior potency and pharmacokinetic properties in rodents and dogs was studied in mouse models of tumor growth. We conclude with the identification of compound 48 (designated CFI-400945) as a novel clinical candidate for cancer therapy.

  12. Antitumor Compounds from Marine Actinomycetes

    PubMed Central

    Olano, Carlos; Méndez, Carmen; Salas, José A.

    2009-01-01

    Chemotherapy is one of the main treatments used to combat cancer. A great number of antitumor compounds are natural products or their derivatives, mainly produced by microorganisms. In particular, actinomycetes are the producers of a large number of natural products with different biological activities, including antitumor properties. These antitumor compounds belong to several structural classes such as anthracyclines, enediynes, indolocarbazoles, isoprenoides, macrolides, non-ribosomal peptides and others, and they exert antitumor activity by inducing apoptosis through DNA cleavage mediated by topoisomerase I or II inhibition, mitochondria permeabilization, inhibition of key enzymes involved in signal transduction like proteases, or cellular metabolism and in some cases by inhibiting tumor-induced angiogenesis. Marine organisms have attracted special attention in the last years for their ability to produce interesting pharmacological lead compounds. PMID:19597582

  13. Potentiated antitumor effects of interleukin 12 and matrix metalloproteinase inhibitor batimastat against B16F10 melanoma in mice.

    PubMed

    Dabrowska, A; Giermasz, A; Marczak, M; Gołab, J; Jakóbisiak, M

    2000-01-01

    The application of antiangiogenic agents in cancer therapy has been studied extensively. Combination of agents with antiangiogenic properties could possibly enhance antitumor effects. Interleukin 12 is a cytokine with potent antitumor activity mediated also via antiangiogenic mechanisms. These effects are attributed to IFN-gamma production stimulated by IL-12. Since IFN-gamma has been reported to augment antitumor effects when combined with one of the metalloproteinase inhibitors--batimastat (BB-94), we have examined a combined treatment with IL-12 and BB-94 in a murine melanoma model. The administration of both agents showed potentiated antitumor activity. Furthermore, we have shown in a tumor-induced angiogenesis model that the combined application of IL-12 and batimastat inhibits the formation of new blood vessels to a greater extent than either agent alone. Our observations show that antiangiogenic effects are at least partly responsible for the enhanced antitumor effects of the combined treatment with IL-12 and BB-94.

  14. The potent opioid agonist, (+)-cis-3-methylfentanyl binds pseudoirreversibly to the opioid receptor complex in vitro and in vivo: Evidence for a novel mechanism of action

    SciTech Connect

    Band, L.; Xu, Heng; Bykov, V.; Rothman, R.B.; Kim, Chongho; Newman, A.; Jacobson, A.E.; Rice, K.C. ); Greig, N. )

    1990-01-01

    The present study demonstrates that pretreatment of rat brain membranes with (+)-cis-3-methylfentanyl ((+)-cis-MF), followed by extensive washing of the membranes, produces a wash-resistant decreasing in the binding of ({sup 3}H)-(D-ala{sup 2}, D-leu{sup 5})enkephalin to the d binding site of the opioid receptor complex ({delta}{sub cx} binding site). Intravenous administration of (+)-cis-MF (50 {mu}g/kg) to rats produced a pronounced catalepsy and also produced a wash-resistant masking of {delta}{sub cx} and {mu} binding sites in membranes prepared 120 min post-injection. Administration of 1 mg/kg i.v. of the opioid antagonist, 6-desoxy-6{beta}-fluoronaltrexone (cycloFOXY), 100 min after the injection of (+)-cis-MF (20 min prior to the preparation of membranes) completely reversed the catatonia and restored masked {delta}{sub cx} binding sites to control levels. This was not observed with (+)-cycloFOXY. The implications of these and other findings for the mechanism of action of (+)-cis-MF and models of the opioid receptors are discussed.

  15. Transloading of tumor cells with foreign major histocompatibility complex class I peptide ligand: a novel general strategy for the generation of potent cancer vaccines.

    PubMed Central

    Schmidt, W; Steinlein, P; Buschle, M; Schweighoffer, T; Herbst, E; Mechtler, K; Kirlappos, H; Birnstiel, M L

    1996-01-01

    The major hurdle to be cleared in active immunotherapy of cancer is the poor immunogenicity of cancer cells. In previous attempts to overcome this problem, whole tumor cells have been used as vaccines, either admixed with adjuvant(s) or genetically engineered to express nonself proteins or immunomodulatory factors before application. We have developed a novel approach to generate an immunogeneic, highly effective vaccine: major histocompatibility complex (MHC) class I-positive cancer cells are administered together with MHC class I-matched peptide ligands of foreign, nonself origin, generated by a procedure we term transloading. Murine tumor lines of the H2-Kd or the H2-Db haplotype, melanoma M-3 and B16-F10, respectively, as well as colon carcinoma CT-26 (H2-Kd), were transloaded with MHC-matched influenza virus-derived peptides and applied as irradiated vaccines. Mice bearing a deposit of live M-3 melanoma cells were efficiently cured by this treatment. In the CT-26 colon carcinoma and the B16-F10 melanoma, high efficacies were obtained against tumor challenge, suggesting the universal applicability of this new type of vaccine. With foreign peptide ligands adapted to the requirements of a desired MHC class I haplotype, this concept may be used for the treatment of human cancers. Images Fig. 1 PMID:8790404

  16. Design, synthesis and antitumor properties of glycosylated antitumor ether lipid (GAEL)- chlorambucil-hybrids.

    PubMed

    Idowu, Temilolu; Samadder, Pranati; Arthur, Gilbert; Schweizer, Frank

    2016-01-01

    Glycosylated antitumor ether lipids (GAELs) kill cancer cells and cancer stem cells via a novel, apoptosis-independent mechanism. In contrast, chlorambucil, a drug in clinical use for the treatment of chronic lymphocytic leukemia reacts with nucleophiles within the major groove of DNA, leading to apoptosis. We hypothesized that hybrid molecules that combine apoptosis-dependent and apoptosis-independent mode of actions in a single molecule may lead to enhanced antitumor activity. Here, we describe the antitumor activities of chlorambucil-linked glucosamine-derived glycerolipid hybrids and investigate the role of the chlorambucil moiety and the effect of cationic charge on the hybrid molecule. Three hybrids and two control GAELs were synthesized and their activities against breast (JIMT1, MDA-MB-231, BT474), pancreas (MiaPaCa2) and prostate (DU145, PC3) cancer cell lines were determined using MTS assay. Hybrid 3 displayed the most potent activity on DU145 at CC50 of 6.0 μM while hybrid 4 displayed the best activity on JIMT1 at 7.5 μM. Hybrid 5 exhibited no activity at the highest concentration tested (CC50 >20 μM), underscoring the significance of the cationic charge at C-2 position as previously reported. Although chlorambucil (2) itself showed very little activity against all the six cell lines (CC50 >150 μM), GAELs 6 and 7 which lack the chlorambucil moiety were consistently less active than 3 and 4, suggesting that the chlorambucil moiety contributes to the overall activity. The hybrids were however not as active as the parent GAEL 1 against MiaPaCa2 whereas 6 restored activity comparable to 1. Copyright © 2015. Published by Elsevier Ireland Ltd.

  17. Single-chain antibody-based immunotoxins targeting Her2/neu: design optimization and impact of affinity on antitumor efficacy and off-target toxicity.

    PubMed

    Cao, Yu; Marks, James D; Huang, Qian; Rudnick, Stephen I; Xiong, Chiyi; Hittelman, Walter N; Wen, Xiaoxia; Marks, John W; Cheung, Lawrence H; Boland, Kim; Li, Chun; Adams, Gregory P; Rosenblum, Michael G

    2012-01-01

    Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10(-8) to 10(-11) mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity. Constructs composed of intermediate-affinity antibodies are also potent agents that are more resistant to immune complex formation. Therefore, affinity is an exceptionally important consideration when evaluating the design and efficacy of targeted therapeutics.

  18. Discovery of 4-{4-[(3R)-3-Methylmorpholin-4-yl]-6-[1-(methylsulfonyl)cyclopropyl]pyrimidin-2-yl}-1H-indole (AZ20): a potent and selective inhibitor of ATR protein kinase with monotherapy in vivo antitumor activity.

    PubMed

    Foote, Kevin M; Blades, Kevin; Cronin, Anna; Fillery, Shaun; Guichard, Sylvie S; Hassall, Lorraine; Hickson, Ian; Jacq, Xavier; Jewsbury, Philip J; McGuire, Thomas M; Nissink, J Willem M; Odedra, Rajesh; Page, Ken; Perkins, Paula; Suleman, Abid; Tam, Kin; Thommes, Pia; Broadhurst, Rebecca; Wood, Christine

    2013-03-14

    ATR is an attractive new anticancer drug target whose inhibitors have potential as chemo- or radiation sensitizers or as monotherapy in tumors addicted to particular DNA-repair pathways. We describe the discovery and synthesis of a series of sulfonylmorpholinopyrimidines that show potent and selective ATR inhibition. Optimization from a high quality screening hit within tight SAR space led to compound 6 (AZ20) which inhibits ATR immunoprecipitated from HeLa nuclear extracts with an IC50 of 5 nM and ATR mediated phosphorylation of Chk1 in HT29 colorectal adenocarcinoma tumor cells with an IC50 of 50 nM. Compound 6 potently inhibits the growth of LoVo colorectal adenocarcinoma tumor cells in vitro and has high free exposure in mouse following moderate oral doses. At well tolerated doses 6 leads to significant growth inhibition of LoVo xenografts grown in nude mice. Compound 6 is a useful compound to explore ATR pharmacology in vivo.

  19. [Combined treatment of palmoplantar syndrome in patients under antitumor therapy].

    PubMed

    Kruglova, L S; Shatokhina, E A; Elfimov, M A; Illarionov, V E; Chervinskaya, A V; Portnov, V V; Filatova, E V; Petrova, M S

    2016-01-01

    Observation covered 12 patients under various antitumor medications. Group 1 was formed of patients with developed palmoplantar syndrome varying in severity, who received complex treatment including IR-therapy and local antioxidant medication. Group 2 included patients without palmoplantar syndrome, who received preventive treatment with IR-therapy. All patients of group 1 demonstrated lower severity of palmoplantar syndrome manifestations. In group 2, 80% of the patients avoided palmoplantar syndrome development, and 20% of the patients had light course of the syndrome manifestations. Patients at high risk of palmoplantar syndrome under antitumor therapy are recommended to undergo IR-therapy and local antioxidant medication.

