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Sample records for antiangiogenic organoselenium compound

  1. Atheroprotective action of a modified organoselenium compound: in vitro evidence.

    PubMed

    Oliveira, Jade DE; Straliotto, Marcos R; Mancini, Gianni; Figueiredo, Claudia P; Braga, Antônio L; Teixeira, João B R; Bem, Andreza F

    2016-01-01

    Oxidation of low-density lipoprotein (LDL) has been strongly suggested to play a significant role in the pathogenesis of atherosclerosis. Thus, reducing LDL oxidation is a potential approach to decrease the risk of the atherosclerosis. Organoselenium compounds have demonstrated promising atheroprotective properties in experimental models. Herein, we tested the in vitro atheroprotective capability of a modified organoselenium compound, Compound HBD, in protecting isolated LDL from oxidation as well as foam cells formation. Moreover, the glutathione peroxidase (GPx)-like activity of Compound HBD was analyzed in order to explore the mechanisms related to the above-mentioned protective effects. The Compound HBD in a concentration-dependent manner reduced the Cu2+-induced formation of conjugated dienes. The protein portion from LDL were also protected from Cu2+-induced oxidation. Furthermore, the Compound HBD efficiently decreased the foam cell formation in J774 macrophage cells exposed to oxidized LDL. We found that the atheroprotective effects of this compound can be, at least in part, related to its GPx-like activity. Our findings demonstrated an impressive effect of Compound HBD against LDL-induced toxicity, a further in vivo study to investigate in more detail the antioxidant and antiatherogenic effects of this compound could be considered.

  2. Sensitization of cisplatin therapy by a naphthalimide based organoselenium compound through modulation of antioxidant enzymes and p53 mediated apoptosis.

    PubMed

    Ghosh, P; Singha Roy, S; Basu, A; Bhattacharjee, A; Bhattacharya, S

    2015-04-01

    The widely used anti-cancer drug cisplatin imparts various toxic manifestations in the host, with nephrotoxicity being the most severe one. The trace element selenium shows antioxidant activity in both human and animals. The present study was designed to assess the chemoprotecting and chemoenhancing efficacy of a naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl)-benzo[de]isoquinoline 1,3-dione during cisplatin chemotherapy in mice bearing Ehrlich ascites carcinoma cells. Cisplatin (5 mg/kg b.w.) was administered intraperitoneally and the organoselenium compound (3 mg/kg b.w.) was given by oral gavage in concomitant and pretreatment schedule. The effects of the test compound was evaluated by assaying biochemical, hematological, histological, genotoxicity parameters and by investigating induction of apoptosis in tumor cells, and calculating tumor growth response in the host. The organoselenium compound significantly prevented cisplatin induced generation of reactive oxygen species (ROS), reactive nitrogen species, and onset of lipid peroxidation in the kidney tissue of the experimental mice. In addition, the test compound was also substantially restored cisplatin induced depleted activities of the renal antioxidant enzymes and reduced glutathione level; prevented the serum blood urea nitrogen level, creatinine level, chromosomal aberration, DNA damage, histological alterations of kidney, and normalized the hematological profile of the tumor bearing mice. Furthermore, the organoselenium compound alone or during combination therapy induced apoptosis in tumor cells through mitochondria mediated and DNA damage mediated pathway and ultimately increased the life span of the tumor bearing host. Hence, the results showed that the test compound not only reduced the toxicity of cisplatin but also enhanced its anti-tumor efficacy.

  3. Chemopreventive mechanisms of α-keto acid metabolites of naturally occurring organoselenium compounds

    PubMed Central

    Pinto, John T.; Lee, Jeong-In; Sinha, Raghu; MacEwan, Melanie E.; Cooper, Arthur J. L.

    2010-01-01

    Previous studies on the chemopreventive mechanisms of dietary selenium have focused on its incorporation into antioxidative selenoproteins, such as glutathione peroxidase and thioredoxin reductase. Several studies, however, have revealed that dietary selenium in the form of L-selenomethionine and the 21st amino acid, selenocysteine, also have intrinsic anti-cancer properties. Biochemical mechanisms previously investigated to contribute to their anticancer effects involve β- and γ-lyase reactions. Some pyridoxal 5′-phosphate (PLP)-containing enzymes can catalyze a β-lyase reaction with Se-methyl-L-selenocysteine (MSC) generating pyruvate and ammonia. Other PLP-enzymes can catalyze a γ-lyase reaction with L-selenomethionine (SM) generating α-ketobutyrate and ammonia. In both cases, a purported third product is methylselenol (CH3SeH). Although not directly quantifiable, as a result of its extreme hydrophobicity and high vapor pressure, CH3SeH has been indirectly observed to act through the alteration of protein-sulfhydryl moieties on redox-responsive signal and transcription factors, thereby maintaining a non-proliferative intracellular environment. We have considered the possibility that α-keto acid analogues of MSC (i.e., methylselenopyruvate; MSP) and SM (i.e., α-keto-γ-methylselenobutyrate; KMSB), generated via a transamination and/or L-amino acid oxidase reaction may also be chemoprotective. Indeed, these compounds were shown to increase the level of histone-H3 acetylation in human prostate and colon cancer cells. MSP and KMSB structurally resemble butyrate, an inhibitor of several histone deacetylases. Thus, the seleno α-keto acid metabolites of MSC and SM, along with CH3SeH derived from β- and γ-lyase reactions, may be potential direct-acting metabolites of organoselenium that lead to de-repression of silenced tumor suppressor proteins and/or regulation of genes and signaling molecules. PMID:20383543

  4. Effects of supplementing broiler breeder diets with organoselenium compounds and polyunsaturated fatty acids on hatchability.

    PubMed

    Pappas, A C; Acamovic, T; Sparks, N H C; Surai, P F; McDevitt, R M

    2006-09-01

    The effects of supplementing broiler breeder diets with polyunsaturated fatty acids (PUFA) and organoselenium compounds on fertility, hatchability, and the weight of 1-d-old chicks was assessed. Prepeak (23 wk) and peak (27 wk) production breeders were fed 1 of 4 diets: a wheat-based commercial breeder diet with 55 g/kg of either soybean oil (SO) or fish oil (FO), but no added Se (only that originating from feed ingredients), and each diet with added Se as Sel-Plex (SO + Se, FO + Se). The diets were designed to contain <0.1 mg/kg of Se and about 0.5 mg/kg of Se for the nonsupplemented (no added Se) and the supplemented diets, respectively. The Se concentration of the eggshell of the hatching egg was measured. The concentration of Se, PUFA, and total lipid content of the brain and liver of the 1-d-old chick was determined. The number of fertile eggs increased, embryonic mortality decreased, and hatchability increased as hen age increased from 23 to 27 wk. The Se concentration in the eggshell and the brain and liver of 1-d-old chicks was higher in the high-Se treatments com pared with the concentration in the low-Se treatments. Fish oil inclusion in the breeder diet increased embryonic mortality in wk 3 of incubation and reduced both hatchability and 1-d-old chick weight in hens of both ages. The addition of Se to the FO diets ameliorated some of these adverse effects, because chicks hatched from eggs laid by 23-wk-old breeders of the FO + Se treatment were heavier than those receiving the FO treatment. The Se concentration in the brain and liver of chicks from the FO hens was higher than that in chicks from the SO hens. The concentration of docosahexaenoic fatty acid was higher in the liver of chicks from the SO + Se treatment compared with that of chicks from the SO treatment, indicating possible protective effects of Se. Hatchability was decreased by increased PUFA and was higher in 27-wk-old compared with 23-wk-old breeders.

  5. In vitro evaluation of glutathione peroxidase (GPx)-like activity and antioxidant properties of an organoselenium compound.

    PubMed

    Ibrahim, Mohammad; Muhammad, Niaz; Naeem, Muhammad; Deobald, Anna Maria; Kamdem, Jean Paul; Rocha, Joao Batista Teixeira

    2015-08-01

    The amine based diselenide, (Z)-N-(4-methylbenzylidene)-1-(2-((2-(1-((E)-4-methyl benzylideneamino)ethyl)phenyl)diselanyl)phenyl)ethanamine ethyl)phenyl) diselanyl) phenyl) ethylimino) methyl)phenol (Compound A) an organoselenium compound that can mimic endogenous antioxidant enzymes, such as glutathione peroxidase (GPx), and diphenyl diselenide (PhSe)2 were tested against lipid peroxidation induced by sodium nitroprusside (SNP) and Fe(II) in rat brain, interaction with 1,1-diphenyl-2-picrylhydrazyl stable free radical (DPPH) and glutathione peroxidase (GPx) like antioxidant activities with H2O2 or tBuOOH as substrates and with PhSH as thiol co-substrates as well as their ability to oxidize thiols were evaluated. From this study, we concluded that Compound A catalyze the reduction of H2O2 with thiol was ∼2-fold more active than (PhSe)2) in both tBuOOH and H2O2 systems when PhSH was used as a substrate. (PhSe)2 exhibited an increased ability to oxidize thiols while Compound A was not a good substrate for the oxidation of thiol used namely DTT and Cystine and showed DPPH radical-scavenging activity, while (PhSe)2 did not present radical scavenging activity. Compound A (amine based diselenide) presented better antioxidant profiles than (PhSe)2 against lipid peroxidation. The results clear showed that nitrogen atom in the Compound A can have a profound effect on their pharmacological properties.

  6. Facile synthesis, structural evaluation, antimicrobial activity and synergistic effects of novel imidazo[1,2-a]pyridine based organoselenium compounds.

    PubMed

    Kumar, Sanjeev; Sharma, Nidhi; Maurya, Indresh K; Bhasin, Aman K K; Wangoo, Nishima; Brandão, Paula; Félix, Vítor; Bhasin, K K; Sharma, Rohit K

    2016-11-10

    A simple and efficient method has been described to synthesize the hitherto unknown imidazo[1,2-a]pyridine selenides (5a-l) by reaction of 2-chloroimidazo [1,2-a]pyridines with aryl/heteroaryl selenols, generated in situ by reduction of various diselenides with hypophosphorous acid. The crystal structures of 3-nitro-2-(phenylselanyl)-imidazo[1,2-a]pyridine (5a), 2-(mesitylselanyl)-3-nitro-imidazo[1,2-a]pyridine (5d) and 3-nitro-2-(pyridin-2-ylselanyl)-imidazo[1,2-a]pyridine (5e) were confirmed by X-ray crystallography and the DFT calculations were performed to determine various structural parameters which were correlated with the X-ray crystal structures. The synthesized compounds were subjected to antimicrobial evaluation and it was found that compounds 5a and 5j were active against gram negative bacterium Escherichia coli whereas compound 5e was active against different fungal strains. Time kill assay was performed to understand the microbial activity of synthesized organoselenium compounds and the toxicity of these compounds was evaluated against human cell lines. Synergistic effects of active compounds 5a and 5e were tested with existing antibiotic drugs which exhibited that the antibiotic combination with synthesized organoselenium compounds efficiently enhanced the antimicrobial activity.

  7. Evaluation of the pharmacological properties of salicylic acid-derivative organoselenium: 2-hydroxy-5-selenocyanatobenzoic acid as an anti-inflammatory and antinociceptive compound.

    PubMed

    Chagas, Pietro Maria; Rosa, Suzan Gonçalves; Sari, Marcel Henrique Marcondes; Oliveira, Carla Elena Sartori; Canto, Rômulo Faria Santos; da Luz, Sônia Cristina Almeida; Braga, Antonio Luiz; Nogueira, Cristina Wayne

    2014-03-01

    The present study evaluated the antinociceptive and anti-inflammatory effects of per oral (p.o.) administration of salicylic acid-derivative organoselenium compounds in chemical models of nociception in mice. The compounds (50 mg/kg; p.o.) were administered 30 and 60 min before the nociceptive behavior and compared to the positive-control, acetylsalicylic acid (ASA; 200 mg/kg; p.o.). In addition, a dose-response curve (25-100 mg/kg) for compounds was carried out in the formalin test. When assessed in the chemical models, acetic acid-induced writhing behavior, formalin and glutamate tests, the compounds showed the following antinociceptive profile 1B>2B>1A>2A, suggesting a chemical structure-dependent relationship. Then, the anti-inflammatory properties and toxicological potential of compound 1B were investigated. Compound 1B, similar to the positive-control, ASA, diminished the edema formation and decreased the myeloperoxidase activity induced by croton oil (2.5%) in the ear tissue. The results also indicate that a single oral administration of 1B caused neither signs of acute toxicity nor those of gastrointestinal injury. The administration of 1B did not alter the water and food intakes, plasma alanine and aspartate aminotransferase activities or urea levels and cerebral or hepatic δ-aminolevulinate dehydratase activity. Salicylic acid-derivative organoseleniums, mainly compound 1B, have been found to be novel compounds with antinociceptive/anti-inflammatory properties; nevertheless, more studies are required to examine their therapeutic potential for pain treatment.

  8. In silico modification of Zn2+ binding group of suberoylanilide hydroxamic acid (SAHA) by organoselenium compounds as Homo sapiens class II HDAC inhibitor of cervical cancer

    NASA Astrophysics Data System (ADS)

    Sumo Friend Tambunan, Usman; Bakri, Ridla; Aditya Parikesit, Arli; Ariyani, Titin; Dyah Puspitasari, Ratih; Kerami, Djati

    2016-02-01

    Cervical cancer is the most common cancer in women, and ranks seventh of all cancers worldwide, with 529000 cases in 2008 and more than 85% cases occur in developing countries. One way to treat this cancer is through the inhibition of HDAC enzymes which play a strategic role in the regulation of gene expression. Suberoyl Anilide Hydroxamic Acid (SAHA) or Vorinostat is a drug which commercially available to treat the cancer, but still has some side effects. This research present in silico SAHA modification in Zinc Binding Group (ZBG) by organoselenium compound to get ligands which less side effect. From molecular docking simulation, and interaction analysis, there are five best ligands, namely CC27, HA27, HB28, IB25, and KA7. These five ligands have better binding affinity than the standards, and also have interaction with Zn2+ cofactor of inhibited HDAC enzymes. This research is expected to produce more potent HDAC inhibitor as novel drug for cervical cancer treatment.

  9. AE-941 (Neovastat): a novel multifunctional antiangiogenic compound.

    PubMed

    Gingras, D; Batist, G; Béliveau, R

    2001-10-01

    AE-941 (Neovastat) is a naturally occurring product extracted from cartilage and has antiangiogenic properties. It has reached Phase III clinical trial evaluation for the treatment of solid tumors (non-small cell lung cancer and renal cell carcinoma) and a pivotal Phase II clinical trial in multiple myeloma is ongoing. AE-941 inhibits several steps of the angiogenesis process, including matrix metalloproteinase activities and VEGF signaling pathways. Moreover, AE-941 induces endothelial cell apoptosis and tissue-type plasminogen activator activity, thus suggesting that it is a multifunctional antiangiogenic drug. Results from Phase I/II clinical trials indicate that AE-941, given orally, is well tolerated. Moreover, the median survival time in patients with renal cell carcinoma and non-small cell lung cancer was significantly longer in patients receiving high doses of AE-941 compared to low doses.

  10. Diphenyl diselenide, a simple organoselenium compound, decreases methylmercury-induced cerebral, hepatic and renal oxidative stress and mercury deposition in adult mice.

    PubMed

    de Freitas, Andressa Sausen; Funck, Vinícius Rafael; Rotta, Mariana dos Santos; Bohrer, Denise; Mörschbächer, Vanessa; Puntel, Robson Luís; Nogueira, Cristina Wayne; Farina, Marcelo; Aschner, Michael; Rocha, João Batista Teixeira

    2009-04-06

    Oxidative stress has been pointed out as an important molecular mechanism in methylmercury (MeHg) intoxication. At low doses, diphenyl diselenide ((PhSe)2), a structurally simple organoselenium compound, has been shown to possess antioxidant and neuroprotective properties. Here we have examined the possible in vivo protective effect of diphenyl diselenide against the potential pro-oxidative effects of MeHg in mouse liver, kidney, cerebrum and cerebellum. The effects of MeHg exposure (2 mg/(kg day) of methylmercury chloride 10 ml/kg, p.o.), as well as the possible antagonist effect of diphenyl diselenide (1 and 0.4 mg/(kg day); s.c.) on body weight gain and on hepatic, cerebellar, cerebral and renal levels of thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), ascorbic acid content, mercury concentrations and activities of antioxidant enzymes (glutathione peroxidase (GPx), catalase (CAT) and superoxide dismutase (SOD)) were evaluated after 35 days of treatment. MeHg caused an increase in TBARS and decreased NPSH levels in all tissues. MeHg also induced a decrease in hepatic ascorbic acid content and in renal GPx and CAT activities. Diphenyl diselenide (1 mg/kg) conferred protection against MeHg-induced hepatic and renal lipid peroxidation and at both doses prevented the reduction in hepatic NPSH levels. Diphenyl diselenide also conferred a partial protection against MeHg-induced oxidative stress (TBARS and NPSH) in liver and cerebellum. Of particular importance, diphenyl diselenide decreased the deposition of Hg in cerebrum, cerebellum, kidney and liver. The present results indicate that diphenyl diselenide can protect against some toxic effects of MeHg in mice. This protection may be related to its antioxidant properties and its ability to reduce Hg body burden. We posit that formation of a selenol intermediate, which possesses high nucleophilicity and high affinity for MeHg, accounts for the ability of diphenyl diselenide to ameliorate Me

  11. Shark cartilage as source of antiangiogenic compounds: from basic to clinical research.

    PubMed

    González, R P; Leyva, A; Moraes, M O

    2001-10-01

    The discovery that angiogenesis is a key condition for the growth of a tumor beyond a millimeter or two, brings about a new approach in the treatment of tumors using drugs able to inhibit the formation of new blood vessels. Also, it has been realized that antiangiogenic drugs can be useful in the treatment of other pathological processes, now classified as angiogenesis-dependent diseases. Initially, cartilage was considered as a possible natural source of antiangiogenic compounds due to its known avascular nature. To date, a number of in vitro and in vivo studies have suggested the existence of antiangiogenic and antitumor compounds in bovine and shark cartilage. However, the potential usefulness of shark cartilage in the treatment of cancer and other angiogenesis-dependent diseases have not been totally accepted due to (i) unsatisfactory patient outcome in clinical trials that have used shark cartilage in cancer patients, (ii) the lack of data that correlates bioavailability with pharmacological effects using oral shark cartilage. Thus, the objective of this review is to describe the main basic and clinical investigations reported in the literature, in which the antiangiogenic and/or antitumor properties of shark cartilage or of its extracts were evaluated. Possible explanations for conflicting results are discussed as well.

  12. Product ion distributions for the reactions of NO+ with some physiologically significant volatile organosulfur and organoselenium compounds obtained using a selective reagent ionization time-of-flight mass spectrometer

    PubMed Central

    Mochalski, Paweł; Unterkofler, Karl; Španěl, Patrik; Smith, David; Amann, Anton

    2014-01-01

    RATIONALE The reactions of NO+ with volatile organic compounds (VOCs) in Selective Reagent Ionization Time-of-Flight Mass Spectrometry (SRI-TOF-MS) reactors are relatively poorly known, inhibiting their use for trace gas analysis. The rationale for this product ion distribution study was to identify the major product ions of the reactions of NO+ ions with 13 organosulfur compounds and 2 organoselenium compounds in an SRI-TOF-MS instrument and thus to prepare the way for their analysis in exhaled breath, in skin emanations and in the headspace of urine, blood and cell and bacterial cultures. METHODS Product ion distributions have been investigated by a SRI-TOF-MS instrument at an E/N in the drift tube reactor of 130 Td for both dry air and humid air (4.9% absolute humidity) used as the matrix gas. The investigated species were five monosulfides (dimethyl sulfide, ethyl methyl sulfide, methyl propyl sulfide, allyl methyl sulfide and methyl 5-methyl-2-furyl sulfide), dimethyl disulfide, dimethyl trisulfide, thiophene, 2-methylthiophene, 3-methylthiophene, methanethiol, allyl isothiocyanate, dimethyl sulfoxide, and two selenium compounds – dimethyl selenide and dimethyl diselenide. RESULTS Charge transfer was seen to be the dominant reaction mechanism in all reactions under study forming the M+ cations. For methanethiol and allyl isothiocyanate significant fractions were also observed of the stable adduct ions NO+M, formed by ion-molecule association, and [M–H]+ ions, formed by hydride ion transfer. Several other minor product channels are seen for most reactions indicating that the nascent excited intermediate (NOM)+* adduct ions partially fragment along other channels, most commonly by the elimination of neutral CH3, CH4 and/or C2H4 species that are probably bound to an NO molecule. Humidity had little effect on the product ion distributions. CONCLUSIONS The findings of this study are of particular importance for data interpretation in studies of volatile

  13. Phenolic Compounds as Antiangiogenic CMG2 Inhibitors from Costa Rican Endophytic Fungi

    PubMed Central

    Cao, Shugeng; Cryan, Lorna; Habeshian, Kaiane A.; Murillo, Catalina; Tamayo-Castillo, Giselle; Rogers, Michael S.; Clardy, Jon

    2013-01-01

    Targeting and inhibiting CMG2 (Capillary Morphogenesis Gene protein 2) represents a new strategy for therapeutic agents for cancer and retinal diseases due to CMG2’s role in blood vessel growth (angiogenesis). A high throughput FRET (Förster Resonance Energy Transfer) assay was developed for the identification of CMG2 inhibitors as anti-angiogenetic agents. Bioassay-guided separation led to the isolation and identification of two new compounds (1 and 2) from CR252M, an endophytic fungus Coccomyces proteae collected from a Costa Rican rainforest, and one known compound (3) from CR1207B (Aurapex penicillata). Secondary in vitro assays indicated anti-angiogenic activity. Compound 3 inhibited the endothelial cell migration at 52 µM, but did not show any endothelial cell antiproliferative effect at 156 µM. The structure of the two new compounds, A (1) and B (2), were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR experiments. PMID:22910038

  14. K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2

    SciTech Connect

    Pan, Chun-Hsu; Lin, Wen-Hsin; Chien, Yi-Chung; Liu, Fon-Chang; Sheu, Ming-Jyh; Kuo, Yueh-Hsiung; Wu, Chieh-Hsi

    2015-01-15

    Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G{sub 2}/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs). - Highlights: • K20E is an oxidative-coupling compound of methyl caffeate. • K20E exhibits anti-tumor and anti-angiogenesis effects. • K20E suppresses the expressions of VEGF and VEGF receptor-2 (VEGFR-2) proteins. • K20E deactivates VEGFR-2-mediated downstream signaling pathways to inhibit angiogenesis. • K20E up-regulates p53-p21 pathway to induce apoptosis and cell arrest at G2/M phase.

  15. Conversion of alkanes to organoseleniums and organotelluriums

    DOEpatents

    Periana, Roy A.; Konnick, Michael M.; Hashiguchi, Brian G.

    2016-11-29

    The invention provides processes and materials for the efficient and costeffective functionalization of alkanes and heteroalkanes, comprising contacting the alkane or heteroalkane and a soft oxidizing electrophile comprising Se(VI) or Te(VI), in an acidic medium, optionally further comprising an aprotic medium, which can be carried out at a temperature of less than 300 C. Isolation of the alkylselenium or alkyltellurium intermediate allows the subsequent conversion to products not necessarily compatible with the initial reaction conditions, such as amines, stannanes, organosulfur compounds, acyls, halocarbons, and olefins.

  16. Antiangiogenic Activity of Glycyrrhiza Extract

    NASA Astrophysics Data System (ADS)

    Li, Ying-Qiu

    The bioactivity of extract of glycyrrhiza was detected by zebrafish antiangiogenic model after 70% ethanol extract of glycyrrhiza was extracted with petroleum ether, ethyl acetate, n-butanol. The inhibition of the extracts in antiangiogenic activity showed that the highest active components existed in ethyl acetate extract of glycyrrhiza. The ethyl acetate extract of glycyrrhiza was separated by polyamide column chromatography to obtain 7 fractions (Fr1-Fr7), which Fr5 and Fr6 showed antiangiogenic activity.

  17. Chemogenesis of an Antiangiogenic Glycosaminoglycan

    PubMed Central

    2014-01-01

    In this letter we report a facile chemical conversion of heparin, a potent anticoagulant with minimal antiangiogenic activity, into an effective antiangiogenic glycosaminoglycan through optimized chemical approaches. This work highlights the potential for industrial scale production of a therapeutic anticancer glycosaminoglycan. PMID:24944736

  18. Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma.

    PubMed

    Pierpaoli, Elisa; Damiani, Elisa; Orlando, Fiorenza; Lucarini, Guendalina; Bartozzi, Beatrice; Lombardi, Paolo; Salvatore, Carmela; Geroni, Cristina; Donati, Abele; Provinciali, Mauro

    2015-10-01

    Berberine (BBR) is a natural isoquinoline alkaloid with proven antiangiogenic and anticancer activities. We recently demonstrated that BBR and its synthetic derivative 13-(4-chlorophenylethyl)berberine iodide, NAX014, exert antiproliferative activity against HER2-overexpressing breast cancer cells, inducing apoptosis, modulating the expression of cell cycle checkpoint molecules involved in cell senescence, and reducing both HER2 expression and phosphorylation on tumor cells. In this study, we examined the anticancer properties of BBR and NAX014 in a transgenic mouse model which spontaneously develops HER2-positive mammary tumors. Repeated intraperitoneal injections of a safety dose (2.5mg/kg) of NAX014 delayed the development of tumors, reducing both the number and size of tumor masses. In vivo sidestream dark field videomicroscopy revealed a significant lower vessel density in mammary tumors from NAX014-treated mice in comparison with the control group. Immunohistochemical evaluation using CD34 antibody confirmed the reduced vessel density in NAX014 group. Statistically significant increase of senescence associated β-galactosidase and p16 expression, and reduced expression of heparanase were observed in tumors from NAX014-treated mice than in tumors from control animals. Finally, NAX014 treatment decreased the level of perforine and granzyme mRNA in mammary tumors. Berberine did not show any statistically significant modulation in comparison with control mice. The results of the present study indicate that NAX014 is more effective than BBR in exerting anticancer activity delaying the development of mammary tumors in mice transgenic for the HER-2/neu oncogene. The antitumor efficacy of NAX014 is mainly related to its effect on tumor vascular network and on induction of tumor cell senescence.

  19. Synergism of peptide receptor-targeted Auger electron radiation therapy with anti-angiogenic compounds in a mouse model of neuroendocrine tumors

    PubMed Central

    2014-01-01

    Background Neuroendocrine tumors are well vascularized and express specific cell surface markers, such as somatostatin receptors and the glucagon-like peptide-1 receptor (GLP-1R). Using the Rip1Tag2 transgenic mouse model of pancreatic neuroendocrine tumors (pNET), we have investigated the potential benefit of a combination of anti-angiogenic treatment with targeted internal radiotherapy. Methods [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, a radiopeptide that selectively binds to GLP-1R expressed on insulinoma and other neuroendocrine tumor cells, was co-administered with oral vatalanib (an inhibitor of vascular endothelial growth factor receptors (VEGFR)) or imatinib (a c-kit/PDGFR inhibitor). The control groups included single-agent kinase inhibitor treatments and [Lys40(Ahx-DTPA-natIn)NH2]-exendin-4 monotherapy. For biodistribution, Rip1Tag2 mice were pre-treated with oral vatalanib or imatinib for 0, 3, 5, or 7 days at a dose of 100 mg/kg. Subsequently, [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 was administered i.v., and the biodistribution was assessed after 4 h. For therapy, the mice were injected with 1.1 MBq [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and treated with vatalanib or imatinib 100 mg/kg orally for another 7 days. Tumor volume, tumor cell apoptosis and proliferation, and microvessel density were quantified. Results Combination of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 and vatalanib was significantly more effective than single treatments (p < 0.05) and reduced the tumor volume by 97% in the absence of organ damage. The pre-treatment of mice with vatalanib led to a reduction in the tumor uptake of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4, indicating that concomitant administration of vatalanib and the radiopeptide was the best approach. Imatinib did not show a synergistic effect with [Lys40(Ahx-DTPA-111In)NH2]-exendin-4. Conclusion The combination of 1.1 MBq of [Lys40(Ahx-DTPA-111In)NH2]-exendin-4 with 100 mg/kg vatalanib had the same effect on a neuroendocrine tumor

  20. Antiangiogenic Eye Gene Therapy.

    PubMed

    Corydon, Thomas J

    2015-08-01

    The idea of treating disease in humans with genetic material was conceived over two decades ago and with that a promising journey involving development and efficacy studies in cells and animals of a large number of novel therapeutic reagents unfolded. In the footsteps of this process, successful gene therapy treatment of genetic conditions in humans has shown clear signs of efficacy. Notably, significant advancements using gene supplementation and silencing strategies have been made in the field of ocular gene therapy, thereby pinpointing ocular gene therapy as one of the compelling "actors" bringing gene therapy to the clinic. Most of all, this success has been facilitated because of (1) the fact that the eye is an effortlessly accessible, exceedingly compartmentalized, and immune-privileged organ offering a unique advantage as a gene therapy target, and (2) significant progress toward efficient, sustained transduction of cells within the retina having been achieved using nonintegrating vectors based on recombinant adeno-associated virus and nonintegrating lentivirus vectors. The results from in vivo experiments and trials suggest that treatment of inherited retinal dystrophies, ocular angiogenesis, and inflammation with gene therapy can be both safe and effective. Here, the progress of ocular gene therapy is examined with special emphasis on the potential use of RNAi- and protein-based antiangiogenic gene therapy to treat exudative age-related macular degeneration.