  20. Memory Antitumor T-Cells Resist Inhibition by Immune Suppressor Cells.

    PubMed

    Gao, Yanhua; Whitaker-Dowling, Patricia; Bergman, Ira

    2015-09-01

    Cancer immune therapy is difficult partly because several classes of suppressor cells, including regulatory T-cells and macrophage-derived suppressor cells, inhibit the antitumor T-cell response. We used treatment studies of implanted tumors in mice to demonstrate that the same inhibitory cells that abrogated an acute therapeutic T-cell response to established tumor did not inhibit the therapeutic response produced by memory T-cells. Generating antitumor memory T-cells may be a highly potent strategy against cancer with late developing metastases. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  1. Synthesis, in vitro and in vivo antitumor activity of pyrazole-fused 23-hydroxybetulinic acid derivatives.

    PubMed

    Zhang, Hengyuan; Zhu, Peiqing; Liu, Jie; Lin, Yan; Yao, Hequan; Jiang, Jieyun; Ye, Wencai; Wu, Xiaoming; Xu, Jinyi

    2015-02-01

    A collection of pyrazole-fused 23-hydroxybetulinic acid derivatives were designed, synthesized and evaluated for their antitumor activity. Most of the newly synthesized compounds exhibited significant antiproliferative activity. Especially compound 15e displayed the most potent activity with the IC50 values of 5.58 and 6.13μM against B16 and SF763 cancer cell lines, respectively. Furthermore, the significant in vivo antitumor activity of 15e was validated in H22 liver cancer and B16 melanoma xenograft mouse models. The structure-activity relationships of these 23-hydroxybetulinic acid derivatives were also discussed based on the present investigation.

  2. Fusogenic oncolytic herpes simplex viruses as a potent and personalized cancer vaccine.

    PubMed

    Li, Qi-Xiang; Liu, Guohong; Zhang, Xiaoliu

    2012-07-01

    The recent FDA approval of Sipuleucel-T for the treatment of prostate cancer represents an important milestone of cancer immunotherapy, which, for the first time, validates the concept of bringing true clinical benefit to cancer patients by stimulating patients' own anti-tumor immunity. Among the different experimental cancer immunotherapies, oncolytic virotherapy may represent a low-cost yet potent and personalized cancer vaccine for the treatment of solid tumors. This review describes the constructions of several human herpes simplex virus (HSV)-derived oncolytic viruses as candidate cancer vaccines, which induce specific and potent anti-tumor immunity in pre-clinical models, and thus resulting in stronger overall anti-tumor efficacy as compared to oncolytic effect alone. This article also describes the approaches to enhance the antitumor immunity of oncolytic HSVs, and in particular, the key role played by integrating membrane-fusion activity into these viruses. Additionally, this article reviews the potential effect of certain chemotherapeutic agents (e.g. cyclophosphamide) in boosting antitumor immunity induced by oncolytic HSV, and the mechanisms behind it. In summary, all the preclinical and clinical data have suggested that HSV-based oncolytic virotherapies could likely be developed as a new generation of cancer vaccines for the treatment of solid tumors.

  3. Screening and analysis of potential anti-tumor components from the stipe of Ganoderma sinense using high-performance liquid chromatography/time-of-flight mass spectrometry with multivariate statistical tool.

    PubMed

    Chan, Kar-Man; Yue, Grace Gar-Lee; Li, Ping; Wong, Eric Chun-Wai; Lee, Julia Kin-Ming; Kennelly, Edward J; Lau, Clara Bik-San

    2017-03-03

    According to Chinese Pharmacopoeia 2015 edition, Ganoderma (Lingzhi) is a species complex that comprise of Ganoderma lucidum and Ganoderma sinense. The bioactivity and chemical composition of G. lucidium had been studied extensively, and it was shown to possess antitumor activities in pharmacological studies. In contrast, G. sinense has not been studied in great detail. Our previous studies found that the stipe of G. sinense exhibited more potent antitumor activity than the pileus. To identify the antitumor compounds in the stipe of G. sinense, we studied its chemical components by merging the bioactivity results with liquid chromatography-mass spectrometry-based chemometrics. The stipe of G. sinense was extracted with water, followed by ethanol precipitation and liquid-liquid partition. The resulting residue was fractionated using column chromatography. The antitumor activity of these fractions were analysed using MTT assay in murine breast tumor 4T1 cells, and their chemical components were studied using the LC-QTOF-MS with multivariate statistical tools. The chemometric and MS/MS analysis correlated bioactivity with five known cytotoxic compounds, 4-hyroxyphenylacetate, 9-oxo-(10E,12E)-octadecadienoic acid, 3-phenyl-2-propenoic acid, 13-oxo-(9E,11E)-octadecadienoic acid and lingzhine C, from the stipe of G. sinense. To the best of our knowledge, 4-hyroxyphenylacetate, 3-phenyl-2-propenoic acid and lingzhine C are firstly reported to be found in G. sinense. These five compounds will be investigated for their antitumor activities in the future. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Potent Antipneumococcal Activity of Gemifloxacin Is Associated with Dual Targeting of Gyrase and Topoisomerase IV, an In Vivo Target Preference for Gyrase, and Enhanced Stabilization of Cleavable Complexes In Vitro

    PubMed Central

    Heaton, Victoria J.; Ambler, Jane E.; Fisher, L. Mark

    2000-01-01

    We investigated the roles of DNA gyrase and topoisomerase IV in determining the susceptibility of Streptococcus pneumoniae to gemifloxacin, a novel fluoroquinolone which is under development as an antipneumococcal drug. Gemifloxacin displayed potent activity against S. pneumoniae 7785 (MIC, 0.06 μg/ml) compared with ciprofloxacin (MIC, 1 to 2 μg/ml). Complementary genetic and biochemical approaches revealed the following. (i) The gemifloxacin MICs for isogenic 7785 mutants bearing either parC or gyrA quinolone resistance mutations were marginally higher than wild type at 0.12 to 0.25 μg/ml, whereas the presence of both mutations increased the MIC to 0.5 to 1 μg/ml. These data suggest that both gyrase and topoisomerase IV contribute significantly as gemifloxacin targets in vivo. (ii) Gemifloxacin selected first-step gyrA mutants of S. pneumoniae 7785 (gemifloxacin MICs, 0.25 μg/ml) encoding Ser-81 to Phe or Tyr, or Glu-85 to Lys mutations. These mutants were cross resistant to sparfloxacin (which targets gyrase) but not to ciprofloxacin (which targets topoisomerase IV). Second-step mutants (gemifloxacin MICs, 1 μg/ml) exhibited an alteration in parC resulting in changes of ParC hot spot Ser-79 to Phe or Tyr. Thus, gyrase appears to be the preferential in vivo target. (iii) Gemifloxacin was at least 10- to 20-fold more effective than ciprofloxacin in stabilizing a cleavable complex (the cytotoxic lesion) with either S. pneumoniae gyrase or topoisomerase IV enzyme in vitro. These data suggest that gemifloxacin is an enhanced affinity fluoroquinolone that acts against gyrase and topoisomerase IV in S. pneumoniae, with gyrase the preferred in vivo target. The marked potency of gemifloxacin against wild type and quinolone-resistant mutants may accrue from greater stabilization of cleavable complexes with the target enzymes. PMID:11036032

  5. Vaccines with interleukin-12-transduced acute myeloid leukemia cells elicit very potent therapeutic and long-lasting protective immunity.

    PubMed

    Dunussi-Joannopoulos, K; Runyon, K; Erickson, J; Schaub, R G; Hawley, R G; Leonard, J P

    1999-12-15

    Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-gamma (IFN-gamma), or CD8(+) T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-gamma on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. (51)Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.

  6. New Oxidovanadium Complexes Incorporating Thiosemicarbazones and 1, 10-Phenanthroline Derivatives as DNA Cleavage, Potential Anticancer Agents, and Hydroxyl Radical Scavenger.

    PubMed

    Ying, Peng; Zeng, Pengfei; Lu, Jiazheng; Chen, Hongyuan; Liao, Xiangwen; Yang, Ning

    2015-10-01

    Four novel oxidovanadium(IV) complexes, [VO(hntdtsc)(PHIP)] (1) (hntdtsc = 2-hydroxy-1-naphthaldehyde thiosemicarbazone, PHIP= 2-phenyl-imidazo[4,5-f]1,10-phenanthroline), [VO(hntdtsc)(DPPZ)](2)(DPPZ= dipyrido[3,2-a:2',3'-c]phenazine), [VO(satsc)(PHIP)](3) (satsc=salicylaldehyde thiosemicarbazone), and [VO(satsc)(DPPZ)](4), have been prepared and characterized. The chemical nuclease activities and photocleavage reactions of the complexes were tested. All four complexes can efficiently cleave pBR322 DNA, and complex 1 has the best cleaving ability. The antitumor properties of these complexes were examined with three different tumor cell lines using MTT assay. Their antitumor mechanism has been analyzed using cell cycle analysis, fluorescence microscopy of apoptosis, and Annexin V-FITC/PI assay. The results showed that the growth of human neuroblastoma (SH-SY5Y, SK-N-SH) and human breast adenocarcinoma (MCF-7) cells were inhibited significantly with very low IC50 values. Complex 1 was found to be the most potent antitumor agent among the four complexes. It can cause G0/G1 phase arrest of the cell cycle and exhibited significant induced apoptosis in SK-N-SH cells and displayed typical morphological apoptotic characteristics. In addition, they all displayed reasonable abilities to scavenge hydroxyl radical, and complex 1 was the best inhibitor.

  7. Antitumor effect of Pt(II) amine phosphonate complexes on sarcoma sa-180 in mice. Crystal structure of cis-dichlorobis(diethyl-4-pyridylmethylphosphonate-kappaN)platinum(II) hydrate, cis-[PtCl2(4-pmpe)2].H20.

    PubMed

    Aranowska, K; Graczyk, J; Checińska, L; Pakulska, W; Ochock, J

    2006-05-01

    The cisplatin analogoues platinum (II) complexes of the general formula cis-[PtL2Cl2], where L is monodentate diethyl 2-, 3- or 4-pyridylmethylphosphonate (2-, 3- or 4-pmpe) ligand, have been synthesized and characterized by means of IR and NMR (1H, 31P, 195Pt) spectroscopy. The crystal and molecular structure of cis-[Pt(4-pmpe)2 Cl2].H2O (A3) shows a square planar geometry of PtL2Cl2, with two organic molecules and two chloride leaving ligands in a cis configuration. The antitumor activity of the platinum (II) complexes was examined against Sarcoma Sa-180 in mice. The obtained results indicate a marked anticancer effect of platinum phosphonate complexes, and moderate nephrotoxicity evaluated in the BUN and creatinine levels in comparison with cisplatin (CDDP).