  1. Antiangiogenic cancer treatment: The great discovery and greater complexity (Review)

    PubMed Central

    Maj, Ewa; Papiernik, Diana; Wietrzyk, Joanna

    2016-01-01

    The discovery of tumor angiogenesis opened a new path in fighting cancer. The approval of different antiangiogenic agents, most targeting vascular endothelial growth factor (VEGF) signaling, has either increased the effectiveness of standard chemotherapy or even replaced it by offering better patient outcomes. However, an increasing number of preclinical and clinical observations have shown that the process of angiogenesis is far from clearly understood. Apart from targeting the VEGF pathway, novel strategies aim to influence other molecular factors that are involved in tumor angiogenesis. In addition, naturally occurring compounds seem to offer additional agents for influencing angiogenesis. The first concept of antiangiogenic therapy aimed to destroy tumor vessels, while it turned out that, paradoxically, antiangiogenic drugs normalized vasculature and as a result offered an improvement in chemotherapeutic delivery. In order to design an effective treatment schedule, methods for detecting the time window of normalization and biomarkers predicting patient response are needed. The initial idea that antiangiogenic therapy would be resistance-free failed to materialize and currently we still face the obstacle of resistance to antiangiogenic therapy. PMID:27826619

  2. Phosphatase inhibitors with anti-angiogenic effect in vitro.

    PubMed

    Sylvest, Lene; Bendiksen, Christine Dam; Houen, Gunnar

    2010-01-01

    Levamisole has previously been identified as an inhibitor of angiogenesis in vitro and in vivo, but the mechanism behind the anti-angiogenic behavior has not yet been established. However, one known effect of levamisole is the inhibition of alkaline phosphatase, and this fact encouraged us to test other phosphatase inhibitors for their anti-angiogenic effects by using the same method as used to identify levamisole: an ELISA-based co-culture angiogenesis assay giving quantitative and qualitative results. Historically, intracellular phosphatases have been associated with the downregulation of signaling pathways, and kinases with their upregulation, but lately, the phospatases have also been coupled to positive signaling, which is why inhibition of phosphatases has become associated with anti-tumorigenic and anti-angiogenic effects. The results obtained in this work reveal several agents with anti-angiogenic potential and give a strong indication that phosphatase inhibition is linked to anti-angiogenic activity. An apparent disruption of endothelial tube formation was seen for seven of eight phosphatase inhibitors tested in the angiogenesis assay. By looking at the morphological results, it was seen that most of the inhibitors impaired proliferation and elongation of the endothelial cells, which still had a differentiated appearance. One inhibitor, PTP inhibitor IV, seemed to impair endothelial cell differentiation and induced the same morphology as when cells were treated with levamisole, although at a 200 times lower concentration than that of levamisole. Hence, our work points out compounds with a potential that may be of use in the search for new medical products for the treatment of malignant tumors, or other conditions where angiogenesis plays a central role.

  3. [Antiangiogenic agents in ARMD treatment].

    PubMed

    Coroi, Mihaela-Cristiana; Demea, Sorina; Todor, Meda; Apopei, Emmanuela

    2012-01-01

    The aim of antiangiogenic agents in the treatment of age related senile macular degeneration is to destroy coroidian neoformation vessels by minimally affecting the central vision. We present a case of important central vision recovery after 3 intravitreal injections of Avastin. The therapeutic decision and patient monitoring have been made using imaging studies, such as OCT and AFG. A modern therapeutic approach of neovascular forms of age related macular degeneration, backed up by AFG and OCT is a modern treatment method of this disabling illness which brings patients optimal functional and structural improvement.

  4. Evaluation of the anti-angiogenic effect of aloe-emodin.

    PubMed

    Cárdenas, C; Quesada, A R; Medina, M A

    2006-12-01

    The present study identified aloe-emodin (AE, a hydroxyanthraquinone from Aloe vera and other plants) as a new anti-angiogenic compound with inhibitory effects in an in vivo angiogenesis assay and evaluates its effects on specific key steps of the angiogenic process. AE inhibits endothelial cell proliferation, but this effect is not cell specific, since AE also inhibits tumor cell proliferation. Cell migration and invasion are not remarkably affected by AE. On the other hand, AE has different effects on endothelial and tumor cell gelatinases. Two main targets of the pharmacological action of AE as an anti-angiogenic compound seem to be urokinase secretion and tubule formation of endothelial cells. Finally, AE produces a remarkable photocytotoxic effect on tumor cells. Taken together, our data indicate that AE can behave both as an anti-tumor and an anti-angiogenic compound and suggest that AE could be a candidate drug for photodynamic therapy.

  5. Chemoprevention of Prostate Cancer by Naturally Occurring and Synthetic Organoselenium Compounds

    DTIC Science & Technology

    2009-05-01

    2007. Sinha R, Facompre N, Kilheffer J, Baatz, J, Russell S, Somiari R, Richie J and El-Bayoumy K. Selenized -yeast supplementation alters serum pre...Profile of Selenized -Yeast Supplemented Healthy Men. Crossover 2006, State College, PA, October 12, 2006. Sinha R, Smith JS, Facompre N, El

  6. Chemoprevention of Prostate Cancer by Naturally Occurring and Synthetic Organoselenium Compounds

    DTIC Science & Technology

    2010-12-01

    Suppression versus induction of androgen receptor functions by the phosphatidylinositol 3-kinase/Akt pathway in prostate cancer LNCaP cells with... prostate cancer , androgen receptor, Akt, mTOR 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF... androgen independent human prostate cancer cells and 2. to determine the in vivo effects of SM and p-XSC on tumorigenesis and biomarkers of cancer ]. The

  7. Antiangiogenic therapy for breast cancer

    PubMed Central

    2010-01-01

    Angiogenesis is an important component of cancer growth, invasion and metastasis. Therefore, inhibition of angiogenesis is an attractive strategy for treatment of cancer. We describe existing clinical trials of antiangiogenic agents and the challenges facing the clinical development and optimal use of these agents for the treatment of breast cancer. Currently, the most promising approach has been the use of bevacizumab, a humanized monoclonal antibody directed against the most potent pro-angiogenic factor, vascular endothelial growth factor (VEGF). Small molecular inhibitors of VEGF tyrosine kinase activity, such as sorafenib, appear promising. While, the role of sunitinib and inhibitors of mammalian target of rapamycin (mTOR) in breast cancer has to be defined. Several unanswered questions remain, such as choice of drug(s), optimal duration of therapy and patient selection criteria. PMID:21067536

  8. Generic nitric oxide (NO) generating surface by immobilizing organoselenium species via layer-by-layer assembly.

    PubMed

    Yang, Jun; Welby, Jenna L; Meyerhoff, Mark E

    2008-09-16

    A universal nitric oxide (NO) generating surface is assembled via Layer-by-Layer (LbL) deposition of sodium alginate (Alg) and organoselenium modified polyethyleneimine (SePEI) on quartz and polymeric substrates. The immobilized SePEI species is capable of catalytically decomposing S-nitrosothiol species (RSNO) to NO in the presence of thiol reducing agents (e.g., glutathione, cysteine, etc.). The stepwise buildup of the multilayer films is monitored by UV-vis spectroscopy, SEM and surface contact angle measurements. X-ray photoelectron spectroscopy is used to study the stoichiometry between the polyanion and polycation, and also the presence of Se in the catalytic LbL film. A reductive annealing process is necessary to improve the stability of freshly coated multilayer films via chain rearrangement. Chemiluminescence measurements illustrate the ability of the LbL films to generate NO from S-nitrosoglutathione (GSNO) in the presence of glutathione (GSH). Enhanced NO fluxes can be achieved by increasing the number of catalytic (SePEI/Alg) bilayers coated on the substrates. Nitric oxide generation is observed even after prolonged contact with sheep whole blood. Preliminary applications of this LbL on silicone rubber tubings and polyurethane catheters reveal similar NO generation behavior from these biomedical grade polymeric substrates.

  9. Amperometric S-nitrosothiol sensor with enhanced sensitivity based on organoselenium catalysts.

    PubMed

    Cha, Wansik; Anderson, Meredith R; Zhang, Fenghua; Meyerhoff, Mark E

    2009-04-15

    A new S-nitrosothiol (RSNO) detection strategy based on an electrochemical sensor is described for rapidly estimating levels of total RSNOs in blood and other biological samples. The sensor employs a cellulose dialysis membrane covalently modified with an organoselenium catalyst that converts RSNOs to NO at the distal tip of an amperometric NO sensor. The sensor is characterized by very low detection limits (<20 nM), good long-term stability, and can be employed for the rapid detection of total low-molecular-weight (LMW) RSNO levels in whole blood samples using a simple standard addition method. A strategy for detecting macromolecular RSNOs is also demonstrated via use of a transnitrosation reaction with added LMW thiols allowing the estimation of total RSNO levels in blood. The sensor is shown to exhibit high selectivity over nitrosamines and nitrite. Such RSNO detection is potentially useful to reveal correlation between blood RSNO levels and endothelial cell dysfunction, which often is associated with cardiovascular diseases.

  10. [Biological activity of selenorganic compounds at heavy metal salts intoxication].

    PubMed

    Rusetskaya, N Y; Borodulin, V B

    2015-01-01

    Possible mechanisms of the antitoxic action of organoselenium compounds in heavy metal poisoning have been considered. Heavy metal toxicity associated with intensification of free radical oxidation, suppression of the antioxidant system, damage to macromolecules, mitochondria and the genetic material can cause apoptotic cell death or the development of carcinogenesis. Organic selenium compounds are effective antioxidants during heavy metal poisoning; they exhibit higher bioavailability in mammals than inorganic ones and they are able to activate antioxidant defense, bind heavy metal ions and reactive oxygen species formed during metal-induced oxidative stress. One of promising organoselenium compounds is diacetophenonyl selenide (DAPS-25), which is characterized by antioxidant and antitoxic activity, under conditions including heavy metal intoxication.

  11. Organoselenium Small Molecules and Chromium(III) Complexes for Intervention in Chronic Low-grade Inflammation and Type 2 Diabetes.

    PubMed

    Zhou, Jun; Xu, Huibi; Huang, Kaixun

    2016-01-01

    There is growing evidence to suggest that chronic, low-grade inflammation occurs in abdominal obesity, insulin resistance, type 2 diabetes mellitus and related complications, and that proinflammatory cytokines play an important role in the onset and progression of type 2 diabetes. These findings consequently provide new opportunities for the use of anti-inflammatory strategies to correct the metabolic disorders. Discovery of new synthetic bioactive small molecules to interfere with chronic, low-grade inflammation and type 2 diabetes has attracted considerable attention in medicinal chemistry. To date, a number of organoselenium small molecules and chromium(III) complexes have been shown to have the potential to alleviate chronic low-grade inflammation and type 2 diabetes, including ebselen, selenomethionine, chromium picolinate, chromium dinicocysteinate, chromium phenylalaninate, trinuclear chromium propionate, chromium histidinate, chromium nicotinate, etc. Here, we review recent advances in development of organoselenium small molecules and chromium(III) complexes to intervene in chronic low-grade inflammation and type 2 diabetes, and discuss their mode of action, potential molecular mechanisms and toxicity.

  12. Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

    PubMed Central

    Kubicka, S.; Falcone, A.; Burkholder, I.; Hacker, U. T.

    2016-01-01

    Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis. Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression. Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58). Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs. PMID:27656206

  13. A novel imaging-based high-throughput screening approach to anti-angiogenic drug discovery.

    PubMed

    Evensen, Lasse; Micklem, David R; Link, Wolfgang; Lorens, James B

    2010-01-01

    The successful progression to the clinic of angiogenesis inhibitors for cancer treatment has spurred interest in developing new classes of anti-angiogenic compounds. The resulting surge in available candidate therapeutics highlights the need for robust, high-throughput angiogenesis screening systems that adequately capture the complexity of new vessel formation while providing quantitative evaluation of the potency of these agents. Available in vitro angiogenesis assays are either cumbersome, impeding adaptation to high-throughput screening formats, or inadequately model the complex multistep process of new vessel formation. We therefore developed an organotypic endothelial-mural cell co-culture assay system that reflects several facets of angiogenesis while remaining compatible with high-throughput/high-content image screening. Co-culture of primary human endothelial cells (EC) and vascular smooth muscle cells (vSMC) results in assembly of a network of tubular endothelial structures enveloped with vascular basement membrane proteins, thus, comprising the three main components of blood vessels. Initially, EC are dependent on vSMC-derived VEGF and sensitive to clinical anti-angiogenic therapeutics. A subsequent phenotypic VEGF-switch renders EC networks resistant to anti-VEGF therapeutics, demarcating a mature vascular phenotype. Conversely, mature EC networks remain sensitive to vascular disrupting agents. Therefore, candidate anti-angiogenic compounds can be interrogated for their relative potency on immature and mature networks and classified as either vascular normalizing or vascular disrupting agents. Here, we demonstrate that the EC-vSMC co-culture assay represents a robust high-content imaging high-throughput screening system for identification of novel anti-angiogenic agents. A pilot high-throughput screening campaign was used to define informative imaging parameters and develop a follow-up dose-response scheme for hit characterization. High

  14. Antiangiogenic and anticancer molecules in cartilage.

    PubMed

    Patra, Debabrata; Sandell, Linda J

    2012-01-19

    Cartilage is one of the very few naturally occurring avascular tissues where lack of angiogenesis is the guiding principle for its structure and function. This has attracted investigators who have sought to understand the biochemical basis for its avascular nature, hypothesising that it could be used in designing therapies for treating cancer and related malignancies in humans through antiangiogenic applications. Cartilage encompasses primarily a specialised extracellular matrix synthesised by chondrocytes that is both complex and unique as a result of the myriad molecules of which it is composed. Of these components, a few such as thrombospondin-1, chondromodulin-1, the type XVIII-derived endostatin, SPARC (secreted protein acidic and rich in cysteine) and the type II collagen-derived N-terminal propeptide (PIIBNP) have demonstrated antiangiogenic or antitumour properties in vitro and in vivo preclinical trials that involve several complicated mechanisms that are not completely understood. Thrombospondin-1, endostatin and the shark-cartilage-derived Neovastat preparation have also been investigated in human clinical trials to treat several different kinds of cancers, where, despite the tremendous success seen in preclinical trials, these molecules are yet to show success as anticancer agents. This review summarises the current state-of-the-art antiangiogenic characterisation of these molecules, highlights their most promising aspects and evaluates the future of these molecules in antiangiogenic applications.

  15. Anti-Angiogenic Action of Neutral Endopeptidase

    DTIC Science & Technology

    2006-11-01

    antagonist of angiogenesis. We report that NEP is indeed antiangiogenic in vivo, significantly inhibiting angiogenesis. Surprisingly, we...Figure 6. Quantitative real time PCR analysis NEP transcripts as a function of oxygen tension in C42 and LNCaP prostate cancer cell lines cultured

  16. First Synthesis of the Antiangiogenic Homoisoflavanone, Cremastranone

    PubMed Central

    Lee, Bit; Basavarajappa, Halesha D.; Sulaiman, Rania S.; Fei, Xiang; Seo, Seung-Yong; Corson, Timothy W.

    2014-01-01

    An antiangiogenic homoisoflavanone, cremastranone, was synthesized for the first time. This scalable synthesis, which includes selective demethylation, could be used to develop lead molecules to treat angiogenesis-induced eye diseases. Synthetic cremastranone inhibited the proliferation, migration and tube formation ability of human retinal microvascular endothelial cells, important steps in pathological angiogenesis. PMID:25167470

  17. Antiangiogenic strategies in medulloblastoma: reality or mystery.

    PubMed

    Grizzi, Fabio; Weber, Christina; Di Ieva, Antonio

    2008-05-01

    Medulloblastoma is the most common malignant brain tumor of childhood. Surgery, radiation therapy, and chemotherapy successfully cure many patients, but survivors can suffer long-term toxicities affecting their neurocognitive and growth potential; furthermore, there is no curative therapy in up to 30% of cases, mainly because of our incomplete understanding of many of the underlying molecular and cellular processes. Angiogenesis is a hallmark of the progression of medulloblastoma and, over the last years, investigators have sought to develop effective and less toxic antiangiogenic strategies, including the inhibition or destruction of abnormal blood vessels using either antiangiogenic or vascular disrupting agents. However, the results are conflicting principally because of the complex biology of tumor vasculature and the irregular geometry of the vascular system in real space. In addition, current targets of antiangiogenic therapy, such as vascular endothelial growth factor (VEGF), are thought to be critical for both physiologic and pathologic angiogenesis, and clinical side effects of anti-VEGF therapy are beginning to emerge. We here review the state-of-the-art concerning antiangiogenic targets for medulloblastoma treatment, and discuss the complexity of the vascular system that intrinsically limits the efficacy of current strategies.