  8. CpG oligodeoxynucleotides potentiate the antitumor activity of anti-BST2 antibody.

    PubMed

    Hiramatsu, Kosuke; Serada, Satoshi; Kobiyama, Kouji; Nakagawa, Satoshi; Morimoto, Akiko; Matsuzaki, Shinya; Ueda, Yutaka; Fujimoto, Minoru; Yoshino, Kiyoshi; Ishii, Ken J; Enomoto, Takayuki; Kimura, Tadashi; Naka, Tetsuji

    2015-10-01

    Numerous monoclonal antibodies (mAb) targeting tumor antigens have recently been developed. Antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) via effector cells such as tumor-infiltrating natural killer (NK) cells and macrophages are often involved in mediating the antitumor activity of mAb. CpG oligodeoxynucleotides (ODN) have a potent antitumor activity and are considered to increase tumor infiltration of NK cells and macrophages. Our group previously reported significant antitumor activity of anti-bone marrow stromal antigen 2 (BST2) mAb against BST2-positive endometrial cancer cells through ADCC. In this study, we evaluated the synergistic antitumor activity of combination therapy with anti-BST-2 mAb and CpG ODN using SCID mice and elucidated the mechanisms underlying this activity. Anti-BST2 mAb and CpG ODN monotherapy had a significant dose-dependent antitumor activity (P = 0.0135 and P = 0.0196, respectively). Combination therapy with anti-BST2 mAb and CpG ODN had a significant antitumor activity in SCID mice (P < 0.01), but not in NOG mice. FACS analysis revealed significantly increased numbers of NK cells and macrophages in tumors treated with a combination of anti-BST2 mAb and CpG ODN and with CpG ODN alone in SCID mice (P < 0.05 and P < 0.01, respectively). These results suggested that the combination therapy with anti-BST2 mAb and CpG ODN has a significant antitumor activity and induces tumor infiltration of NK cells and macrophages. Combination therapy with CpG ODN and anti-BST2 mAb or other antitumor mAb depending on ADCC may represent a new treatment option for cancer.

  9. Antitumor Agents 286. Design, Synthesis and Structure-Activity Relationships of 3′R,4′R-Disubstituted-2′,2′-dimethyldihydropyrano[2,3-f]chromone (DSP) Analogs as Potent Chemosensitizers to Overcome Multidrug Resistance

    PubMed Central

    Zhou, Ting; Shi, Qian; Bastow, Kenneth F.; Lee, Kuo-Hsiung

    2010-01-01

    In this study, various 3′R,4′R-disubstituted-2′,2′-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogs (5–28) were synthesized and evaluated against a multi-drug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogs exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI50 value of VCR by 12–349-fold. At a concentration of 1μg/mL, three compounds, 11, 14 and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a twofold increase compared to verapamil, a first generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3′ and 4′ substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogs results from inhibition of P-glycoprotein (P-gp) over-expressed in MDR cancer cells.1 PMID:21082774

  10. New insights into DHFR interactions: analysis of Pneumocystis carinii and mouse DHFR complexes with NADPH and two highly potent 5-(omega-carboxy(alkyloxy) trimethoprim derivatives reveals conformational correlations with activity and novel parallel ring stacking interactions.

    PubMed

    Cody, Vivian; Pace, Jim; Chisum, Kim; Rosowsky, Andre

    2006-12-01

    Structural data are reported for two highly potent antifolates, 2,4-diamino-5-[3',4'-dimethoxy-5'-(5-carboxy-1-pentynyl)]benzylpyrimidine (PY1011), with 5000-fold selectivity for Pneumocystis carinii dihydrofolate reductase (pcDHFR), relative to rat liver DHFR, and 2,4-diamino-5-[2-methoxy-5-(4-carboxybutyloxy)benzyl]pyrimidine (PY957), that has 80-fold selectivity for pcDHFR. Crystal structures are reported for NADPH ternary complexes with PY957 and pcDHFR, refined to 2.2 A resolution; with PY1011 and pcDHFR, refined to 2.0 A resolution; and with PY1011 and mouse DHFR (mDHFR), refined to 2.2 A resolution. These results reveal that the carboxylate of the omega-carboxyalkyloxy side chain of these inhibitors form ionic interactions with the conserved Arg in the substrate binding pocket of DHFR. These data suggest that the enhanced inhibitory activity of PY1011 compared with PY957 is, in part, due to the favorable contacts with Phe69 of pcDHFR by the methylene carbons of the inhibitor side chain that are oriented by the triple bond of the 1-pentynyl side chain. These contacts are not present in the PY957 pcDHFR complex, or in the PY1011 mDHFR complex. In the structure of mDHFR the site of Phe69 in pcDHFR is occupied by Asn64. These data also revealed a preference for an unusual parallel ring stacking interaction between Tyr35 of the active site helix and Phe199 of the C-terminal beta sheet in pcDHFR and by Tyr33 and Phe179 in mDHFR that is independent of bound ligand. A unique His174-His187 parallel ring stacking interaction was also observed only in the structure of pcDHFR. These ring stacking interactions are rarely found in any other protein families and may serve to enhance protein stability. (c) 2006 Wiley-Liss, Inc.

  11. Data for comparative proteomics analysis of the antitumor effect of CIGB-552 peptide in HT-29 colon adenocarcinoma cells

    PubMed Central

    Núñez de Villavicencio-Díaz, Teresa; Ramos Gómez, Yassel; Oliva Argüelles, Brizaida; Fernández Masso, Julio R.; Rodríguez-Ulloa, Arielis; Cruz García, Yiliam; Guirola-Cruz, Osmany; Perez-Riverol, Yasset; Javier González, Luis; Tiscornia, Inés; Victoria, Sabina; Bollati-Fogolín, Mariela; Besada Pérez, Vladimir; Guerra Vallespi, Maribel

    2015-01-01

    CIGB-552 is a second generation antitumor peptide that displays potent cytotoxicity in lung and colon cancer cells. The nuclear subproteome of HT-29 colon adenocarcinoma cells treated with CIGB-552 peptide was identified and analyzed [1]. This data article provides supporting evidence for the above analysis. PMID:26306321

  12. Crocodiles and alligators: Antiamoebic and antitumor compounds of crocodiles.

    PubMed

    Siddiqui, Ruqaiyyah; Jeyamogan, Shareni; Ali, Salwa Mansoor; Abbas, Fatima; Sagathevan, K A; Khan, Naveed Ahmed

    2017-09-14

    Crocodiles exist in unsanitary environments, feed on rotten meat, are often exposed to heavy metals such as arsenic, cadmium, cobalt, chromium, mercury, nickel, lead, selenium, tolerate high levels of radiation, and are amid the very few species to survive the catastrophic Cretaceous-Tertiary extinction event, nonetheless they can live for up to a 100 years. Moreover, as they live in unhygienic conditions, they regularly come across pathogens. Logically, we postulate that crocodiles possess mechanisms to defend themselves from noxious agents as well as protecting themselves from pathogens. To test this hypothesis, various organ lysates and serum of Crocodylus palustris were prepared. Amoebicidal assays were performed using Acanthamoeba castellanii belonging to the T4 genotype. Cytotoxicity assays were performed using Prostate cancer cells culture by measuring lactate dehydrogenase release as a marker for cell death. Growth inhibition assays were performed to determine the growth inhibitory effects of various organ lysates. Serum and heart lysates of Crocodylus palustris exhibited powerful anti-tumor activity exhibiting more than 70% Prostate cancer cell death (P < 0.05). Additionally, lysates from gall bladder and bile also showed significant host cell cytotoxicity, however intestine, lungs and brain showed partial cytotoxicity. Both sera and heart lysates of Crocodylus palustris abolished Prostate cells growth. Moreover, serum completely abolished A. castellanii viability. For the first time, these findings showed that the organ lysates of Crocodylus palustris exhibit potent anti-amoebic and anti-tumor activity. The discovery of antimicrobial and antitumor activity in crocodile will stimulate research in finding therapeutic molecules from unusual sources, and has potential for the development of novel antitumor/antimicrobial compound(s) that may also overcome drug resistance. Nevertheless, rigorous research in the next few years will be necessary to realize

  13. Antitumor Efficacy of 7β, 17α-Dimethyltestosterone (Calusterone) in Advanced Female Breast Cancer

    PubMed Central

    Gordan, Gilbert S.; Halden, Allan; Walter, Robert M.

    1970-01-01

    Twenty-two women with far advanced, hormone-refractory breast cancer were treated with 7β,17α dimethyltestosterone (calusterone), 150 to 300 mg per day by mouth, to test its antitumor efficacy. Using the strict criteria of the Cooperative Breast Cancer Group, 14 of the women (64 percent) obtained objective regressions. Regressions lasted for from 3 to 20 months, averaging 7 months. Undesirable actions are those of a 17α-alkylated, weak androgen with inconstant bromsulphalein retention, but without elevation of serum bilirubin levels or of hepatic enzymes. This compound has potent antitumor efficacy in women with advanced breast cancer, is better tolerated than most chemotherapeutic or steroidal antitumor agents, and will probably assume an important position in the care of these patients. ImagesFigure 1Figure 2Figure 3Figure 3Figure 4Figure 5Figure 5 PMID:5457511

  14. Total Synthesis of the Antitumor Antibiotic (±)-Streptonigrin: First- and Second-Generation Routes for de Novo Pyridine Formation Using Ring-Closing Metathesis

    PubMed Central

    2013-01-01

    The total synthesis of (±)-streptonigrin, a potent tetracyclic aminoquinoline-5,8-dione antitumor antibiotic that reached phase II clinical trials in the 1970s, is described. Two routes to construct a key pentasubstituted pyridine fragment are depicted, both relying on ring-closing metathesis but differing in the substitution and complexity of the precursor to cyclization. Both routes are short and high yielding, with the second-generation approach ultimately furnishing (±)-streptonigrin in 14 linear steps and 11% overall yield from inexpensive ethyl glyoxalate. This synthesis will allow for the design and creation of druglike late-stage natural product analogues to address pharmacological limitations. Furthermore, assessment of a number of chiral ligands in a challenging asymmetric Suzuki–Miyaura cross-coupling reaction has enabled enantioenriched (up to 42% ee) synthetic streptonigrin intermediates to be prepared for the first time. PMID:24328139

  15. Preparative isolation and purification of anti-tumor agent ansamitocin P-3 from fermentation broth of Actinosynnema pretiosum using high-performance counter-current chromatography.