  18. Emerging Roles of Propolis: Antioxidant, Cardioprotective, and Antiangiogenic Actions

    PubMed Central

    Daleprane, Julio Beltrame; Abdalla, Dulcinéia Saes

    2013-01-01

    Propolis has attracted attention in recent years due to its beneficial effects, which make it a potential preventive and therapeutic agent as well as a useful additive in food and cosmetics. The aim of this review is to discuss the growing evidence that propolis may, via a diverse array of biological actions, assist in the prevention of some inflammation-mediated pathologies including cardiovascular disease. The active components of propolis that have been identified so far include polyphenols and flavonoids. These compounds have cardioprotective, vasoprotective, antioxidant, antiatherosclerotic, anti-inflammatory and antiangiogenic actions. Many studies have been undertaken to elucidate the mechanism(s) by which propolis acts, which involve cellular signaling targets and interactions at the genomic level. This review will highlight the effects of propolis that may assist in the prevention of chronic degenerative diseases, such as cardiovascular disease. PMID:23662115

  19. Radiotherapy and Antiangiogenic TM in Lung Cancer

    PubMed Central

    Khan, Mohamed K; Miller, Meredith W; Taylor, Jeremy; Gill, Navkiranjit K; Dick, Robert D; Van Golen, Kenneth; Brewer, George J; Merajver, Sofia D

    2002-01-01

    Abstract Tetrathiomolybdate (TM) is a potent nontoxic orally delivered copper complexing agent under development for the last several years for the treatment of Wilson's disease. It has been shown to block angiogenesis in primary and metastatic tumors. Therefore, the combination of cytotoxic radiotherapy (RT) and antiangiogenic TM could target both the existing tumor and the tumor microvasculature in a comprehensive strategy. Using a Lewis lung high metastatic (LLHM) carcinoma mouse tumor model, we demonstrate that the combination of TM and RT is more effective than either used as monotherapy. We also show that their therapeutic effects are additive, with no additional toxicity. We show that TM has no significant cytotoxicity in vitro against LLHM tumor cells, further supporting the antiangiogenic mechanism for its action. PMID:11896571

  20. The anti-proliferative and anti-angiogenic effect of the methanol extract from brittle star

    PubMed Central

    Baharara, Javad; Amini, Elaheh; Mousavi, Marzieh

    2015-01-01

    Background: Anti-angiogenic therapy is a crucial step in cancer treatment. The discovery of new anti-angiogenic compounds from marine organisms has become an attractive concept in anti-cancer therapy. Because little data correlated to the pro- and anti-angiogenic efficacies of Ophiuroidea, which include brittle star, the current study was designed to explore the anti-angiogenic potential of brittle star methanol extract in vitro and in vivo. Methods: The anti-proliferative effect of brittle star extract on A2780cp cells was examined by MTT assays, and transcriptional expression of VEGF and b-FGF was evaluated by RT-PCR. In an in vivo model, 40 fertilized Ross eggs were divided into control and three experimental groups. The experimental groups were incubated with brittle star extract at concentrations of 25, 50 and 100 µg/ml, and photographed by photo-stereomicroscopy. Ultimately, numbers and lengths of vessels were measured by Image J software. Data were analyzed with SPSS software (p<0.05). Results: Results illustrated that the brittle star extract exerted a dose- and time-dependent anti-proliferative effect on A2780cp cancer cells. In addition, VEGF and b-FGF expression decreased with brittle star methanol extract treatment. Macroscopic evaluations revealed significant changes in the second and third experimental group compared to controls (p<0.05). Conclusion: These finding revealed the anti-angiogenic effects of brittle star methanol extract in vitro and in vivo confer novel insight into the application of natural marine products in angiogenesis-related pathologies. PMID:26989740

  1. Recent molecular discoveries in angiogenesis and antiangiogenic therapies in cancer.

    PubMed

    Welti, Jonathan; Loges, Sonja; Dimmeler, Stefanie; Carmeliet, Peter

    2013-08-01

    Four decades ago, angiogenesis was recognized as a therapeutic target for blocking cancer growth. Because of its importance, VEGF has been at the center stage of antiangiogenic therapy. Now, several years after FDA approval of an anti-VEGF antibody as the first antiangiogenic agent, many patients with cancer and ocular neovascularization have benefited from VEGF-targeted therapy; however, this anticancer strategy is challenged by insufficient efficacy, intrinsic refractoriness, and resistance. Here, we examine recent discoveries of new mechanisms underlying angiogenesis, discuss successes and challenges of current antiangiogenic therapy, and highlight emerging antiangiogenic paradigms.

  2. Methylselenocysteine - a Promising Antiangiogenic Agent for Overcoming Drug Delivery Barriers in Solid Malignancies for Therapeutic Synergy with Anticancer Drugs

    PubMed Central

    Bhattacharya, Arup

    2011-01-01

    Introduction Despite progress, chemotherapeutic response in solid malignancies has remained limited. While initial results of the use of antiangiogenic agents in combination chemotherapy indicated an enhanced therapeutic response, recent data indicates that the surviving cancer is not only able to surmount therapy, but is actually able to adapt a more aggressive metastatic phenotype. Thus, selecting an antiangiogenic agent that is less likely to lead to tumor resurgence is a key to future therapeutic success of antiangiogenic agents, in a combinatorial setting. Areas covered Against the broad spectrum of currently used antiangiogenic agents in the clinic, the putative benefits of the use of organo selenium (Se) compounds, such as methylselenocysteine (MSC), are discussed in this reiew. Expert opinion MSC, being part of the mammalian physiology, is a well tolerated, versatile and economical antiangiogenic agent. It down regulates multiple key upstream tumor survival markers, and enhances tumor drug delivery, at a given systemic dose of an anticancer agent, while protecting normal tissue from cytotoxic adverse effects. Further clinical trials, especially in poorly differentiated cancers, are warranted. PMID:21473705

  3. Intramolecular interactions between chalcogen atoms: organoseleniums derived from 1-bromo-4-tert-butyl-2,6-di(formyl)benzene.

    PubMed

    Zade, Sanjio S; Panda, Snigdha; Singh, Harkesh B; Sunoj, Raghavan B; Butcher, Ray J

    2005-04-29

    [structure: see text] The synthesis and characterization of a series of low-valent organoselenium compounds derived from 1-bromo-4-tert-butyl-2,6-di(formyl)benzene (22) is described. The synthesis of diselenide 25 was achieved by the lithiation route whereas bis(4-tert-butyl-2,6-di(formyl)phenyl) diselenide (26) was synthesized by treating 22 with disodium diselenide. A series of monoselenides (27, 28, and 29) was obtained by facile nucleophilic substitution of bromine in 22, using the corresponding selenolates as nucleophiles. The halogenation reactions of bis(4-tert-butyl-2,6-di(formyl)phenyl) diselenide (26) did not afford the corresponding selenenyl halides but resulted in the isolation of an unexpected cyclic selenenate ester 34 as a product. The selenide 32 was synthesized by the treatment of dimethoxymethyl diselenide with trilithiated 2-bromo-5-tert-butyl-N,N'-di(phenyl)isophthalamide. The existence of potential Se...O intramolecular nonbonding interactions was examined by IR, (1)H, and (77)Se NMR spectroscopy, X-ray crystallography, and computational studies. The X-ray crystal structures of 26 and 27, having two ortho formyl groups, reveal the absence of any Se...O interactions. However, the Se...O interactions were observed in the selenenate ester 34 where one of the formyl groups has been utilized for the selenenate ring formation. The crystal structures of 26 and 27 exhibited intermolecular short-range C-H...Se interactions (hydrogen bonding). Although there are four heteroatoms in carbamoyl moieties ortho to selenium capable of forming a five-membered ring on intramolecular coordination, no such intramolecular Se...X (X = N, O) interaction was observed in the crystal structure of 32. The density functional theory calculations at the B3LYP/6-31G* level predicted that for all the diformyl systems (47a-c, 48a-c), the anti,anti conformer (when both formyl oxygen atoms point away from the selenium) is more stable. This preference was found to be reversed in

  4. Clinical trials of antiangiogenic therapy for hepatocellular carcinoma.

    PubMed

    Taketomi, Akinobu

    2016-04-01

    Angiogenesis is a promising therapeutic target to inhibit tumor growth. This review summarizes data from clinical trials of antiangiogenic agents in hepatocellular carcinoma. A systematic search of PubMed was performed to identify clinical trials of specific antiangiogenic agents in hepatocellular carcinoma treatment, particularly phase III trials involving treatment guidelines for advanced hepatocellular carcinoma. Sorafenib is the only systemic drug approved for the treatment of advanced hepatocellular carcinoma. Two large-scale, randomized phase III trials using sorafenib involving patients with unresectable HCC showed a significant survival benefit compared with placebo control groups. However, subsequent phase III trials of antiangiogenic agents in hepatocellular carcinoma have failed to improve survival compared with standard treatment protocols using sorafenib. The efficacy of antiangiogenic agents in combination with other drugs, transarterial chemoembolization, and surgical resection is currently being investigated. Future research is expected to optimize antiangiogenic therapies in combination with standard treatment with sorafenib.

  5. The effect of the presence of volatile organoselenium compounds on the determination of inorganic selenium by hydride generation.

    PubMed

    Moreno, M Eva; Pérez-Conde, Concepción; Cámara, Carmen

    2003-03-01

    As a result of microbiological activity it is possible to find dimethylselenium (DMSe) and dimethyldiselenium (DMDSe) in a wide type of environmental samples, such as soils, sediments, sewage sludges and plants where methylation can take place. Selenium determination by hydride-generation (HG) techniques requires its presence as Se(IV). Consequently, inorganic speciation by hydride generation techniques is done by first determining Se(IV) and then, after reduction of Se (VI) to Se(IV), the total selenium. Therefore, the concentration of Se (VI) is evaluated as the difference between total inorganic selenium and Se(IV). In the present work it could be demonstrated that DMSe and DMDSe are forming other volatile species by reaction with sodium borohydride, applying the same reduction condition as for inorganic selenium. These species are subsequently detected by several atomic techniques (atomic absorption AAS, atomic fluorescence AFS and inductively coupled plasma-mass spectrometry ICP-MS). The error that their presence can cause in determination of inorganic selenium has been evaluated. The magnitude of this error depends on the specific analytical detector used.The coupling of pervaporation-atomic fluorescence is proposed for the identification of these species and pervaporation-gas chromatography-atomic fluorescence for their individual quantification.

  6. Dual-targeting anti-angiogenic cyclic peptides as potential drug leads for cancer therapy

    PubMed Central

    Chan, Lai Yue; Craik, David J.; Daly, Norelle L.

    2016-01-01

    Peptide analogues derived from bioactive hormones such as somatostatin or certain growth factors have great potential as angiogenesis inhibitors for cancer applications. In an attempt to combat emerging drug resistance many FDA-approved anti-angiogenesis therapies are co-administered with cytotoxic drugs as a combination therapy to target multiple signaling pathways of cancers. However, cancer therapies often encounter limiting factors such as high toxicities and side effects. Here, we combined two anti-angiogenic epitopes that act on different pathways of angiogenesis into a single non-toxic cyclic peptide framework, namely MCoTI-II (Momordica cochinchinensis trypsin inhibitor-II), and subsequently assessed the anti-angiogenic activity of the novel compound. We hypothesized that the combination of these two epitopes would elicit a synergistic effect by targeting different angiogenesis pathways and result in improved potency, compared to that of a single epitope. This novel approach has resulted in the development of a potent, non-toxic, stable and cyclic analogue with nanomolar potency inhibition in in vitro endothelial cell migration and in vivo chorioallantoic membrane angiogenesis assays. This is the first report to use the MCoTI-II framework to develop a 2-in-1 anti-angiogenic peptide, which has the potential to be used as a form of combination therapy for targeting a wide range of cancers. PMID:27734947

  7. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM).

    PubMed

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-10-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment.

  8. Antiproliferative and Antiangiogenic Effects of Punica granatum Juice (PGJ) in Multiple Myeloma (MM)

    PubMed Central

    Tibullo, Daniele; Caporarello, Nunzia; Giallongo, Cesarina; Anfuso, Carmelina Daniela; Genovese, Claudia; Arlotta, Carmen; Puglisi, Fabrizio; Parrinello, Nunziatina L.; Bramanti, Vincenzo; Romano, Alessandra; Lupo, Gabriella; Toscano, Valeria; Avola, Roberto; Brundo, Maria Violetta; Di Raimondo, Francesco; Raccuia, Salvatore Antonio

    2016-01-01

    Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line. The aim of present investigation is to assess the antiproliferative and antiangiogenic potential of the PGJ in human multiple myeloma cell lines. Our data demonstrate the anti-proliferative potential of PGJ in MM cells; its ability to induce G0/G1 cell cycle block and its anti-angiogenic effects. Interestingly, sequential combination of bortezomib/PGJ improved the cytotoxic effect of the proteosome inhibitor. We investigated the effect of PGJ on angiogenesis and cell migration/invasion. Interestingly, we observed an inhibitory effect on the tube formation, microvessel outgrowth aorting ring and decreased cell migration and invasion as showed by wound-healing and transwell assays, respectively. Analysis of angiogenic genes expression in endothelial cells confirmed the anti-angiogenic properties of pomegranate. Therefore, PGJ administration could represent a good tool in order to identify novel therapeutic strategies for MM treatment, exploiting its anti-proliferative and anti-angiogenic effects. Finally, the present research supports the evidence that PGJ could play a key role of a future therapeutic approach for treatment of MM in order to optimize the pharmacological effect of bortezomib, especially as adjuvant after treatment. PMID:27706074

  9. Therapeutic application of anti-angiogenic nanomaterials in cancers

    NASA Astrophysics Data System (ADS)

    Mukherjee, Sudip; Patra, Chitta Ranjan

    2016-06-01

    Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the last couple of decades, scientists have been developing angiogenesis inhibitors for the treatment of cancers. However, conventional anti-angiogenic therapy has several limitations including drug resistance that can create problems for a successful therapeutic strategy. Therefore, a new comprehensive treatment strategy using antiangiogenic agents for the treatment of cancer is urgently needed. Recently researchers have been developing and designing several nanoparticles that show anti-angiogenic properties. These nanomedicines could be useful as an alternative strategy for the treatment of various cancers using anti-angiogenic therapy. In this review article, we critically focus on the potential application of anti-angiogenic nanomaterial and nanoparticle based drug/siRNA/peptide delivery systems in cancer therapeutics. We also discuss the basic and clinical perspectives of anti-angiogenesis therapy, highlighting its importance in tumor angiogenesis, current status and future prospects and challenges.Angiogenesis, the formation of new blood vessels from pre-existing vasculature, plays a vital role in physiological and pathological processes (embryonic development, wound healing, tumor growth and metastasis). The overall balance of angiogenesis inside the human body is maintained by pro- and anti-angiogenic signals. The processes by which drugs inhibit angiogenesis as well as tumor growth are called the anti-angiogenesis technique, a most promising cancer treatment strategy. Over the

  10. Anti-angiogenic peptides for cancer therapeutics

    PubMed Central

    Rosca, Elena V.; Koskimaki, Jacob E.; Rivera, Corban G.; Pandey, Niranjan B.; Tamiz, Amir P.; Popel, Aleksander S.