    PubMed

    Yao, Yuqin; Cheng, Zhihui; Ye, Haoyu; Xie, Yongmei; He, Jing; Tang, Minghai; Shen, Tao; Wang, Jiangman; Zhou, Yan; Lu, Zejun; Luo, Feng; Chen, Lijuan; Yu, Luoting; Yang, Jin-Liang; Peng, Aihua; Wei, Yuquan

    2010-05-01

    Ansamitocin P-3 is a potent anti-tumor maytansinoid found in Actinosynnema pretiosum. However, due to the complexity of the fermentation broth of Actinomycete, how to effectively separate ansamitocin P-3 is still a challenge. In this study, both analytical and preparative high-performance counter-current chromatography were successfully used to separate and purify ansamitocin P-3 from fermentation broth. A total of 28.8 mg ansamitocin P-3 with purity of 98.4% was separated from 160 mg crude sample of fermentation broth in less than 80 min with the two-phase solvent system of hexane-ethyl acetate-methanol-water (0.6:1:0.6:1, v/v/v/v). The purity and structural identification were determined by HPLC, (1)H NMR, (13)C NMR and mass spectroscopy.

  16. Identification of new potent phthalazine derivatives with VEGFR-2 and EGFR kinase inhibitory activity.

    PubMed

    Amin, Kamilia M; Barsoum, Flora F; Awadallah, Fadi M; Mohamed, Nehal E

    2016-11-10

    Efforts to develop new antitumor agents are now directed towards multitarget therapies that are believed to have high potency and low tendency to resistance compared to conventional drugs. Herein, we highlighted the synthesis and antitumor activity of five series of phthalazine-based compounds featuring a variety of bioactive chemical fragments at position 1 of the phthalazine nucleus. The antitumor activity of the target compounds was performed against fourteen cancer cell lines where all compounds were active in the nanomolar level. In addition, the mechanism of action of the target compounds was investigated through an enzymatic inhibitory assay against VEGFR-2 and EGFR kinases, revealing potent and preferential activity toward VEGFR-2. Binding mode of the most active compounds was studied using docking experiment.

  17. Cytotoxic and anti-tumor activities of lignans from the seeds of Vietnamese nutmeg Myristica fragrans.

    PubMed

    Thuong, Phuong Thien; Hung, Tran Manh; Khoi, Nguyen Minh; Nhung, Hoang Thi My; Chinh, Nguyen Thi; Quy, Nguyen Thi; Jang, Tae Su; Na, Minkyun

    2014-03-01

    Four lignans, meso-dihydroguaiaretic acid (DHGA), macelignan, fragransin A2 and nectandrin B, were isolated from the seeds of Myristica fragrans (Vietnamese nutmeg) and investigated for their cytotoxic activity against eight cancer cell lines. Of these, DHGA exhibited potent cytotoxicity against H358 with IC50 value of 10.1 μM. In addition, DHGA showed antitumor activity in allogeneic tumor-bearing mice model.

  18. Ten metal complexes of vitamin B3/niacin: Spectroscopic, thermal, antibacterial, antifungal, cytotoxicity and antitumor studies of Mn(II), Fe(III), Co(II), Ni(II), Cu(II), Zn(II), Pd(II), Cd(II), Pt(IV) and Au(III) complexes

    NASA Astrophysics Data System (ADS)

    Al-Saif, Foziah A.; Refat, Moamen S.

    2012-08-01

    Ten coordination compounds, namely Mn(NA)2Cl2·4H2O (1), Fe(NA)Cl3(H2O)2 (2), Co(NA)2(NO3)2·6H2O (3), Ni(NA)Cl2·5H2O (4), Cu(NA)Cl2·3H2O (5), Zn(NA)(NO3)2·H2O (6), Pd(NA)2Cl2·H2O (7), Cd(NA)Cl2·H2O (8), Pt(NA)2Cl4·5H2O (9) and Au(NA)Cl3 (10) were obtained by the reactions of the corresponding transition metal salts with vitamin B3/niacin (NA) in the presence of 1:4 (v:v) distilled water: methanol solvent at 70 °C for about 30 min, and their suggested structures were determined by elemental analyses, molar conductivity, (infrared, UV-vis) spectra, effective magnetic moment in Bohr magnetons, electron spin resonance (ESR), thermal analysis (TG), X-ray powder diffraction (XRD) as well as scanning electron microscopy (SEM). The results revealed that in complexes 1, 3, 7, and 9 both of two NA ligand coordinates one metal ion to form four or six coordinated structures, while in compound 10, one NA ligand coordinate to Au+++ ion to form a square-planar geometry with N-bonded pyridine ligand is suggested, and (2, 4, 5, 6 and, 8) complexes have 1:1 structures. Antimicrobial and antitumor activities were assessment against some kind of (G+ and G-) bacteria, fungi and breast carcinoma cells (MCF-7-cell line).

  19. Jacalin-Activated Macrophages Exhibit an Antitumor Phenotype

    PubMed Central

    Danella Polli, Cláudia; Pereira Ruas, Luciana; Chain Veronez, Luciana; Herrero Geraldino, Thais; Rossetto de Morais, Fabiana; Roque-Barreira, Maria Cristina; Pereira-da-Silva, Gabriela

    2016-01-01

    Tumor-associated macrophages (TAMs) have an ambiguous and complex role in the carcinogenic process, since these cells can be polarized into different phenotypes (proinflammatory, antitumor cells or anti-inflammatory, protumor cells) by the tumor microenvironment. Given that the interactions between tumor cells and TAMs involve several players, a better understanding of the function and regulation of TAMs is crucial to interfere with their differentiation in attempts to skew TAM polarization into cells with a proinflammatory antitumor phenotype. In this study, we investigated the modulation of macrophage tumoricidal activities by the lectin jacalin. Jacalin bound to macrophage surface and induced the expression and/or release of mainly proinflammatory cytokines via NF-κB signaling, as well as increased iNOS mRNA expression, suggesting that the lectin polarizes macrophages toward the antitumor phenotype. Therefore, tumoricidal activities of jacalin-stimulated macrophages were evaluated. High rates of tumor cell (human colon, HT-29, and breast, MCF-7, cells) apoptosis were observed upon incubation with supernatants from jacalin-stimulated macrophages. Taken together, these results indicate that jacalin, by exerting a proinflammatory activity, can direct macrophages to an antitumor phenotype. Deep knowledge of the regulation of TAM functions is essential for the development of innovative anticancer strategies. PMID:27119077

  20. Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies.

    PubMed

    Abdel-Aziz, Alaa A-M; El-Azab, Adel S; Alanazi, Amer M; Asiri, Yousif A; Al-Suwaidan, Ibrahim A; Maarouf, Azza R; Ayyad, Rezk R; Shawer, Taghreed Z

    2016-10-01

    The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63-3.09 µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI50; 22.60 µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 µM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

  1. Antitumor Activity of Monoterpenes Found in Essential Oils

    PubMed Central

    Sobral, Marianna Vieira; Xavier, Aline Lira; Lima, Tamires Cardoso; de Sousa, Damião Pergentino

    2014-01-01

    Cancer is a complex genetic disease that is a major public health problem worldwide, accounting for about 7 million deaths each year. Many anticancer drugs currently used clinically have been isolated from plant species or are based on such substances. Accumulating data has revealed anticancer activity in plant-derived monoterpenes. In this review the antitumor activity of 37 monoterpenes found in essential oils is discussed. Chemical structures, experimental models, and mechanisms of action for bioactive substances are presented. PMID:25401162

  2. [Advances on antitumor effect of parasites].

    PubMed

    Wang, Su-wen; Sun, Jun

    2014-08-01

    Immune response induced by parasites could inhibit tumor growth and promote apoptosis of tumor cells. The investigation into this character will provide new insights on the anti-tumor effect of parasites. The mechanism of parasite immune evasion may provide a reference for tumor research. Furthermore, some anti-parasitic drugs have shown antitumor effect indicating that the development of antitumor drugs may get inspiration from anti-parasitic drug studies.

  3. Molecular design, synthesis and biological research of novel pyridyl acridones as potent DNA-binding and apoptosis-inducing agents.

    PubMed

    Zhang, Bin; Chen, Kang; Wang, Ning; Gao, Chunmei; Sun, Qinsheng; Li, Lulu; Chen, Yuzong; Tan, Chunyan; Liu, Hongxia; Jiang, Yuyang

    2015-03-26

    A series of novel pyridyl acridone derivatives comprised of a pseudo-five-cyclic system to extend the π-conjugated acridone chromophore, were designed and synthesized as potent DNA binding antitumor compounds. Most synthesized compounds displayed good activity against human leukemia K562 cells in MTT tests, with compound 6d exhibiting the highest activity with IC50 value at 0.46 μM. Moreover, 6d showed potent activities against solid tumor cell lines (0.16-3.79 μM). Several experimental studies demonstrated that the antitumor mode of action of compound 6d involves DNA intercalation, topoisomerase I inhibition, and apoptosis induction through the mitochondrial pathway. In summary, compound 6d represents a novel and promising lead structure for the development of new potent anticancer DNA-binding agents. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  4. Synergistic antitumor efficacy of antibacterial helvolic acid from Cordyceps taii and cyclophosphamide in a tumor mouse model.

    PubMed

    Xiao, Jian-Hui; Zhang, Yao; Liang, Gui-You; Liu, Ru-Ming; Li, Xiao-Gang; Zhang, Ling-Tao; Chen, Dai-Xiong; Zhong, Jian-Jiang

    2017-01-01

    The antibacterial agent helvolic acid, which was isolated from the active antitumor fraction of Cordyceps taii, showed potent cytotoxicity against different human cancer cells. In the present study, the in vivo antitumor effect of helvolic acid was investigated in murine sarcoma S180 tumor-bearing mice. Doses of 10 and 20 mg/kg/day helvolic acid did not exert significant antitumor activity. Interestingly, co-administration of 10 mg/kg/day helvolic acid and 20 mg/kg/day cyclophosphamide (CTX) - a well-known chemotherapy drug - showed promising antitumor activity with a growth inhibitory rate of 70.90%, which was much higher than that of CTX alone (19.5%). Furthermore, the combination markedly prolonged the survival of tumor-bearing mice. In addition, helvolic acid enhanced the immune organ index. The protein expression levels of β-catenin, cyclin D1, and proliferating cell nuclear antigen were significantly suppressed in mice treated with 20 mg/kg/day helvolic acid and in those receiving combination therapy. Taken together, these results indicated that helvolic acid in combination with CTX showed potent in vivo synergistic antitumor efficacy, and its mechanism of action may involve the Wnt/ β-catenin signaling pathway.