    2011-01-01

    Peptides have emerged as important therapeutics that are being rigorously tested in angiogenesis-dependent diseases due to their low toxicity and high specificity. Since the discovery of endogenous proteins and protein fragments that inhibit microvessel formation (thrombospondin, endostatin) several peptides have shown promise in pre-clinical and clinical studies for cancer. Peptides have been derived from thrombospondin, collagens, chemokines, coagulation cascade proteins, growth factors, and other classes of proteins and target different receptors. Here we survey recent developments for anti-angiogenic peptides with length not exceeding 50 amino acid residues that have shown activity in pre-clinical models of cancer or have been tested in clinical trials; some of the peptides have been modified and optimized, e.g., through L-to-D and non-natural amino acid substitutions. We highlight technological advances in peptide discovery and optimization including computational and bioinformatics tools and novel experimental techniques. PMID:21470139

  11. Anti-angiogenic peptides for cancer therapeutics.

    PubMed

    Rosca, Elena V; Koskimaki, Jacob E; Rivera, Corban G; Pandey, Niranjan B; Tamiz, Amir P; Popel, Aleksander S

    2011-08-01

    Peptides have emerged as important therapeutics that are being rigorously tested in angiogenesis-dependent diseases due to their low toxicity and high specificity. Since the discovery of endogenous proteins and protein fragments that inhibit microvessel formation (thrombospondin, endostatin) several peptides have shown promise in pre-clinical and clinical studies for cancer. Peptides have been derived from thrombospondin, collagens, chemokines, coagulation cascade proteins, growth factors, and other classes of proteins and target different receptors. Here we survey recent developments for anti-angiogenic peptides with length not exceeding 50 amino acid residues that have shown activity in pre-clinical models of cancer or have been tested in clinical trials; some of the peptides have been modified and optimized, e.g., through L-to-D and non-natural amino acid substitutions. We highlight technological advances in peptide discovery and optimization including computational and bioinformatics tools and novel experimental techniques.

  12. Anti-Angiogenic Properties of Cafestol and Kahweol Palmitate Diterpene Esters.

    PubMed

    Moeenfard, Marzieh; Cortez, Alice; Machado, Vera; Costa, Raquel; Luís, Carla; Coelho, Pedro; Soares, Raquel; Alves, Arminda; Borges, Nuno; Santos, Alejandro

    2016-12-01

    Epidemiological studies support the association of coffee-specific diterpenes, with various beneficial health effects. Although anti-antiangiogenic properties of free cafestol and kahweol have been recently described, available data regarding their esterified form, in particular palmitate esters as the main diterpene esters present in coffee, are still rare. Given that angiogenesis plays an important role in many pathological conditions, including cancer growth and metastasis, this study aimed to assess and compare the potential anti-angiogenic effects of cafestol palmitate (CP) and kahweol palmitate (KP) in an in vitro angiogenesis model. According to our findings, both compounds inhibited angiogenesis steps on human microvascular endothelial cells (HMVECs), although a more significant effect was observed for KP. Compared to control, HMVECs viability decreased in a dose-dependent manner upon incubation either with CP or KP. Concentrations of 75 and 100 μM of each compound were cytotoxic. Cell proliferation was also dramatically reduced by both diterpene esters at 50 μM, although KP had a stronger inhibitory effect. However, CP and KP did not induce apoptosis on HMVECs. Both compounds reduced cell migration, but this effect was only statistically significant after KP incubation. Inhibition of VEGFR2 expression and its downstream effector Akt, but not Erk, was also observed in CP- and KP-treated HMVECs. These findings were confirmed using ELISA assay for phosphorylated (active) VEGFR-2. Taken together, these data indicate that both CP and KP can be considered potent compounds against angiogenesis-dependent disorders. Our findings further indicate that KP exerts more potent anti-angiogenic effects than CP, in most of assays. J. Cell. Biochem. 117: 2748-2756, 2016. © 2016 Wiley Periodicals, Inc.

  13. The antiangiogenic agent Neovastat (AE-941) induces endothelial cell apoptosis.

    PubMed

    Boivin, Dominique; Gendron, Sébastien; Beaulieu, Edith; Gingras, Denis; Béliveau, Richard

    2002-08-01

    Neovastat (AE-941), a naturally occurring multifunctional antiangiogenic agent, has been shown to inhibit key components of the angiogenic process, including matrix metalloproteinases and vascular endothelial growth factor-mediated signaling events. In this study, we report the presence of a proapoptotic activity within this compound. Neovastat treatment of bovine aortic endothelial cells caused cell death with characteristics of apoptosis, including chromatin condensation and DNA fragmentation. Neovastat markedly induced caspase-3, caspase-8, and caspase-9 activities, at similar levels to those measured in cells treated with tumor necrosis factor-alpha. Activation of caspases by Neovastat appears to be essential for its proapoptotic effects because all apoptotic features were blocked by zVAD-fmk, a broad-spectrum caspase inhibitor. The activation of caspases was correlated with the cleavage of the nuclear substrate poly(ADP-ribose) polymerase, and by a concomitant release of cytochrome c from mitochondria to the cytoplasm. Neovastat-induced apoptosis appears to be specific to endothelial cells because treatment of other cell types such as U-87, COS-7, NIH-3T3, and SW1353 did not result in increased caspase-3 activity. These results demonstrate that Neovastat contains a proapoptotic factor that specifically induces the activation of caspases in endothelial cells and the resulting apoptosis of these cells.

  14. Sharks: a potential source of antiangiogenic factors and tumor treatments.

    PubMed

    Cho, Jung; Kim, Young

    2002-12-01

    Since angiogenesis is a key feature of tumor growth, inhibiting this process is one way to treat cancer. Cartilage is a natural source of material with strong antiangiogenic activity. This report reviews knowledge of the anticancer properties of shark cartilage and clinical information on drugs such as neovastat and squalamine. Because their entire endoskeleton is composed of cartilage, sharks are thought to be an ideal source of angiogenic and tumor growth inhibitors. Shark cartilage extract has shown antiangiogenic and antitumor activities in animals and humans. The oral administration of cartilage extract was efficacious in reducing angiogenesis. Purified antiangiogenic factors from shark cartilage, such as U-995 and neovastat (AE-941), also showed antiangiogenic and antitumor activity. AE-941 is under phase III clinical investigation. Squalamine, a low molecular weight aminosterol, showed strong antitumor activity when combined with chemotherapeutic materials. The angiogenic tissue inhibitor of metalloprotease 3 (TIMP-3) and tumor suppressor protein (snm23) genes from shark cartilage were cloned and characterized.

  15. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells

    PubMed Central

    Pinto, Mauricio P.; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H.; Owen, Gareth I.

    2016-01-01

    Tumor angiogenesis is widely recognized as one of the “hallmarks of cancer”. Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1) upregulation of compensatory/alternative pathways for angiogenesis; (2) vasculogenic mimicry; and (3) vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses. PMID:27608016

  16. Escaping Antiangiogenic Therapy: Strategies Employed by Cancer Cells.

    PubMed

    Pinto, Mauricio P; Sotomayor, Paula; Carrasco-Avino, Gonzalo; Corvalan, Alejandro H; Owen, Gareth I

    2016-09-06

    Tumor angiogenesis is widely recognized as one of the "hallmarks of cancer". Consequently, during the last decades the development and testing of commercial angiogenic inhibitors has been a central focus for both basic and clinical cancer research. While antiangiogenic drugs are now incorporated into standard clinical practice, as with all cancer therapies, tumors can eventually become resistant by employing a variety of strategies to receive nutrients and oxygen in the event of therapeutic assault. Herein, we concentrate and review in detail three of the principal mechanisms of antiangiogenic therapy escape: (1) upregulation of compensatory/alternative pathways for angiogenesis; (2) vasculogenic mimicry; and (3) vessel co-option. We suggest that an understanding of how a cancer cell adapts to antiangiogenic therapy may also parallel the mechanisms employed in the bourgeoning tumor and isolated metastatic cells delivering responsible for residual disease. Finally, we speculate on strategies to adapt antiangiogenic therapy for future clinical uses.

  17. ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling.

    PubMed

    Su, Min; Huang, Jingjia; Li, Jijia; Qin, Xiyuan; Tang, Xiaoning; Jin, Fang; Chen, Shali; Jiang, Chuanming; Zou, Zizheng; Peng, Kunjian; Nuruzzaman, Mohammed; Zhang, Jianting; Luo, Junli; Liu, Suyou; Luo, Zhiyong

    2016-04-05

    Inhibition of angiogenesis is a promising therapeutic strategy against cancer. In this study, we reported that ZLM-7, a combretastain A-4 (CA-4) derivative, exhibited anti-angiogenic activity in vitro and in vivo. In vitro, ZLM-7 induced microtubule cytoskeletal disassembly. It decreased VEGF-induced proliferation, migration, invasion and tube formation in endothelial cells, which are critical steps in angiogenesis. In vivo, ZLM-7 significantly inhibited neovascularization in a chicken chorioallantoic membrane (CAM) model and reduced the microvessel density in tumor tissues of MCF-7 xenograft mouse model. ZLM-7 also displayed comparable antiangiogenic and anti-tumor activities associated with the lead compound CA-4, but exhibited lower toxicity compared with CA-4. The anti-angiogenic effect of ZLM-7 was exerted via blockade of VEGF/VEGFR-2 signaling. ZLM-7 treatment suppressed the expression and secretion of VEGF in endothelial cells and MCF-7 cells under hypoxia. Further, ZLM-7 suppressed the VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling mediators including activated AKT, MEK and ERK in endothelial cells. Overall, these results demonstrate that ZLM-7 exhibits anti-angiogenic activities by impairing endothelial cell function and blocking VEGF/VEGFR-2 signaling, suggesting that ZLM-7 might be a potential angiogenesis inhibitor.

  18. Synthesis and biological evaluation of novel indolocarbazoles with anti-angiogenic activity.

    PubMed

    Acero, Nuria; Braña, Miguel F; Añorbe, Loreto; Domínguez, Gema; Muñoz-Mingarro, Dolores; Mitjans, Francesc; Piulats, Jaume

    2012-02-01

    A novel series of indolocarbazoles were synthesized and their antiproliferative activity against HUVEC, LoVo, DLD-1 and ST-486 cell lines, was investigated. Those staurosporine analogs in which a substituted dimethylaminoalkoxy chain was attached to the indolic nitrogen showed interesting activity and selectivity with respect to HUVEC proliferation. The effect on capillary tube formation in 3-dimensional matrigel matrix was studied using the most active compounds. Evaluation of their in vivo anti-angiogenic activity in a murine Lewis lung cancer model was also analyzed.

  19. Resveratrol and related stilbenes: their anti-aging and anti-angiogenic properties.

    PubMed

    Kasiotis, Konstantinos M; Pratsinis, Harris; Kletsas, Dimitris; Haroutounian, Serkos A

    2013-11-01

    Dietary stilbenes comprise a class of natural compounds that display significant biological activities of medicinal interest. Among them, their antioxidant, anti-aging and anti-angiogenesic properties are well established and subjects of numerous research endeavors. This mini-review aspires to account and present the literature reports published on research concerning various natural and synthetic stilbenes, such as trans-resveratrol. Special focus was given to most recent research findings, while the mechanisms underlying their anti-aging and anti-angiogenic effects as well as the respective signaling pathways involved were also presented and discussed.

  20. Tumour biology: Herceptin acts as an anti-angiogenic cocktail

    NASA Astrophysics Data System (ADS)

    Izumi, Yotaro; Xu, Lei; di Tomaso, Emmanuelle; Fukumura, Dai; Jain, Rakesh K.

    2002-03-01

    Malignant tumours secrete factors that enable them to commandeer their own blood supply (angiogenesis), and blocking the action of these factors can inhibit tumour growth. But because tumours may become resistant to treatments that target individual angiogenic factors by switching over to other angiogenic molecules, a cocktail of multiple anti-angiogenic agents should be more effective. Here we show that herceptin, a monoclonal antibody against the cell-surface receptor HER2 (for human epidermal growth factor receptor-2; ref. 4), induces normalization and regression of the vasculature in an experimental human breast tumour that overexpresses HER2 in mice, and that it works by modulating the effects of different pro- and anti-angiogenic factors. As a single agent that acts against multiple targets, herceptin, or drugs like it, may offer a simple alternative to combination anti-angiogenic treatments.

  1. Anti-Angiogenic and Anti-Inflammatory Effects of Statins: Relevance to Anti-Cancer Therapy

    PubMed Central

    Dulak, Józef; Józkowicz, Alicja

    2006-01-01

    Angiogenesis is indispensable for the growth of solid tumors and angiogenic factors are also involved in the progression of hematological malignancies. Targeting the formation of blood vessels is therefore regarded as a promising strategy in cancer therapy. Interestingly, besides demonstration of some beneficial effects of novel anti-angiogenic compounds, recent data on the activity of already available drugs point to their potential application in anti-angiogenic therapy. Among these are the statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Statins are very efficient in the treatment of hypercholesterolemia in cardiovascular disorders; however, their effects are pleiotropic and some are not directly related to the inhibition of cholesterol synthesis. Some reports particularly highlight the pro-angiogenic effects of statins, which are caused by low, nanomolar concentrations and are regarded as beneficial for the treatment of cardiovascular diseases. On the other hand, the anti-angiogenic activities, observed at micromolar concentrations of statins, may be of special significance for cancer therapy. Those effects are caused by the inhibition of both proliferation and migration and induction of apoptosis in endothelial cells. Moreover, the statin-mediated inhibition of vascular endothelial growth factor synthesis, the major angiogenic mediator, may contribute to the attenuation of angiogenesis. It has been suggested that the anti-cancer effect of statins can be potentially exploited for the cancer therapy. However, several clinical trials aimed at the inhibition of tumor growth by treatment with very high doses of statins did not provide conclusive data. Herein, the reasons for those outcomes are discussed and the rationale for further studies is presented. PMID:16375664

  2. Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.

    PubMed

    da Costa, Patrícia Marçal; da Costa, Marcilia Pinheiro; Carvalho, Adriana Andrade; Cavalcanti, Suellen Melo Tibúrcio; de Oliveira Cardoso, Marcos Veríssimo; de Oliveira Filho, Gevânio Bezerra; de Araújo Viana, Daniel; Fechine-Jamacaru, Francisco Vagnaldo; Leite, Ana Cristina Lima; de Moraes, Manoel Odorico; Pessoa, Claudia; Ferreira, Paulo Michel Pinheiro

    2015-09-05

    The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d revealed weak antiproliferative activity on HL-60, Sarcoma 180 (S180) and normal peripheral blood mononuclear cells. Thalidomide, 2a and 2b were able to inhibit tumor growth (53.5%, 67.9% and 67.4%, respectively) in S180-bearing mice and presented moderate and reversible toxicity on liver, kidneys and spleens. Both analogs (2a and 2b) inhibited cell migration of endothelial (HUVEC) and melanoma cells (MDA/MB-435) at 50μg/mL. Immunohistochemistry labeling assays with CD-31 (PECAM-1) antibody showed microvascular density (MVD) was significantly reduced in thalidomide, 2a and 2b groups (30±4.9, 64.6±1.8 and 46.5±19.5%, respectively) (p<0.05). Neovascularization evaluated by Chorioallantoic Membrane Assay (CAM) with compounds 2a and 2b showed reduction of vessels' number (12. 9±2.3 and 14.8±3.3%), neovascularization area (13.1±1.7 and 14.3±1.7%) and total length of vessels (9.2±1.5 and 9.9±1.9%). On the other hand, thalidomide did not alter vascularization parameters. Consequently, addition of thiosemicarbazone pharmacophore group into the phthalimidic ring improved the in vivo antitumor and antiangiogenic potential of the analogs 2a and 2b.