  5. Antitumor activity of 6-(cyclohexylamino)-1, 3-dimethyl-5(2-pyridyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione and Its Ti(IV), Zn(II), Fe(III), and Pd(II) complexes on K562 and Jurkat cell lines.

    PubMed

    Shabani, Fahmideh; Ghammamy, Shahriar; Mehrani, Khayroallah; Teimouri, Mohammad Bagher; Soleimani, Masoud; Kaviani, Saeid

    2008-01-01

    (6-(cyclohexylamino)-1,3-dimethyl-5(2-pyridyl)furo[2,3-d]pyrimidine-2,4(1H,3H)-dione) abbreviated as CDP was synthesized and characterized. Ti(IV), Zn(II), Fe(III), and Pd(II) metal complexes of this ligand are prepared by the reaction of salts of Ti(IV), Zn(II), Fe(III), and Pd(II) with CDP in acetonitrile. Characterization of the ligand and its complexes was made by microanalyses, FT-IR, (1)H NMR, (13)C NMR, and UV-Visible spectroscopy. All complexes were characterized by several techniques using elemental analysis (C, H, N), FT-IR, electronic spectra, and molar conductance measurements. The elemental analysis data suggest the stoichiometry to be 1:1 [M:L] ratio formation. The molar conductance measurements reveal the presence of 1:1 electrolytic nature complexes. These new complexes showed excellent antitumor activity against two kinds of cancer cells that are K562 (human chronic myeloid leukemia) cells and Jurkat (human T lymphocyte carcinoma) cells.

  6. Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity.

    PubMed

    Fox, Barbara A; Sanders, Kiah L; Rommereim, Leah M; Guevara, Rebekah B; Bzik, David J

    2016-07-01

    Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the

  7. Secretion of Rhoptry and Dense Granule Effector Proteins by Nonreplicating Toxoplasma gondii Uracil Auxotrophs Controls the Development of Antitumor Immunity

    PubMed Central

    Fox, Barbara A.; Sanders, Kiah L.; Rommereim, Leah M.; Bzik, David J.

    2016-01-01

    Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the

  8. Hsp72 mediates stronger antigen-dependent non-classical MHC class Ib anti-tumor responses than hsc73 in Xenopus laevis.

    PubMed

    Nedelkovska, Hristina; Robert, Jacques

    2013-01-01

    The heat shock proteins (HSPs) gp96 and HSP70 mediate potent antigen-dependent anti-tumor T cell responses in both mammals and Xenopus laevis. We have shown that frogs immunized with total HSP70 generate CD8+ T cell responses against the Xenopus thymic lymphoid tumor 15/0 that expresses several non-classical MHC class Ib (class Ib) genes, but no classical MHC class Ia (class Ia). In the absence of class Ia, we hypothesized that hsp72 can prime class Ib-mediated anti-tumor unconventional CD8+ T cells in an antigen-dependent manner. To test this, we produced Xenopus recombinant HSP70 proteins (both the cognate hsc73 and the inducible hsp72) from stable 15/0 tumor transfectants. We used an in vivo cross-presentation assay to prime animals by adoptive transfer of HSP-pulsed antigen-presenting cells (APCs) and showed that both hsp72-and hsc73-Ag complexes have a similar potential to elicit class Ia-mediated T cell responses against minor histocompatibility (H) Ag skin grafts. In contrast, our in vivo cross-presentation assay revealed that hsp72 was more potent than hsc73 in generating protective immune responses against the class Ia-negative 15/0 tumors in an Ag-dependent and class Ib-mediated manner. These results suggest that hsp72 can stimulate class Ib-mediated immune responses and represents a promising candidate for immunotherapy against malignancies with downregulated class Ia expression.

  9. Hsp72 mediates stronger antigen-dependent non-classical MHC class Ib anti-tumor responses than hsc73 in Xenopus laevis

    PubMed Central

    Nedelkovska, Hristina; Robert, Jacques

    2013-01-01

    The heat shock proteins (HSPs) gp96 and HSP70 mediate potent antigen-dependent anti-tumor T cell responses in both mammals and Xenopus laevis. We have shown that frogs immunized with total HSP70 generate CD8+ T cell responses against the Xenopus thymic lymphoid tumor 15/0 that expresses several non-classical MHC class Ib (class Ib) genes, but no classical MHC class Ia (class Ia). In the absence of class Ia, we hypothesized that hsp72 can prime class Ib-mediated anti-tumor unconventional CD8+ T cells in an antigen-dependent manner. To test this, we produced Xenopus recombinant HSP70 proteins (both the cognate hsc73 and the inducible hsp72) from stable 15/0 tumor transfectants. We used an in vivo cross-presentation assay to prime animals by adoptive transfer of HSP-pulsed antigen-presenting cells (APCs) and showed that both hsp72-and hsc73-Ag complexes have a similar potential to elicit class Ia-mediated T cell responses against minor histocompatibility (H) Ag skin grafts. In contrast, our in vivo cross-presentation assay revealed that hsp72 was more potent than hsc73 in generating protective immune responses against the class Ia-negative 15/0 tumors in an Ag-dependent and class Ib-mediated manner. These results suggest that hsp72 can stimulate class Ib-mediated immune responses and represents a promising candidate for immunotherapy against malignancies with downregulated class Ia expression. PMID:23390375

  10. Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.

    PubMed

    Metelitsa, L S; Naidenko, O V; Kant, A; Wu, H W; Loza, M J; Perussia, B; Kronenberg, M; Seeger, R C

    2001-09-15

    alpha-Galactosylceramide (alphaGalCer) stimulates NKT cells and has antitumor activity in mice. Murine NKT cells may directly kill tumor cells and induce NK cell cytotoxicity, but the mechanisms are not well defined. Newly developed human CD1d/alphaGalCer tetrameric complexes were used to obtain highly purified human alphaGalCer-reactive NKT cell lines (>99%), and the mechanisms of NKT cell cytotoxicity and activation of NK cells were investigated. Human NKT cells were cytotoxic against CD1d(-) neuroblastoma cells only when they were rendered CD1d(+) by transfection and pulsed with alphaGalCer. Four other CD1d(-) tumor cell lines of diverse origin were resistant to NKT cells, whereas Jurkat and U937 leukemia cell lines, which are constitutively CD1d(+), were killed. Killing of the latter was greatly augmented in the presence of alphaGalCer. Upon human CD1d/alphaGalCer recognition, NKT cells induced potent cytotoxicity of NK cells against CD1d(-) neuroblastoma cell lines that were not killed directly by NKT cells. NK cell activation depended upon NKT cell production of IL-2, and was enhanced by secretion of IFN-gamma. These data demonstrate that cytotoxicity of human NKT cells can be CD1d and ligand dependent, and that TCR-stimulated NKT cells produce IL-2 that is required to induce NK cell cytotoxicity. Thus, NKT cells can mediate potent antitumor activity both directly by targeting CD1d and indirectly by activating NK cells.

  11. Antitumor Effects of Laminaria Extract Fucoxanthin on Lung Cancer.

    PubMed

    Mei, ChengHan; Zhou, ShunChang; Zhu, Lin; Ming, JiaXiong; Zeng, FanDian; Xu, Rong

    2017-02-15

    Lung cancer is the leading cause of cancer mortality worldwide and non-small-cell lung cancer (NSCLC) is the most common type. Marine plants provide rich resources for anticancer drug discovery. Fucoxanthin (FX), a Laminaria japonica extract, has attracted great research interest for its antitumor activities. Accumulating evidence suggests anti-proliferative effects of FX on many cancer cell lines including NSCLCs, but the detailed mechanisms remain unclear. In the present investigation, we confirmed molecular mechanisms and in vivo anti-lung cancer effect of FX at the first time. Flow cytometry, real-time PCR, western blotting and immunohistochemistry revealed that FX arrested cell cycle and induced apoptosis by modulating expression of p53, p21, Fas, PUMA, Bcl-2 and caspase-3/8. These results show that FX is a potent marine drug for human non-small-cell lung cancer treatment.

  12. Antitumor Effects of Laminaria Extract Fucoxanthin on Lung Cancer

    PubMed Central

    Mei, ChengHan; Zhou, ShunChang; Zhu, Lin; Ming, JiaXiong; Zeng, FanDian; Xu, Rong

    2017-01-01

    Lung cancer is the leading cause of cancer mortality worldwide and non-small-cell lung cancer (NSCLC) is the most common type. Marine plants provide rich resources for anticancer drug discovery. Fucoxanthin (FX), a Laminaria japonica extract, has attracted great research interest for its antitumor activities. Accumulating evidence suggests anti-proliferative effects of FX on many cancer cell lines including NSCLCs, but the detailed mechanisms remain unclear. In the present investigation, we confirmed molecular mechanisms and in vivo anti-lung cancer effect of FX at the first time. Flow cytometry, real-time PCR, western blotting and immunohistochemistry revealed that FX arrested cell cycle and induced apoptosis by modulating expression of p53, p21, Fas, PUMA, Bcl-2 and caspase-3/8. These results show that FX is a potent marine drug for human non-small-cell lung cancer treatment. PMID:28212270

  13. IL-28 elicits antitumor responses against murine fibrosarcoma.

    PubMed

    Numasaki, Muneo; Tagawa, Masatoshi; Iwata, Fumi; Suzuki, Takashi; Nakamura, Akira; Okada, Masahiro; Iwakura, Yoichiro; Aiba, Setsuya; Yamaya, Mutsuo

    2007-04-15

    IL-28 is a recently described antiviral cytokine. In this study, we investigated the biological effects of IL-28 on tumor growth to evaluate its antitumor activity. IL-28 or retroviral transduction of the IL-28 gene into MCA205 cells did not affect in vitro growth, whereas in vivo growth of MCA205IL-28 was markedly suppressed along with survival advantages when compared with that of controls. When the metastatic ability of IL-28-secreting MCA205 cells was compared with that of controls, the expression of IL-28 resulted in a potent inhibition of metastases formation in the lungs. IL-28-mediated suppression of tumor growth was mostly abolished in irradiated mice, indicating that irradiation-sensitive cells, presumably immune cells, are primarily involved in the IL-28-induced suppression of tumor growth. In vivo cell depletion experiments displayed that polymorphonuclear neutrophils, NK cells, and CD8 T cells, but not CD4 T cells, play an equal role in the IL-28-mediated inhibition of in vivo tumor growth. Consistent with these findings, inoculation of MCA205IL-28 into mice evoked enhanced IFN-gamma production and cytotoxic T cell activity in spleen cells. Antitumor action of IL-28 is partially dependent on IFN-gamma and is independent of IL-12, IL-17, and IL-23. IL-28 increased the total number of splenic NK cells in SCID mice and enhanced IL-12-induced IFN-gamma production in vivo and expanded spleen cells in C57BL/6 mice. Moreover, IL-12 augmented IL-28-mediated antitumor activity in the presence or absence of IFN-gamma. These findings indicate that IL-28 has bioactivities that induce innate and adaptive immune responses against tumors.