  3. Compound

    NASA Astrophysics Data System (ADS)

    Suzumura, Akitoshi; Watanabe, Masaki; Nagasako, Naoyuki; Asahi, Ryoji

    2014-06-01

    Recently, Cu-based chalcogenides such as Cu3SbSe4, Cu2Se, and Cu2SnSe3 have attracted much attention because of their high thermoelectric performance and their common feature of very low thermal conductivity. However, for practical use, materials without toxic elements such as selenium are preferable. In this paper, we report Se-free Cu3SbS4 thermoelectric material and improvement of its figure of merit ( ZT) by chemical substitutions. Substitutions of 3 at.% Ag for Cu and 2 at.% Ge for Sb lead to significant reductions in the thermal conductivity by 37% and 22%, respectively. These substitutions do not sacrifice the power factor, thus resulting in enhancement of the ZT value. The sensitivity of the thermal conductivity to chemical substitutions in these compounds is discussed in terms of the calculated phonon dispersion and previously proposed models for Cu-based chalcogenides. To improve the power factor, we optimize the hole carrier concentration by substitution of Ge for Sb, achieving a power factor of 16 μW/cm K2 at 573 K, which is better than the best reported for Se-based Cu3SbSe4 compounds.

  4. Odisolane, a Novel Oxolane Derivative, and Antiangiogenic Constituents from the Fruits of Mulberry (Morus alba L.).

    PubMed

    Lee, Seoung Rak; Park, Jun Yeon; Yu, Jae Sik; Lee, Sung Ok; Ryu, Ja-Young; Choi, Sang-Zin; Kang, Ki Sung; Yamabe, Noriko; Kim, Ki Hyun

    2016-05-18

    Mulberry, the fruit of Morus alba L., is known as an edible fruit and commonly used in Chinese medicines as a warming agent and as a sedative, tonic, laxative, odontalgic, expectorant, anthelmintic, and emetic. Systemic investigation of the chemical constituents of M. alba fruits led to the identification of a novel oxolane derivative, (R*)-2-((2S*,3R*)-tetrahydro-2-hydroxy-2-methylfuran-3-yl)propanoic acid (1), namely, odisolane, along with five known heterocyclic compounds (2-6). The structure of the new compound was elucidated on the basis of HR-MS, 1D and 2D NMR ((1)H-(1)H COSY, HSQC, HMBC, and NOESY) data analysis. Compound 1 has a novel skeleton that consists of 8 carbon units with an oxolane ring, which until now has never been identified in natural products. The isolated compounds were subjected to several activity tests to verify their biological function. Among them, compounds 1, 3, and 5 significantly inhibited cord formation in HUVECs. The action mechanism of compound 3, which had the strongest antiangiogenic activity, was mediated by decreasing VEGF, p-Akt, and p-ERK protein expression. These results suggest that compounds isolated from M. alba fruits might be beneficial in antiangiogenesis therapy for cancer treatment.

  5. Biomarkers of response and resistance to antiangiogenic therapy

    PubMed Central

    Jain, Rakesh K.; Duda, Dan G.; Willett, Christopher G.; Sahani, Dushyant V.; Zhu, Andrew X.; Loeffler, Jay S.; Batchelor, Tracy T.; Sorensen, A. Gregory

    2011-01-01

    No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I–III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured Ktrans, circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1α, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy. PMID:19483739

  6. Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent.

    PubMed

    Gingras, Denis; Nyalendo, Carine; Di Tomasso, Geneviève; Annabi, Borhane; Béliveau, Richard

    2004-07-16

    We recently reported that Neovastat, an antiangiogenic drug that is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer, may inhibit angiogenesis through an increase in tPA activity. Here, we show that Neovastat also stimulates tPA gene transcription in endothelial cells, in a TNFalpha-like manner. RT-PCR analysis and gene reporter assays using the human tPA promoter indicated that upregulation of the tPA gene transcription by both Neovastat and TNFalpha was correlated with the phosphorylation of JNK1/2 and of IkappaB and that SP600125 and BAY11-7082, inhibitors of JNK and IkappaK, respectively, inhibit the increase of tPA gene transcription induced by Neovastat and TNFalpha. These results suggest that Neovastat induces tPA gene transcription through activation of the JNK and NFkappaB signaling pathways, leading to an increase of tPA secretion by endothelial cells. This may lead to the localized destruction of the fibrin provisional matrix that is necessary for neovessel formation and thus contribute to the reported antiangiogenic properties of this compound.

  7. Apoptotic and anti-angiogenic effects of Salvia triloba extract in prostate cancer cell lines.

    PubMed

    Atmaca, Harika; Bozkurt, Emir

    2016-03-01

    Plants, due to their remarkable composition, are considered as natural resources of bioactive compounds with specific biological activities. Salvia genus (Lamiaceae) has been used around the world in complementary medicine since ancient times. We investigated the cytotoxic, apoptotic and anti-angiogenic effects of methanolic Salvia triloba extract (STE) in prostate cancer cells. Cell viability was evaluated by XTT; apoptosis was investigated by DNA fragmentation and caspase 3/7 activity assays. Changes in the angiogenic cytokine levels were investigated by human angiogenesis antibody array. Scratch assay was used to determine the cell motility. STE induced cytotoxicity and apoptosis in a concentration-dependent manner in both cancer cells; however, it was not cytotoxic to normal cells. Cell motility was reduced in PC-3, DU-145 and HUVEC cells by STE treatment. ANG, ENA-78, bFGF, EGF, IGF-1 and VEGF-D levels were significantly decreased by -2.9, -3.7, -1.7, -1.7, -2.0 and -1.8 fold in STE-treated DU-145 cells, however, ANG, IL-8, LEP, RANTES, TIMP-1, TIMP-2 and VEGF levels were significantly decreased by -5.1, -2.0, -2.4, -3.1, -1.5, -2.0 and -2.5 fold in PC-3 cells. These data suggest that STE might be a promising candidate for anti-tumor and anti-angiogenic treatment of prostate cancer.

  8. Mitochondrially Targeted α-Tocopheryl Succinate Is Antiangiogenic: Potential Benefit Against Tumor Angiogenesis but Caution Against Wound Healing

    PubMed Central

    Kluckova, Katarina; Zobalova, Renata; Goodwin, Jacob; Tilly, David; Stursa, Jan; Pecinova, Alena; Philimonenko, Anatoly; Hozak, Pavel; Banerjee, Jaideep; Ledvina, Miroslav; Sen, Chandan K.; Houstek, Josef; Coster, Mark J.

    2011-01-01

    Abstract Aims A plausible strategy to reduce tumor progress is the inhibition of angiogenesis. Therefore, agents that efficiently suppress angiogenesis can be used for tumor suppression. We tested the antiangiogenic potential of a mitochondrially targeted analog of α-tocopheryl succinate (MitoVES), a compound with high propensity to induce apoptosis. Results MitoVES was found to efficiently kill proliferating endothelial cells (ECs) but not contact-arrested ECs or ECs deficient in mitochondrial DNA, and suppressed angiogenesis in vitro by inducing accumulation of reactive oxygen species and induction of apoptosis in proliferating/angiogenic ECs. Resistance of arrested ECs was ascribed, at least in part, to the lower mitochondrial inner transmembrane potential compared with the proliferating ECs, thus resulting in the lower level of mitochondrial uptake of MitoVES. Shorter-chain homologs of MitoVES were less efficient in angiogenesis inhibition, thus suggesting a molecular mechanism of its activity. Finally, MitoVES was found to suppress HER2-positive breast carcinomas in a transgenic mouse as well as inhibit tumor angiogenesis. The antiangiogenic efficacy of MitoVES was corroborated by its inhibitory activity on wound healing in vivo. Innovation and Conclusion We conclude that MitoVES, a mitochondrially targeted analog of α-tocopheryl succinate, is an efficient antiangiogenic agent of potential clinical relevance, exerting considerably higher activity than its untargeted counterpart. MitoVES may be helpful against cancer but may compromise wound healing. Antioxid. Redox Signal. 15, 2923–2935. PMID:21902599

  9. IKKβ Regulates VEGF Expression and Is a Potential Therapeutic Target for Ovarian Cancer as an Antiangiogenic Treatment.

    PubMed

    Kinose, Yasuto; Sawada, Kenjiro; Makino, Hiroshi; Ogura, Tomonori; Mizuno, Tomoko; Suzuki, Noriko; Fujikawa, Tomoyuki; Morii, Eiichi; Nakamura, Koji; Sawada, Ikuko; Toda, Aska; Hashimoto, Kae; Isobe, Aki; Mabuchi, Seiji; Ohta, Tsuyoshi; Itai, Akiko; Morishige, Ken-ichirou; Kurachi, Hirohisa; Kimura, Tadashi

    2015-04-01

    The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer.

  10. Evading anti-angiogenic therapy: resistance to anti-angiogenic therapy in solid tumors

    PubMed Central

    Dey, Nandini; De, Pradip; Brian, Leyland-Jones

    2015-01-01

    Vascular endothelial growth factor (VEGF) dependent tumor angiogenesis is an essential step for the initiation and promotion of tumor progression. The hypothesis that VEGF-driven tumor angiogenesis is necessary and sufficient for metastatic progression of the tumor, has been the major premise of the use of anti-VEGF therapy for decades. While the success of anti-VEGF therapy in solid tumors has led to the success of knowledge-based-therapies over the past several years, failures of this therapeutic approach due to the development of inherent/acquired resistance has led to the increased understanding of VEGF-independent angiogenesis. Today, tumor-angiogenesis is not a synonymous term to VEGF-dependent function. The extensive study of VEGF-independent angiogenesis has revealed several key factors responsible for this phenomenon including the role of myeloid cells, and the contribution of entirely new phenomenon like vascular mimicry. In this review, we will present the cellular and molecular factors related to the development of anti-angiogenic resistance following anti-VEGF therapy in different solid tumors. PMID:26692917

  11. Antiangiogenic properties of cafestol, a coffee diterpene, in human umbilical vein endothelial cells

    SciTech Connect

    Wang, Shuaiyu; Yoon, Yeo Cho; Sung, Mi-Jeong; Hur, Haeng-Jeon; Park, Jae-Ho

    2012-05-11

    Highlights: Black-Right-Pointing-Pointer Cafestol inhibits tube formation and migration of VEGF-stimulated HUVEC. Black-Right-Pointing-Pointer Cafestol inhibits phosphorylation of FAK and Akt. Black-Right-Pointing-Pointer Cafestol decreases NO production. -- Abstract: As angiogenesis plays important roles in tumor growth and metastasis, searching for antiangiogenic compounds is a promising tactic for treating cancers. Cafestol, a diterpene found mainly in unfiltered coffee, provides benefit through varied biological activity, including antitumorigenic, antioxidative, and anti-inflammatory effects. This study aimed to investigate the effects of cafestol on angiogenesis and to uncover the associated mechanism. We show that cafestol inhibits angiogenesis of human umbilical vascular endothelial cells. This inhibition affects the following specific steps of the angiogenic process: proliferation, migration, and tube formation. The inhibitory effects of cafestol are accompanied by decreasing phosphorylation of FAK and Akt and by a decrease in nitric oxide production. Overall, cafestol inhibits angiogenesis by affecting the angiogenic signaling pathway.

  12. Synthesis and evaluation of antioxidant phenolic diaryl hydrazones as potent antiangiogenic agents in atherosclerosis.

    PubMed

    Vanucci-Bacqué, Corinne; Camare, Caroline; Carayon, Chantal; Bernis, Corinne; Baltas, Michel; Nègre-Salvayre, Anne; Bedos-Belval, Florence

    2016-08-15

    A series of bis-hydrazones derived from diaryl and diaryl ether hydroxybenzaldehyde frames 1 and 2 have been synthesized as potential antioxidant and antiangiogenic agents, two properties required to limit atherogenesis and cardiovascular events. These compounds were evaluated for their ability to neutralize free radical formation, to block endothelial cell-induced low-density lipoprotein oxidation (monitored by the formation of TBARS), an essential step in atherogenesis, and subsequent toxicity, to prevent angiogenesis evoked by low oxidized LDL concentration (monitored by the formation of capillary tubes on Matrigel) and to inhibit intracellular ROS increase involved in the angiogenic signaling. A structure/activity study has been carried out and finally allowed to select the phenolic diaryl ether hydralazine derivative 2a, sharing all these protective properties, as a promising hit for further development.

  13. Diterpenoids from the roots of Croton crassifolius and their anti-angiogenic activity.

    PubMed

    Wang, Jia-Jian; Chung, Hau Yin; Zhang, Yu-Bo; Li, Guo-Qiang; Li, Yao-Lan; Huang, Wei-Huan; Wang, Guo-Cai

    2016-02-01

    Six diterpenoids [crassifolin J, K, L, M, N and O] along with eleven known ones were isolated from the supercritical fluid extract (SFE) of the roots of Croton crassifolius (Euphorbiaceae). Their structures were elucidated using spectroscopic methods (IR, UV, HRESIMS, 1D and 2D NMR). The structure and stereochemistry of crassifolin J was confirmed by single-crystal X-ray diffraction analysis, and the absolute configurations of crassifolin K-M were determined by CD spectra. Twenty-three diterpenoids from this plant were screened for their anti-angiogenic activity using a wild-type zebrafish in vivo model. Four of the known compounds were active, of which penduliflaworosin possessed the best activity relative to the positive control (SU5416). Further study demonstrated that penduliflaworosin could inhibit vessel formation on Tg(fli1a:EGFP)y1-type zebrafish embryos.

  14. Neovastat--a novel antiangiogenic drug for cancer therapy.

    PubMed

    Gingras, Denis; Boivin, Dominique; Deckers, Christophe; Gendron, Sébastien; Barthomeuf, Chantal; Béliveau, Richard

    2003-02-01

    Neovastat (AE-941) is an antiangiogenic drug isolated from marine cartilage. It interferes with several steps associated with the development of angiogenesis through its ability to induce endothelial cell apoptosis, and to inhibit matrix metalloproteinase activities and vascular endothelial growth factor-mediated signaling pathways, suggesting that Neovastat behaves as a multifunctional antiangiogenic drug. Neovastat is orally bioavailable, and shows significant antitumor and antimetastatic properties in animal models. An excellent safety profile with few side effects has been monitored in more than 800 patients who have been exposed to Neovastat, some of whom for more than 4 years. This indicates that Neovastat is suitable for long-term use, either alone or in combination with other anticancer therapies. Accordingly, Neovastat is currently under evaluation in three pivotal clinical studies with two phase III clinical trials in patients with lung and renal carcinoma, and a phase II clinical trial in patients with multiple myeloma is ongoing.