  14. Synthesis, antimicrobial, antiquorum-sensing and antitumor activities of new benzimidazole analogs.

    PubMed

    El-Gohary, N S; Shaaban, M I

    2017-09-08

    New benzimidazole analogs were prepared and tested for antimicrobial efficacy toward Escherichia coli ATCC 12435, Bacillus cereus UW 85, Staphylococcus aureus ATCC 29213, Candida albicans and Aspergillus fumigatus 293. Results indicated that compound 10 has potent and broad spectrum antimicrobial activity. In addition, 4b and 5c showed eminent antimicrobial efficacy toward B. cereus, S. aureus, C. albicans and A. fumigatus. Furthermore, 12 and 14 demonstrated interesting antifungal activity toward C. albicans. Antiquorum-sensing efficacy of the new compounds toward Chromobacterium violacium ATCC 12472 was also examined. In vitro antitumor screening of the new benzimidazoles toward HepG2, HCT-116 and MCF-7 cancer cell lines demonstrated that 4b and 5b,c are the most potent analogs toward all tested cell lines. The three potent in vitro antitumor analogs were further assessed for in vivo antitumor activity toward EAC in mice, and in vitro cytotoxicity toward W138 normal cell line. Results revealed that 4b has the highest in vivo activity, and that the three tested analogs are less cytotoxic than 5-FU toward W138 normal cell line. The most active antimicrobial and antitumor analogs were examined for DNA-binding affinity, whereas 4b and 5c displayed the highest affinity. The in silico studies illustrated that all of the new benzimidazoles meet the optimal requirements for good oral absorption and bioavailability. Moreover, in silico toxicity assessment has been reported. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  15. Phenylethylchromones with In Vitro Antitumor Promoting Activity from Aquilaria filaria.

    PubMed

    Suzuki, Airi; Miyake, Katsunori; Saito, Yohei; Rasyid, Faradiba Abdul; Tokuda, Harukuni; Takeuchi, Misa; Suzuki, Nobutaka; Ichiishi, Eiichiro; Fujie, Tetsuo; Goto, Masuo; Sasaki, Yohei; Nakagawa-Goto, Kyoko

    2017-02-01

    A new chromone, 2-(2-hydroxy-2-phenylethyl)chromone (1), was isolated together with ten known phenylethyl chromones from MeOH extracts of agarwood (Aquilaria filaria). The selected compounds were evaluated in an antiproliferative assay against five human tumor cell lines, including a multidrug-resistant cell line. They were also tested for antitumor promoting activity, as mediated by 12-O-tetradecanoylphorbol-13-acetate-induced activation of the Epstein-Barr virus early antigen in Raji cells. Among all compounds, 4',7-dimethyoxy-6-hydroxychromone (2) displayed broad spectrum antiproliferative activity against all tumor cell lines tested with IC50 values of 25-38 µM, while 8 was selectively inhibitory against multidrug-resistant cells. All tested compounds suppressed tumor promotion at noncytotoxic concentrations. 4',6-Dihydroxyphenylethylchromone (7) exhibited the most potent effect with an IC50 value of 319 mol ratio relative to 12-O-tetradecanoylphorbol-13-acetate. This study is the first to report the antitumor promoting activity of 2-(2-phenylethyl)chromone derivatives, as well as the selective antiproliferative activity of 8 against a multidrug-resistant tumor cell line.

  16. Optimization of Antitumor Modulators of Pre-mRNA Splicing

    PubMed Central

    Lagisetti, Chandraiah; Palacios, Gustavo; Goronga, Tinopiwa; Freeman, Burgess; Caufield, William; Webb, Thomas R.

    2014-01-01

    The spliceosome regulates pre-mRNA splicing, which is a critical process in normal mammalian cells. Recently recurrent mutations in numerous spliceosomal proteins have been associated with a number of cancers. Previously natural product antitumor agents have been shown to interact with one of the proteins that is subject to recurrent mutations (SF3B1). We report the optimization of a class of tumor-selective spliceosome modulators, which demonstrate significant in vivo antitumor activity. This optimization culminated in the discovery of sudemycin D6, which shows potent cytotoxic activity in the melanoma line SK-MEL-2 (IC50= 39 nM) and other tumor lines, including: JeKo-1 (IC50= 26 nM), HeLa (IC50= 50 nM), and SK-N-AS (IC50= 81 nM). We also report improved processes for the synthesis of these compounds. Our work supports the idea that sudemycin D6 is worthy of further investigation as a novel preclinical anticancer agent with application in the treatment of numerous human cancers. PMID:24325474

  17. Hepatitis C virus NS5A replication complex inhibitors. Part 6: Discovery of a novel and highly potent biarylimidazole chemotype with inhibitory activity toward genotypes 1a and 1b replicons.

    PubMed

    Belema, Makonen; Nguyen, Van N; Romine, Jeffrey L; St Laurent, Denis R; Lopez, Omar D; Goodrich, Jason T; Nower, Peter T; O'Boyle, Donald R; Lemm, Julie A; Fridell, Robert A; Gao, Min; Fang, Hua; Krause, Rudolph G; Wang, Ying-Kai; Oliver, A Jayne; Good, Andrew C; Knipe, Jay O; Meanwell, Nicholas A; Snyder, Lawrence B

    2014-03-13

    A medicinal chemistry campaign that was conducted to address a potential genotoxic liability associated with an aniline-derived scaffold in a series of HCV NS5A inhibitors with dual GT-1a/-1b inhibitory activity is described. Anilides 3b and 3c were used as vehicles to explore structural modifications that retained antiviral potency while removing the potential for metabolism-based unmasking of the embedded aniline. This effort resulted in the discovery of a highly potent biarylimidazole chemotype that established a potency benchmark in replicon assays, particularly toward HCV GT-1a, a strain with significant clinical importance. Securing potent GT-1a activity in a chemotype class lacking overt structural liabilities was a critical milestone in the effort to realize the full clinical potential of targeting the HCV NS5A protein.

  18. Separation, antitumor activities, and encapsulation of polypeptide from Chlorella pyrenoidosa.

    PubMed

    Wang, Xiaoqin; Zhang, Xuewu

    2013-01-01

    Chlorella pyrenoidosa is a unicellular green algae and has been a popular foodstuff worldwide. However, no reports on the antitumor peptides from such a microalgae are available in the literature. In this study, using low-temperature high-pressure extraction, enzymatic hydrolysis, ion exchange, and gel filtration chromatography, we separated a polypeptide that exhibited inhibitory activity on human liver cancer HepG2 cells, and named the polypeptide CPAP (C. pyrenoidosa antitumor polypeptide). Furthermore, the micro- and nanoencapsulation of CPAP were investigated by using two methods: complex coacervation and ionotropic gelation. The in vitro release tests revealed that CPAP was well preserved against gastric enzymatic degradation after micro/nanoencapsulation and the slowly controlled release in the intestine could be potentially achieved. These results suggest that CPAP may be a useful ingredient in food, nutraceutical, and pharmaceutical applications. © 2013 American Institute of Chemical Engineers.

  19. Synthesis and activities of antitumor agents.

    PubMed

    Suami, T; Machinami, T; Hisamatsu, T

    1979-03-01

    N-(2-Chloroethyl)-N-nitrosocarbamoyl derivatives of glycosylamines have been prepared. Six N-(2-chloroethyl)-N-nitrosoureas, including three disaccharide derivatives, were submitted to a determination of antitumor activity. All the compounds tested exhibited strong antitumor activity against leukemia L1210 in mice.

  20. In silico study of subtilisin-like protease 1 (SUB1) from different Plasmodium species in complex with peptidyl-difluorostatones and characterization of potent pan-SUB1 inhibitors.

    PubMed

    Brogi, Simone; Giovani, Simone; Brindisi, Margherita; Gemma, Sandra; Novellino, Ettore; Campiani, Giuseppe; Blackman, Michael J; Butini, Stefania

    2016-03-01

    Plasmodium falciparum subtilisin-like protease 1 (SUB1) is a novel target for the development of innovative antimalarials. We recently described the first potent difluorostatone-based inhibitors of the enzyme ((4S)-(N-((N-acetyl-l-lysyl)-l-isoleucyl-l-threonyl-l-alanyl)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (1) and (4S)-(N-((N-acetyl-l-isoleucyl)-l-threonyl-l-alanylamino)-2,2-difluoro-3-oxo-4-aminopentanoyl)glycine (2)). As a continuation of our efforts towards the definition of the molecular determinants of enzyme-inhibitor interaction, we herein propose the first comprehensive computational investigation of the SUB1 catalytic core from six different Plasmodium species, using homology modeling and molecular docking approaches. Investigation of the differences in the binding sites as well as the interactions of our inhibitors 1,2 with all SUB1 orthologues, allowed us to highlight the structurally relevant regions of the enzyme that could be targeted for developing pan-SUB1 inhibitors. According to our in silico predictions, compounds 1,2 have been demonstrated to be potent inhibitors of SUB1 from all three major clinically relevant Plasmodium species (P. falciparum, P. vivax, and P. knowlesi). We next derived multiple structure-based pharmacophore models that were combined in an inclusive pan-SUB1 pharmacophore (SUB1-PHA). This latter was validated by applying in silico methods, showing that it may be useful for the future development of potent antimalarial agents.

  1. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity.

    PubMed

    Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V; Martinon, Fabio; Modlin, Robert L; Speiser, Daniel E; Gilliet, Michel

    2015-12-15

    Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma.