  15. Current protein-based anti-angiogenic therapeutics.

    PubMed

    Chakrabarti, Sanjukta; Barrow, Colin J; Kanwar, Rupinder K; Ramana, Venkata; Kanwar, Jagat R

    2014-01-01

    Angiogenesis is a multistep process for the formation of new blood vessels. Interactions between several cellular factors including growth factors, cytokines and hematopoietic factors lead to activation of various cellular pathways finally resulting in the extracellular matrix (ECM) degradation, endothelial cell proliferation, survival and migration. Normally, angiogenesis is an essential requirement for vascular development in growing embryos as well as in adult tissues where this process depends on the intricate balance between the activities of the pro- and anti-angiogenic factors. Abnormal angiogenesis results in aberrant vasculature leading to various pathological conditions. The most important factor implicated in angiogenic processes is vascular endothelial growth factor (VEGF) and its family of ligands and receptors. Several anti-angiogenic drugs have been developed and many more are currently in different phases of clinical trials, which target various angiogenesis-inducing agents including VEGF, VEGF receptors, angiopoietins and ECM components such as integrins. Anti-angiogenic therapy can be divided into gene-based therapy and protein-based therapy. Gene-based therapies include the use of antisense oligonucleotides, siRNA, aptamers, catalytic oligonucleotides including ribozymes and DNAzymes and transcription decoys. Protein-based therapeutics includes monoclonal antibodies, peptidomimetics, fusion proteins and decoy receptors. The later class of therapeutics has several advantages over gene-based and small molecule drugs, including specificity and complexity in functions, better tolerability, less interference with normal biological processes and lesser adverse effects due to decreased immune response by virtue of being mostly body's natural proteins. This review provides a comprehensive overview of angiogenesis and on the current protein-based anti-angiogenic therapeutics under research and in the clinic.

  16. Investigations of Antiangiogenic Mechanisms Using Novel Imaging Techniques

    DTIC Science & Technology

    2011-02-01

    Wilson, “ Intravital high-resolution optical imaging of individual vessel re- sponse to photodynamic treatment,” J. Biomed. Opt. 134, 040502 2008. 7...nanoparticles ∼80–100 nm diam. 1.2 Microscope A Zeiss MPS intravital microscope was used for all imaging , using a 2.5X objective. A DAPI excitation filter...Jan 2011 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER BC083195 Investigation of Antiangiogenic Mechanisms Using Novel Imaging Techniques 5b

  17. Comparison of anti-angiogenic properties of pristine carbon nanoparticles

    PubMed Central

    2013-01-01

    Angiogenesis is vital for tumour formation, development and metastasis. Recent reports show that carbon nanomaterials inhibit various angiogenic signalling pathways and, therefore, can be potentially used in anti-angiogenic therapy. In the present study, we compared the effect of different carbon nanomaterials on blood vessel development. Diamond nanoparticles, graphite nanoparticles, graphene nanosheets, multi-wall nanotubes and C60 fullerenes were evaluated for their angiogenic activities using the in ovo chick embryo chorioallantoic membrane model. Diamond nanoparticles and multi-wall nanotubes showed the greatest anti-angiogenic properties. Interestingly, fullerene exhibited the opposite effect, increasing blood vessel development, while graphite nanoparticles and graphene had no effect. Subsequently, protein levels of pro-angiogenic growth factor receptors were analysed, showing that diamond nanoparticles decreased the expression of vascular endothelial growth factor receptor. These results provide new insights into the biological activity of carbon nanomaterials and emphasise the potential use of multi-wall nanotubes and diamond nanoparticles in anti-angiogenic tumour therapy. PMID:23618362

  18. Comparison of anti-angiogenic properties of pristine carbon nanoparticles

    NASA Astrophysics Data System (ADS)

    Wierzbicki, Mateusz; Sawosz, Ewa; Grodzik, Marta; Prasek, Marta; Jaworski, Slawomir; Chwalibog, André

    2013-04-01

    Angiogenesis is vital for tumour formation, development and metastasis. Recent reports show that carbon nanomaterials inhibit various angiogenic signalling pathways and, therefore, can be potentially used in anti-angiogenic therapy. In the present study, we compared the effect of different carbon nanomaterials on blood vessel development. Diamond nanoparticles, graphite nanoparticles, graphene nanosheets, multi-wall nanotubes and C60 fullerenes were evaluated for their angiogenic activities using the in ovo chick embryo chorioallantoic membrane model. Diamond nanoparticles and multi-wall nanotubes showed the greatest anti-angiogenic properties. Interestingly, fullerene exhibited the opposite effect, increasing blood vessel development, while graphite nanoparticles and graphene had no effect. Subsequently, protein levels of pro-angiogenic growth factor receptors were analysed, showing that diamond nanoparticles decreased the expression of vascular endothelial growth factor receptor. These results provide new insights into the biological activity of carbon nanomaterials and emphasise the potential use of multi-wall nanotubes and diamond nanoparticles in anti-angiogenic tumour therapy.

  19. Antiangiogenic (metronomic) chemotherapy for brain tumors: current and future perspectives.

    PubMed

    Samuel, David P; Wen, Patrick Y; Kieran, Mark W

    2009-07-01

    Significant advances in the diagnosis and treatment of brain tumors have been made through better imaging, surgical techniques and advances in radiation therapy. However, the cure rate for most adult and pediatric brain tumor patients has not mirrored this success. Angiogenesis, the development of neovascularization, provides the required nutrients and oxygen to an expanding tumor and is controlled by a complex balance of proangiogenic cytokines and antiangiogenic factors. A series of new inhibitors of angiogenesis are now in clinical trials. Most of these rely on inhibiting tumor cell-mediated cytokines or blocking the activation of their cognate receptors. Cytotoxic chemotherapy, by contrast, targets dividing cells but can be modulated to attack dividing endothelial cells. This review will focus on the use of low-dose antiangiogenic (also called metronomic) chemotherapy to inhibit endothelial cell function and resultant neovascularization in the treatment of adult and pediatric brain tumors. By examining the biology and preclinical findings that led to the development of antiangiogenic/metronomic chemotherapy, clinical studies have been undertaken that support the role of this approach in the clinic, and have led to the introduction of a number of markers being used to better predict active combinations and appropriate patient populations.

  20. Circulating Carbonic Anhydrase IX and Antiangiogenic Therapy in Breast Cancer

    PubMed Central

    Brown-Glaberman, Ursa; Marron, Marilyn; Chalasani, Pavani; Livingston, Robert; Iannone, Maria; Specht, Jennifer; Stopeck, Alison T.

    2016-01-01

    Introduction. Carbonic anhydrase IX (CAIX) is a hypoxia regulated metalloenzyme integral to maintaining cellular pH. Increased CAIX expression is associated with poor prognosis in breast cancer. To explore CAIX as a biomarker for breast cancer therapies, we measured plasma CAIX levels in healthy control subjects and in breast cancer patients. Methods. In control subjects we evaluated plasma CAIX stability via commercially available ELISA. We then similarly quantified plasma CAIX levels in (1) locally advanced breast cancer (LABC) patients treated with neoadjuvant paclitaxel + sunitinib (T + S) followed by doxorubicin and cyclophosphamide (AC); (2) metastatic breast cancer (MBC) patients treated with systemic chemotherapy. Results. Plasma CAIX levels were stable at room temperature for at least 48 hours in control subjects. Mean baseline plasma CAIX levels were lower in controls compared to patients with LABC or MBC. In LABC, CAIX levels rose significantly in response to administration of antiangiogenic therapy (T + S) (p = 0.02) but not AC (p = 0.37). In patients with MBC treated without an antiangiogenic agent CAIX levels did not change with therapy. Conclusions. Our results suggest that CAIX may be an easily obtained, stable measure of tumor associated hypoxia as well as a useful pharmacodynamic biomarker for antiangiogenic therapy. PMID:26941473

  1. In vitro and ex vivo antiangiogenic activity of Salvia officinalis.

    PubMed

    Keshavarz, Maryam; Mostafaie, Ali; Mansouri, Kamran; Bidmeshkipour, Ali; Motlagh, Hamid Reza Mohammadi; Parvaneh, Shahram

    2010-10-01

    Angiogenesis is a key process in the promotion of cancer and its metastasis. Herein, the antiangiogenic activity of Salvia officinalis extract and its fractions was investigated. S. officinalis aerial parts were extracted with ethanol and its successive hexane, ethyl acetate, n-butanol and aqueous fractions were evaluated for their antiangiogenic activities using human umbilical vein endothelial cells (HUVEC) capillary tube formation and rat aorta models in a three-dimensional collagen matrix. Furthermore, antimigrative effects of the fractions were assessed using a wound healing model. The ethanol extract of S. officinalis (ESO) potently inhibited capillary tube formation in HUVEC and rat aorta models of angiogenesis, and its hexane fraction (HSO) exerted the highest inhibitory effect. In addition, the ethanol extract of S. officinalis and its hexane fraction showed a dose-dependent inhibitory activity on the migration of the endothelial cells in the wound healing model. Furthermore, ESO inhibited endothelial cell proliferation at 50-200 μg/mL in a dose-dependent manner. These findings indicated some new pharmacological activities of S. officinalis such as antiangiogenic in vitro and ex vivo, and antimigrative activity in vitro. Therefore, S. officinalis could be a candidate as a useful herb with therapeutic or preventive activity against angiogenesis related disorders.

  2. Screening the antiangiogenic activity of medicinal plants grown and sold in Jordan.

    PubMed

    Zihlif, Malek; Afifi, Fatma; Muhtaseb, Ruba; Al-Khatib, Sondos; Abaza, Ismail; Naffa, Randa

    2012-02-01

    Angiogenesis is essential for the growth, invasion, and metastasis of most solid tumors and has become a valuable pharmacological target for cancer prevention and treatment. This study was performed to assess the antiangiogenic activity of 31 medicinal plants grown and sold in Jordan. The antiangiogenic activity was assessed using the rat aortic ring assay. Out of 31 extracts, 15 extracts showed more than 50 % inhibition of the blood vessels outgrowth from the primary tissue explants (p = 0.000). Three of these 15 extracts showed a potential cytotoxic effect on normal fibroblast cells. Four extracts shared antiangiogenic and antiproliferative activity towards MCF7 breast cancer cell lines. Eight extracts demonstrated selective antiangiogenic activity. This is the first report demonstrating the potential antiangiogenic activity of Artemisia judaica, Aloysia citriodora, Salvia egyptiaca, and Calendula arvensis. Some extracts with antiangiogenic activity exhibited selectivity against the endothelial cells proliferation, demonstrating a direct inhibitory activity against the key step in tumor angiogenesis.

  3. Leads for development of new naphthalenesulfonate derivatives with enhanced antiangiogenic activity: crystal structure of acidic fibroblast growth factor in complex with 5-amino-2-naphthalene sulfonate.

    PubMed

    Fernández-Tornero, Carlos; Lozano, Rosa M; Redondo-Horcajo, Mariano; Gómez, Ana M; López, José C; Quesada, Ernesto; Uriel, Clara; Valverde, Serafín; Cuevas, Pedro; Romero, Antonio; Giménez-Gallego, Guillermo

    2003-06-13

    Inhibition of angiogenesis-promoting factors such as fibroblast growth factors is considered to be a potential procedure for inhibiting solid tumor growth. Although several peptide-based inhibitors are currently under study, the development of antiangiogenic compounds of small molecular size is a pharmacological goal of considerable interest. We have already shown that certain naphthalene sulfonates constitute minimal functional substitutes of the antiangiogenic compounds of the suramin and suradista family. Using those data as a lead, we have carried out a rational search for new angiogenesis inhibitors that could provide new pharmacological insights for the development of antiangiogenic treatments. The results of the study strongly underline the relevance of the stereochemistry for an efficient inhibition of acidic fibroblast growth factor mitogenic activity by the naphthalene sulfonate family and allow us to formulate rules to aid in searching for new inhibitors and pharmaceutical developments. To provide further leads for such developments and acquire a detailed insight into the basis of the inhibitory activity of the naphthalene sulfonate derivatives, we solved the three-dimensional structure of acidic fibroblast growth factor complexed to 5-amino-2-naphthalenesulfonate, the most pharmacologically promising of the identified inhibitors. The structure shows that binding of this compound would hamper the interaction of acidic fibroblast growth factor with the different components of the cell membrane mitogenesis-triggering complex.

  4. Synthetic stigmasterol derivatives inhibit capillary tube formation, herpetic corneal neovascularization and tumor induced angiogenesis: Antiangiogenic stigmasterol derivatives.

    PubMed

    Michelini, Flavia M; Lombardi, María Gabriela; Bueno, Carlos A; Berra, Alejandro; Sales, María Elena; Alché, Laura E

    2016-11-01

    Angiogenesis plays a critical role in initiating and promoting several diseases, such as cancer and herpetic stromal keratitis (HSK). Herein, we studied the inhibitory effect of two synthetic stigmasterol derivatives on capillary tube-like structures and on cell migration in human umbilical vein endothelial cells (HUVEC): (22S,23S)-22,23-dihydroxystigmast-4-en-3-one (compound 1) and (22S,23S)-3β-bromo-5α,22,23-trihydroxystigmastan-6-one (compound 2). We also studied their effect on VEGF expression in IL-6 stimulated macrophages and in LMM3 breast cancer cells. Furthermore, we investigated the antiangiogenic activity of the compounds on corneal neovascularization in the murine model of HSK and in an experimental model of tumor-induced angiogenesis in mice. Both compounds inhibited capillary tube-like formation, but only compound 1 restrained cell migration. Compound 1, unlike compound 2, was able to reduce VEGF expression. Only compound 1 not only reduced the incidence and severity of corneal neovascularization, when administered at the onset of HSK, but it also restrained the development of neovascular response induced by tumor cells in mice skin. Our results show that compound 1 inhibits angiogenesis in vitro and in vivo. Therefore, compound 1 would be a promising drug in the treatment of those diseases where angiogenesis represents one of the main pathogenic events.

  5. Targeting CD9 produces stimulus-independent antiangiogenic effects predominantly in activated endothelial cells during angiogenesis: A novel antiangiogenic therapy

    SciTech Connect

    Kamisasanuki, Taro; Tokushige, Saori; Terasaki, Hiroto; Khai, Ngin Cin; Wang, Yuqing; Sakamoto, Taiji; Kosai, Ken-ichiro

    2011-09-16

    Highlights: {yields} CD9 plays stimulus-independent roles in angiogenesis in vitro and in vivo. {yields} Targeting CD9 expression is effective in an angiogenic disease model. {yields} Targeting CD9 expression predominantly affects activated endothelial cells. {yields} CD9 is involved in endothelial cell proliferation, but not survival. {yields} CD9 is part of angiogenic machinery in endothelial cells during angiogenesis. -- Abstract: The precise roles of tetraspanin CD9 are unclear. Here we show that CD9 plays a stimulus-independent role in angiogenesis and that inhibiting CD9 expression or function is a potential antiangiogenic therapy. Knocking down CD9 expression significantly inhibited in vitro endothelial cell migration and invasion induced by vascular endothelial growth factor (VEGF) or hepatocyte growth factor (HGF). Injecting CD9-specific small interfering RNA (siRNA-CD9) markedly inhibited HGF- or VEGF-induced subconjunctival angiogenesis in vivo. Both results revealed potent and stimulus-independent antiangiogenic effects of targeting CD9. Furthermore, intravitreous injections of siRNA-CD9 or anti-CD9 antibodies were therapeutically effective for laser-induced retinal and choroidal neovascularization in mice, a representative ocular angiogenic disease model. In terms of the mechanism, growth factor receptor and downstream signaling activation were not affected, whereas abnormal localization of integrins and membrane type-1 matrix metalloproteinase was observed during angiogenesis, by knocking down CD9 expression. Notably, knocking down CD9 expression did not induce death and mildly inhibited proliferation of quiescent endothelial cells under conditions without an angiogenic stimulus. Thus, CD9 does not directly affect growth factor-induced signal transduction, which is required in angiogenesis and normal vasculature, but is part of the angiogenesis machinery in endothelial cells during angiogenesis. In conclusion, targeting CD9 produced stimulus

  6. The antiangiogenic and antinociceptive activities of n-propyl gallate.

    PubMed

    Jung, H-J; Lim, C-J

    2011-10-01

    n-Propyl gallate dose-dependently displayed an inhibitory effect on chick chorioallantoic membrane (CAM) angiogenesis. It markedly increased the endostatin level in both isolated CAM tissues and human umbilical vein endothelial cells (HUVECs). n-Propyl gallate was also able to enhance the endostatin mRNA level in HUVECs. Antinociceptive activity of n-propyl gallate was assessed using an acetic acid-induced writhing test in mice. In brief, n-propyl gallate possesses antiangiogenic activity via up-regulation of endostatin.