  2. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity

    PubMed Central

    Demaria, Olivier; De Gassart, Aude; Coso, Sanja; Gestermann, Nicolas; Di Domizio, Jeremy; Flatz, Lukas; Gaide, Olivier; Michielin, Olivier; Hwu, Patrick; Petrova, Tatiana V.; Martinon, Fabio; Modlin, Robert L.; Speiser, Daniel E.; Gilliet, Michel

    2015-01-01

    Spontaneous CD8 T-cell responses occur in growing tumors but are usually poorly effective. Understanding the molecular and cellular mechanisms that drive these responses is of major interest as they could be exploited to generate a more efficacious antitumor immunity. As such, stimulator of IFN genes (STING), an adaptor molecule involved in cytosolic DNA sensing, is required for the induction of antitumor CD8 T responses in mouse models of cancer. Here, we find that enforced activation of STING by intratumoral injection of cyclic dinucleotide GMP-AMP (cGAMP), potently enhanced antitumor CD8 T responses leading to growth control of injected and contralateral tumors in mouse models of melanoma and colon cancer. The ability of cGAMP to trigger antitumor immunity was further enhanced by the blockade of both PD1 and CTLA4. The STING-dependent antitumor immunity, either induced spontaneously in growing tumors or induced by intratumoral cGAMP injection was dependent on type I IFNs produced in the tumor microenvironment. In response to cGAMP injection, both in the mouse melanoma model and an ex vivo model of cultured human melanoma explants, the principal source of type I IFN was not dendritic cells, but instead endothelial cells. Similarly, endothelial cells but not dendritic cells were found to be the principal source of spontaneously induced type I IFNs in growing tumors. These data identify an unexpected role of the tumor vasculature in the initiation of CD8 T-cell antitumor immunity and demonstrate that tumor endothelial cells can be targeted for immunotherapy of melanoma. PMID:26607445

  3. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression12

    PubMed Central

    Chen, Chong-Sheng; Doloff, Joshua C; Waxman, David J

    2014-01-01

    Metronomic chemotherapy using cyclophosphamide (CPA) is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25%) reduction in CPA dose. Moreover, an ∼20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses. PMID:24563621

  4. Expanded Human Blood-Derived γδT Cells Display Potent Antigen-Presentation Functions

    PubMed Central

    Khan, Mohd Wajid A.; Curbishley, Stuart M.; Chen, Hung-Chang; Thomas, Andrew D.; Pircher, Hanspeter; Mavilio, Domenico; Steven, Neil M.; Eberl, Matthias; Moser, Bernhard

    2014-01-01

    Cell-based immunotherapy strategies target tumors directly (via cytolytic effector cells) or aim at mobilizing endogenous anti-tumor immunity. The latter approach includes dendritic cells (DC) most frequently in the form of in vitro cultured peripheral blood monocytes-derived DC. Human blood γδT cells are selective for a single class of non-peptide agonists (“phosphoantigens”) and develop into potent antigen-presenting cells (APC), termed γδT-APC within 1–3 days of in vitro culture. Availability of large numbers of γδT-APC would be advantageous for use as a novel cellular vaccine. We here report optimal γδT cell expansion (>107 cells/ml blood) when peripheral blood mononuclear cells (PBMC) from healthy individuals and melanoma patients were stimulated with zoledronate and then cultured for 14 days in the presence of IL-2 and IL-15, yielding γδT cell cultures of variable purity (77 ± 21 and 56 ± 26%, respectively). They resembled effector memory αβT (TEM) cells and retained full functionality as assessed by in vitro tumor cell killing as well as secretion of pro-inflammatory cytokines (IFNγ, TNFα) and cell proliferation in response to stimulation with phosphoantigens. Importantly, day 14 γδT cells expressed numerous APC-related cell surface markers and, in agreement, displayed potent in vitro APC functions. Day 14 γδT cells from PBMC of patients with cancer were equally effective as their counterparts derived from blood of healthy individuals and triggered potent CD8+ αβT cell responses following processing and cross-presentation of simple (influenza M1) and complex (tuberculin purified protein derivative) protein antigens. Of note, and in clear contrast to peripheral blood γδT cells, the ability of day 14 γδT cells to trigger antigen-specific αβT cell responses did not depend on re-stimulation. We conclude that day 14 γδT cell cultures provide a convenient source of autologous APC for use in immunotherapy of patients

  5. Combination of ruthenium(II)-arene complex [Ru(η6-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity

    PubMed Central

    Berndsen, Robert H.; Weiss, Andrea; Abdul, U. Kulsoom; Wong, Tse J.; Meraldi, Patrick; Griffioen, Arjan W.; Dyson, Paul J.; Nowak-Sliwinska, Patrycja

    2017-01-01

    Ruthenium-based compounds show strong potential as anti-cancer drugs and are being investigated as alternatives to other well-established metal-based chemotherapeutics. The organometallic compound [Ru(η6-p-cymene)Cl2(pta)], where pta = 1,3,5-triaza-7-phosphaadamantane (RAPTA-C) exhibits broad acting anti-tumor efficacy with intrinsic angiostatic activity. In the search for an optimal anti-angiogenesis drug combination, we identified synergistic potential between RAPTA-C and the epidermal growth factor receptor (EGFR) inhibitor, erlotinib. This drug combination results in strong synergistic inhibition of cell viability in human endothelial (ECRF24 and HUVEC) and human ovarian carcinoma (A2780 and A2780cisR) cells. Additionally, erlotinib significantly enhances the cellular uptake of RAPTA-C relative to treatment with RAPTA-C alone in human ovarian carcinoma cells, but not endothelial cells. Drug combinations induce the formation of chromosome bridges that persist after mitotic exit and delay abscission in A2780 and A2780cisR, therefore suggesting initiation of cellular senescence. The therapeutic potential of these compounds and their combination is further validated in vivo on A2780 tumors grown on the chicken chorioallantoic membrane (CAM) model, and in a preclinical model in nude mice. Immunohistochemical analysis confirms effective anti-angiogenic and anti-proliferative activity in vivo, based on a significant reduction of microvascular density and a decrease in proliferating cells. PMID:28223694

  6. Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma

    PubMed Central

    Liu, Xu-Jie; Li, Liang; Liu, Xiu-Jun; Li, Yi; Zhao, Chun-Yan; Wang, Rui-Qi; Zhen, Yong-Su

    2017-01-01

    Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1–2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P<0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy. PMID:28769562

  7. Oxazole: A Promising Building Block for the Development of Potent Antitumor Agents.

    PubMed

    Zhou, Hua; Cheng, Jiang-Qun; Wang, Zhi-Sen; Chen, Fei-Hu; Liu, Xin-Hua

    2016-01-01

    Oxazole derivatives are found to have a variety of biological activities. A large number of studies have revealed their outstanding anticancer activities. Here we review four different types of oxazole derivatives with anticancer potential reported over the last ten years. We focus our discussion on their activity, selectivity in different cancer cell lines, mechanisms of action, and their structural evolution.

  8. Mithramycin-loaded mPEG-PLGA nanoparticles exert potent antitumor efficacy against pancreatic carcinoma.

    PubMed

    Liu, Xu-Jie; Li, Liang; Liu, Xiu-Jun; Li, Yi; Zhao, Chun-Yan; Wang, Rui-Qi; Zhen, Yong-Su

    2017-01-01

    Previous studies have shown that mithramycin A (MIT) is a promising candidate for the treatment of pancreatic carcinoma through inhibiting transcription factor Sp1. However, systemic toxicities may limit its clinical application. Here, we report a rationally designed formulation of MIT-loaded nanoparticles (MIT-NPs) with a small size and sustained release for improved passive targeting and enhanced therapeutic efficacy. Nearly spherical MIT-NPs with a mean particle size of 25.0±4.6 nm were prepared by encapsulating MIT into methoxy poly(ethylene glycol)-block-poly(d,l-lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) with drug loading of 2.11%±0.51%. The in vitro release of the MIT-NPs lasted for >48 h with a sustained-release pattern. The cytotoxicity of MIT-NPs to human pancreatic cancer BxPC-3 and MIA Paca-2 cells was comparable to that of free MIT. Determined by flow cytometry and confocal microscopy, the NPs internalized into the cells quickly and efficiently, reaching the peak level at 1-2 h. In vivo fluorescence imaging showed that the prepared NPs were gradually accumulated in BxPC-3 and MIA Paca-2 xenografts and retained for 168 h. The fluorescence intensity in both BxPC-3 and MIA Paca-2 tumors was much stronger than that of various tested organs. Therapeutic efficacy was evaluated with the poorly permeable BxPC-3 pancreatic carcinoma xenograft model. At a well-tolerated dose of 2 mg/kg, MIT-NPs suppressed BxPC-3 tumor growth by 96%. Compared at an equivalent dose, MIT-NPs exerted significantly higher therapeutic effect than free MIT (86% versus 51%, P<0.01). Moreover, the treatment of MIT and MIT-NPs reduced the expression level of oncogene c-Myc regulated by Sp1, and notably, both of them decreased the protein level of CD47. In summary, the novel formulation of MIT-NPs shows highly therapeutic efficacy against pancreatic carcinoma xenograft. In addition, MIT-NPs can downregulate CD47 expression, implying that it might play a positive role in cancer immunotherapy.

  9. Understanding the Biosynthesis of SF2575: A Potent Antitumor Compound with Novel Modes of Action

    DTIC Science & Technology

    2010-03-01

    this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including...1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202- 4302. Respondents should be aware that notwithstanding any other provision of law...no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB

  10. Understanding the Biosynthesis SF2575: A Potent Antitumor Compound With Novel Modes of Action

    DTIC Science & Technology

    2009-09-01

    analyzed on HPLC and LCMS to try to identify any potential stable intermediates that may be present (Figure 3). Using selected ion monitoring, the... polyketides . One known example is that of thermorubin, in which the salicylate moiety is Figure 6: Proposed biosynthetic pathways for the pendants 30...DISTRIBUTION STATEMENT: (Check one ) X Approved for public release; distribution unlimited Distribution limited to U.S

  11. Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy

    SciTech Connect

    Yu, Yao; Cai, Wei; Pei, Chong-gang; Shao, Yi

    2015-03-20

    Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo.

  12. Ley specific antibody with potent anti-tumor activity is internalized and degraded in lysosomes.

    PubMed Central

    Garrigues, J.; Garrigues, U.; Hellström, I.; Hellström, K. E.

    1993-01-01

    BR96 is a monoclonal antibody (MAb) that recognizes many human carcinomas and can kill antigen-positive tumor cells in vitro. Using both gold and radiolabeled MAb, the distribution and cellular processing of BR96 during cytolysis has been determined. After a brief (< 3 minutes) MAb treatment, cells in suspension are stained by the nuclear viability dye propidium iodide. Whole MAb and F(ab')2 fragments are equally cytotoxic; monovalent F(ab) fragments, however, have no effect on dye uptake unless cross-linked with goat anti-mouse IgG. The level of toxicity is dependent on both MAb dose and on cell surface receptor density. Cell contact may regulate receptor expression. BR96 receptors are more abundant on cells migrating into the open areas of a scratch wounded confluent culture than on the adjacent contact-inhibited cells. BR96 can also inhibit the anchorage-independent growth of tumor cells in soft agar showing that its effects on propidium iodide staining are not due to transient changes in membrane permeability. Immunogold electron microscopy reveals that, after a 1-minute treatment, BR96 induces significant infolding of the plasma membrane and that internalized MAb is localized to these structures. Immediately thereafter, large cell surface and intracellular vesicles form, mitochondria are swollen, and membrane integrity is lost. Therefore, BR96 seems to cause morphological changes characteristic of necrosis rather than apoptosis. When bound to adherent carcinoma cells, BR96 is distributed uniformly on the apical surface of cells labeled at 4 C and is enriched at points of cell substratum contact. Upon warming of the cells to 37 C, BR96 localizes in small perinuclear clusters and the cell margin is now devoid of label. Immunogold electron microscopy reveals that BR96 undergoes receptor mediated internalization and is localized within the same coated pits, endosomes, and lysosomes as the transferrin receptor. Quantitative studies using iodinated BR96 show that after 6 hours of chase, a maximum of 53% of the radiolabel is located within the intracellular pool. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis indicates that 84% of this fraction is nondegraded. BR96 probably cycles between the medium and intracellular pools because the remainder of the radiolabel is in the medium as intact MAb. By 24 hours of chase, the intracellular fraction drops to 30%, while the remaining 70% is present in the culture medium, mostly as low molecular weight degradation products. Images Figure 1 Figure 2 Figure 4 Figure 5 p614-a Figure 6 Figure 7 Figure 8 Figure 9 PMID:8434651

  13. Synthesis and antitumor activity of new alkylphospholipids containing modifications of the phosphocholine moiety.

    PubMed

    Ukawa, K; Imamiya, E; Yamamoto, H; Mizuno, K; Tasaka, A; Terashita, Z; Okutani, T; Nomura, H; Kasukabe, T; Hozumi, M

    1989-05-01

    New antitumor alkylglycerophospholipids, in which primarily the phosphocholine moiety of the platelet activating factor (PAF) molecule was modified, were synthesized from 1-alkyl-2-substituted glycerols by introducing polar head phosphoryl groups having methylene bridges of various lengths (from 2 to 14 carbons). They were tested for PAF agonistic activity and antitumor properties. In a series of 1-octadecyl-2-acetoacetylglycerophospholipids (1a-f), an increase in the length of the methylene bridge separating the phosphate and trimethylammonio group in the polar head side chain at position 3 of the glycerol backbone resulted in a progressive decrease in PAF agonistic activity and a characteristic change in antitumor activity against human promyelocytic leukemia cells (HL-60). Maximal potency was obtained with the compound having a decamethylene bridge (1e, IC50 value = 1.5 microgram/ml). Thus, alkylphospholipids possessing a decamethylene bridge and a variety of substituents at position 2 (1g-n) were synthesized. They showed potent inhibitory activity with IC50 values ranging from 0.4 to 1.9 micrograms/ml, depending on the nature of the 2-substituent in the phospholipid molecule. In in vivo tests of the present series of alkylglycerophospholipids (1a--n), using mice bearing sarcoma 180 and mice with mammary carcinoma MM46 (both cells and compounds were given i.p.), 1-octadecyl-2-acetoacetyl-3-glyceryl omega-trimethylammoniodecyl phosphate (1e) showed the most potent life-prolonging effect. The structure-activity relationships are discussed.

  14. Calcium pterin as an antitumor agent.

    PubMed

    Moheno, Phillip B B

    2004-03-01

    A series of in vivo studies are reported that provide evidence for an immunologically mediated mechanism for the antitumor response from a calcium pterin (CaPterin) suspension. Strong antitumor efficacy was demonstrated in fully immunocompetent female C3H/HeN-MTV+ mice (retired breeders) presenting spontaneous mammary gland adenocarcinomas. Comparison of results obtained by testing CaPterin in either nude or SCID mice (severely compromised immunodeficient) implanted with MDA-MB-231 human cancer cells showed a significant antitumor response in the nudes and no response in the SCIDs. This comparison argues for B-cell immunological involvement in the mechanism of CaPterin antitumor activity since nude mice possess B-cell capability while SCID mice do not. This comparison also indicates that there is no measurable direct cancer cell toxicity from the CaPterin. Results showing no CaPterin antitumor efficacy against EMT6 tumor cells implanted in Balb/c mice also suggest an antitumor mechanism involving B-cells, since transforming growth factor beta (TGF-beta), produced by EMT6 cells, is known to cause B-cell apoptosis. Taken together, these results, along with those of other researchers, indicate that CaPterin's antitumor mechanism involves antibody-dependent cellular cytotoxicity (ADCC) mediated, for example, by natural killer (NK) cells, interlukin-2, and CaPterin.

  15. Antitumor germacranolides from Anvillea garcinii.

    PubMed

    Abdel Sattar, E; Galal, A M; Mossa, G S

    1996-04-01

    The aerial parts of Anvillea garcinii yielded two new germacranolides, 9 alpha-hydroxy-1 beta, 10 alpha-epoxyparthenolide (4) and parthenolid-9-one (5), in addition to the known 9 alpha-hydroxyparthenolide (1), 9 beta-hydroxyparthenolide (2), and 9 beta-hydroxy-1 beta, 10 alpha-epoxyparthenolide (3). The structures of the new compounds were elucidated from their spectral data (IR, MS, 1H- and 13C-NMR, 1H-1H COSY, and 1H-13C HETCOR) and by chemical derivatization. The hitherto unreported 13C-NMR data and carbon atom assignments of the previously isolated lactones 1, 2, and 3 were given. The in-vitro antitumor and anti-HIV activities were evaluated for the isolated compounds.

  16. A novel cationic lipid with intrinsic antitumor activity to facilitate gene therapy of TRAIL DNA.

    PubMed

    Luo, Cong; Miao, Lei; Zhao, Yi; Musetti, Sara; Wang, Yuhua; Shi, Kai; Huang, Leaf

    2016-09-01

    Metformin (dimethylbiguanide) has been found to be effective for the treatment of a wide range of cancer. Herein, a novel lipid (1,2-di-(9Z-octadecenoyl)-3-biguanide-propane (DOBP)) was elaborately designed by utilizing biguanide as the cationic head group. This novel cationic lipid was intended to act as a gene carrier with intrinsic antitumor activity. When compared with 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP), a commercially available cationic lipid with a similar structure, the blank liposomes consisting of DOBP showed much more potent antitumor effects than DOTAP in human lung tumor xenografts, following an antitumor mechanism similar to metformin. Given its cationic head group, biguanide, DOBP could encapsulate TNF-related apoptosis-inducing ligand (TRAIL) plasmids into Lipid-Protamine-DNA (LPD) nanoparticles (NPs) for systemic gene delivery. DOBP-LPD-TRAIL NPs demonstrated distinct superiority in delaying tumor progression over DOTAP-LPD-TRAIL NPs, due to the intrinsic antitumor activity combined with TRAIL-induced apoptosis in the tumor. These results indicate that DOBP could be used as a versatile and promising cationic lipid for improving the therapeutic index of gene therapy in cancer treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. [Synthesis of 1-furfuryl-indolin-2-one derivatives and preliminary evaluation of their antitumor activities].

    PubMed

    Dong, Xiao-Chun; Zhou, Fu-Sheng; Zheng, Jian-Bin; Wen, Ren

    2008-01-01

    In order to find new indolin-2-one derivatives as antitumor agents, a series of 3-pyrrole substituted 1-(5-formyl-2-furanylmethyl) indolin-2-one derivatives were designed and synthesized. 5-Formyl-2 ,4-dimethyl-lH-pyrrole-3-carboxylic acid ethyl ester was condensed with 5-substituted indolin-2-one 2a-2d to afford 3-[(pyrrol-2-yl) -methylidenyl] indolin-2-ones 3a-3d. Through N-alkylation, 1-(5-formyl-furfuryl) -indolin-2-one 4a-4d were prepared. Compounds 4a-4d were then condensed with indolin-2-one to afford bis-indolin-2-one derivatives 5a-5d. The structures of the synthesized compounds were determined by 1H NMR, MS and element analysis. Antitumor activities of all the synthesized compounds in vitro were tested. All the 12 synthesized compounds possess antitumor activities against SPC-A1 strain. Especially the compounds 5a-5d possess potent antitumor activities better than sunitinib. Their IC50 are all below 5 micromol x L(-1).

  18. Curcuma increasing antitumor effect of Rhizoma paridis saponins through absorptive enhancement of paridis saponins.

    PubMed

    Man, Shuli; Li, Yuanyuan; Fan, Wei; Gao, Wenyuan; Liu, Zhen; Li, Nan; Zhang, Yao; Liu, Changxiao

    2013-09-15

    Rhizoma paridis saponins (RPS) played a good antitumor role in many clinical applications. However, low oral bioavailability limited its application. In this research, water extract of Curcuma (CW) significantly increased antitumor effect of Rhizoma paridis saponins (RPS). GC-MS was used to identify its polar composition. HPLC was applied for determination of the content of curcuminoids in CW. As a result, 47 analytes with 0.65% of curcuminoids were identified in CW. According to the in vivo anti-tumor data, the best proportion of curcuminoids in CW with RPS was 16:500 (w/w). Using this ratio, curcuminoids significantly increased absorption of RPS in the everted rat duodenum sac system. In addition, curcuminoids decreased the promotion of RPS on rhodamine 123 efflux. The effect of curcuminoids was similar to that of the P-gp inhibitor, cyclosporin A in combination with RPS. In conclusion, drug combination of water extract of Curcuma with RPS was a good method to increase the antitumor effect of RPS. This combination would be a potent anticancer agent used in the prospective application. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.