  7. Targetable Polymer - Antiangiogenic Drug Conjugates for Systemic Breast Cancer Therapy

    DTIC Science & Technology

    2005-09-01

    1.7FL G-Fu_ Legends: HPMA= N-(2-hydroxypropyl) methacrylamide, G=Glycine, F=Phenylalanine, L= Leucine , Fu=Fumagillol, M,=weight average molecular...CM. The anti-angiogenic agent fumagillin covalently binds and inhibits the methionine aminopeptidase , MetAP-2. Proc NatlAcad Sci USA. 1997; 94(12...covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase . Proc Natl Acad Sci USA. 1998; 95(21): 12153-7

  8. Vertebrate embryos as tools for anti-angiogenic drug screening and function.

    PubMed

    Beedie, Shaunna L; Diamond, Alexandra J; Fraga, Lucas Rosa; Figg, William D; Vargesson, Neil

    2016-11-22

    The development of new angiogenic inhibitors highlights a need for robust screening assays that adequately capture the complexity of vessel formation, and allow for the quantitative evaluation of the teratogenicity of new anti-angiogenic agents. This review discusses the use of screening assays in vertebrate embryos, specifically focusing upon chicken and zebrafish embryos, for the detection of anti-angiogenic agents.

  9. Evaluation of Antioxidant and Antiangiogenic Properties of Caesalpinia Echinata Extracts

    PubMed Central

    da Silva Gomes, Elisangela Christhianne Barbosa; Jimenez, George Chaves; da Silva, Luis Claudio Nascimento; de Sá, Fabrício Bezerra; de Souza, Karen Pena Cavalcanti; Paiva, Gerson S.; de Souza, Ivone Antônia

    2014-01-01

    Natural products contain important combinations of ingredients, which may to some extent help to modulate the effects produced by oxidation substrates in biological systems. It is known that substances capable of modulating the action of these oxidants on tissue may be important allies in the control of neovascularization in pathological processes. The aim of this study was to evaluate the antioxidant and antiangiogenic properties of an ethanol extract of Caesalpinia echinata. The evaluation of antioxidant properties was tested using two methods (DPPH inhibition and sequestration of nitric oxide). The antiangiogenic properties were evaluated using the inflammatory angiogenesis model in the corneas of rats. The extract of C. echinata demonstrated a high capacity to inhibit free radicals, with IC50 equal to 42.404 µg/mL for the DPPH test and 234.2 µg/mL for nitric oxide. Moreover, it showed itself capable of inhibiting the inflammatory angiogenic response by 77.49%. These data suggest that biochemical components belonging to the extract of C. echinata interfere in mechanisms that control the angiogenic process, mediated by substrates belonging to the arachidonic acid cascade, although the data described above also suggest that the NO buffer may contribute to some extent to the reduction in the angiogenic response. PMID:24563668

  10. Anti-angiogenic therapies for advanced esophago-gastric cancer

    PubMed Central

    Fontana, Elisa; Sclafani, Francesco; Cunningham, David

    2014-01-01

    Neo-vascularization is a vital process for tumor growth and development which involves the interaction between tumor cells and stromal endothelial cells through several growth factors and membranous receptors which ultimately activate pro-angiogenic intracellular signaling pathways. Inhibition of angiogenesis has become a standard treatment option for several tumor types including colorectal cancer, glioblastoma and ovarian cancer. In gastric cancer, the therapeutic role of anti-angiogenic agents is more controversial. Bevacizumab and ramucirumab, two monoclonal antibodies, which target vascular endothelial growth factor-A and vascular endothelial growth factor receptor-2, respectively, have been demonstrated antitumor activity in patients with tumors of the stomach or esophagogastric junction. However, especially for bevacizumab, this antitumor activity has not consistently translated into a survival advantage over standard treatment in randomized trials. In this article, we provide an overview of the role of angiogenesis in gastric cancer and discuss the results of clinical trials that investigated safety and effectiveness of antiangiogenic therapies in this disease. A review of the literature has been done using PubMed, ClinicalTrials.gov website and the ASCO Annual Meeting Library. PMID:25538401

  11. Novel approaches in anti-angiogenic treatment targeting endothelial F-actin: a new anti-angiogenic strategy?

    PubMed

    Thoenes, Lilja; Günther, Michael

    2008-12-01

    As a functional blood supply is crucial for growth of solid tumors, the development of anticancer agents to inhibit the formation of new tumor blood vessels is an area of extensive research. Endothelial cell motility driven by the dynamics of the cytoskeleton is a key feature of angiogenesis. Agents that preferentially target endothelial tubulin are well established, and inhibition of the endothelial actin dynamics appears to be another promising anti-angiogenic strategy. Remodeling of the actin cytoskeleton is regulated by several pathways involving a large number of signaling proteins. Therefore, therapeutic strategies for the modulation of actin dynamics include agents that target the actin cytoskeleton directly, as well as inhibitors of actin binding proteins and regulators in upstream pathways. This review provides an overview of the regulation of the actin cytoskeleton and proteins that could potentially be targeted by therapeutic agents. In addition, an outline of promising agents, which includes recombinant proteins, endogenous effectors and treatment regimes that exert anti-angiogenic effects partly mediated by affecting endothelial actin dynamics is provided.

  12. Anti-carcinogenic and anti-angiogenic properties of the extracts of Acorus calamus on gastric cancer cells

    PubMed Central

    Rahamooz Haghighi, Samaneh; Asadi, Malek Hossein; Akrami, Hassan; Baghizadeh, Amin

    2017-01-01

    Objective: Acorus calamus (A. calamus) has been used as a medicinal plant in Asia for its effects on digestive system for the last 2000 years. To investigate the anti-cancer activity of rhizome of A. calamus, the ethanolic and methanolic extracts and essential oil of the rhizome were prepared and their effects were assessed on human gastric cancer cell line (AGS). Materials and Methods: The viability of cells which were treated with the extracts and the essential oil was assessed by MTT assay. To evaluate the anti-angiogenic property of the extracts, in vitro tube formation assay was done. Cell cycle distribution and the expression of Oct4 and Nucleostemin, after treatments, were checked by flowcytometry and quantitative RT-PCR, respectively. Furthermore, analysis of essential oil from A.calamus was done by GC-MS. Results: Our results showed that the growth of AGS cells was inhibited by the extracts and essential oil and the extracts inhibited the angiogenesis in HUVEC cells. Our data revealed that the extracts and essential oil of A. calamus caused G1 arrest in AGS cells and downregulation of Oct4 and NS after treatment. By GC-MS analysis, we found new compounds such as epiprezizaene, valencene and isocyclocitral in essential oil of A. Conclusion: All together, our results showed that the extracts of A. calamus have anti-proliferative and anti-angiogenic effects on cancer cells. PMID:28348970

  13. Contrasting responses of non-small cell lung cancer to antiangiogenic therapies depend on histological subtype

    PubMed Central

    Larrayoz, Marta; Pio, Ruben; Pajares, María J; Zudaire, Isabel; Ajona, Daniel; Casanovas, Oriol; Montuenga, Luis M; Agorreta, Jackeline

    2014-01-01

    The vascular endothelial growth factor (VEGF) pathway is a clinically validated antiangiogenic target for non-small cell lung cancer (NSCLC). However, some contradictory results have been reported on the biological effects of antiangiogenic drugs. In order to evaluate the efficacy of these drugs in NSCLC histological subtypes, we analyzed the anticancer effect of two anti-VEGFR2 therapies (sunitinib and DC101) in chemically induced mouse models and tumorgrafts of lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC). Antiangiogenic treatments induced vascular trimming in both histological subtypes. In ADC tumors, vascular trimming was accompanied by tumor stabilization. In contrast, in SCC tumors, antiangiogenic therapy was associated with disease progression and induction of tumor proliferation. Moreover, in SCC, anti-VEGFR2 therapies increased the expression of stem cell markers such as aldehyde dehydrogenase 1A1, CD133, and CD15, independently of intratumoral hypoxia. In vitro studies with ADC cell lines revealed that antiangiogenic treatments reduced pAKT and pERK signaling and inhibited proliferation, while in SCC-derived cell lines the same treatments increased pAKT and pERK, and induced survival. In conclusion, this study evaluates for the first time the effect of antiangiogenic drugs in lung SCC murine models in vivo and sheds light on the contradictory results of antiangiogenic therapies in NSCLC. PMID:24500694

  14. Impact of Absolute Stereochemistry on the Antiangiogenic and Antifungal Activities of Itraconazole

    PubMed Central

    2010-01-01

    Itraconazole is used clinically as an antifungal agent and has recently been shown to possess antiangiogenic acitivity. Itraconazole has three chiral centers that give rise to eight stereoisomers. The complete role of stereochemistry in the two activities of itraconazole, however, has not been addressed adequately. For the first time, all eight stereoisomers of itraconazole (1a−h) have been synthesized and evaluated for activity against human endothelial cell proliferation and for antifungal activity against five fungal strains. Distinct antiangiogenic and antifungal activity profiles of the trans stereoisomers, especially 1e and 1f, suggest different molecular mechanisms underlying the antiangiogenic and antifungal activities of itraconazole. PMID:21892383

  15. Antiangiogenic Agents in Combination with Chemotherapy in Patients with Advanced Non-Small Cell Lung Cancer

    PubMed Central

    Ulahannan, Susanna V; Brahmer, Julie R

    2011-01-01

    Most patients with non-small cell lung cancer (NSCLC) present with advanced disease requiring systemic chemotherapy. Treatment with the antiangiogenic agent bevacizumab in combination with standard platinum-based doublet chemotherapy has been shown to improve outcomes in patients with advanced NSCLC. Several multitargeted antiangiogenic tyrosine kinase inhibitors (e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, and axitinib) are also being evaluated in combination with standard chemotherapy. Here we review current clinical data with combination therapy involving antiangiogenic agents and cytotoxic chemotherapy in patients with advanced NSCLC. PMID:21469981

  16. Antiangiogenic Therapy for Glioblastoma: Current Status and Future Prospects

    PubMed Central

    Batchelor, Tracy T.; Reardon, David A.; de Groot, John F.; Wick, Wolfgang; Weller, Michael

    2014-01-01

    Glioblastoma is characterized by high expression levels of pro-angiogenic cytokines and microvascular proliferation, highlighting the potential value of treatments targeting angiogenesis. Antiangiogenic treatment likely achieves a beneficial impact through multiple mechanisms of action. Ultimately, however, alternative pro-angiogenic signal transduction pathways are activated leading to the development of resistance, even in tumors that initially respond. The identification of biomarkers or imaging parameters to predict response and to herald resistance is of high priority. Despite promising phase 2 clinical trial results and patient benefit in terms of clinical improvement and longer progression-free survival, an overall survival benefit has not been demonstrated in 4 randomized phase 3 trials of bevacizumab or cilengitide in newly diagnosed glioblastoma or cediranib or enzastaurin recurrent glioblastoma. However, future studies are warranted: predictive markers may allow appropriate patient enrichment, combination with chemotherapy may ultimately prove successful in improving overall survival, and novel agents targeting multiple pro-angiogenic pathways may prove effective. PMID:25398844

  17. Gastrointestinal Toxicities With Combined Antiangiogenic and Stereotactic Body Radiation Therapy

    SciTech Connect

    Pollom, Erqi L.; Deng, Lei; Pai, Reetesh K.; Brown, J. Martin; Giaccia, Amato; Loo, Billy W.; Shultz, David B.; Le, Quynh Thu; Koong, Albert C.; Chang, Daniel T.

    2015-07-01

    Combining the latest targeted biologic agents with the most advanced radiation technologies has been an exciting development in the treatment of cancer patients. Stereotactic body radiation therapy (SBRT) is an ablative radiation approach that has become established for the treatment of a variety of malignancies, and it has been increasingly used in combination with biologic agents, including those targeting angiogenesis-specific pathways. Multiple reports have emerged describing unanticipated toxicities arising from the combination of SBRT and angiogenesis-targeting agents, particularly of late luminal gastrointestinal toxicities. In this review, we summarize the literature describing these toxicities, explore the biological mechanism of action of toxicity with the combined use of antiangiogenic therapies, and discuss areas of future research, so that this combination of treatment modalities can continue to be used in broader clinical contexts.

  18. Anti-angiogenic and cytotoxicity studies of some medicinal plants.

    PubMed

    Ng, Kwok-Wen; Salhimi, Salizawati Muhamad; Majid, Amin Malik; Chan, Kit-Lam

    2010-06-01

    Angiogenesis plays an important role in tumor formation and proliferation. The development of anti-angiogenic agents to block new blood vessel growth will inhibit metastasis and induce apoptosis of the cancer cells. Nine medicinal plants, Strobilanthes crispus, Phyllanthus niruri, Phyllanthus pulcher, Phyllanthus urinaria, Ailanthus malabarica, Irvingia malayana, Smilax myosotiflora, Tinospora crispa and blumea balsamifera were screened for anti-angiogenic properties using the rat aortic ring assay. Of these, the methanol extracts of Phyllanthus species and Irvingia malayana exhibited the highest activity. At 100 microg/mL, P. pulcher, P. niruri, P. urinaria and I. malayana recorded an inhibition of 78.8 %, 59.5 %, 56.7 % and 46.4 %, respectively, against rat aortic vascular growth. Their activities were further investigated by the tube formation assay involving human umbilical vein endothelial cells (HUVEC) on Matrigel. I. malayana, P. niruri and P. urinaria showed a significant decrease of 45.5, 37.9 and 35.6 %, respectively, whilst P. pulcher showed a much lower decrease of 15.5 % when compared with that of the rat aortic ring assay. All the plant extracts were evaluated for cytotoxicity on a panel of human cancer cell lines using the MTT assay. None of them displayed acute cytotoxicity. The HPLC of P. niruri, P. urinaria and P. pulcher indicated the extracts contained some identical chromatographic peaks of lignans. Further fractionation of I. malayana yielded betulinic acid reported in this plant for the first time and at 100 microg/mL it exhibited a 67.3 % inhibition of vessel outgrowth and 46.5 % inhibition of tube formation.

  19. Anti-angiogenic actions of the mangosteen polyphenolic xanthone derivative α-mangostin

    PubMed Central

    Jittiporn, Kanjana; Suwanpradid, Jutamas; Patel, Chintan; Rojas, Modesto; Thirawarapan, Suwan; Moongkarndi, Primchanien; Suvitayavat, Wisuda; Caldwell, Ruth B.

    2014-01-01

    Retinal neovascularization is a major cause of vision loss in diseases characterized by retinal ischemia and is characterized by the pathological growth of abnormal vessels. Vascular Endothelial Growth Factor (VEGF) is known to play an important role in this process. Oxidative stress has been strongly implicated in up regulation of VEGF associated with neovascularization in various tissues. Hence, compounds with anti-oxidant actions can prevent neovascularization. α-mangostin, a component of mangosteen (Garcinia mangostana Linn), has been shown to have an anti-oxidant property in pathological conditions involving angiogenesis such as cancer. However, the effect of α-mangostin on ROS formation and angiogenic function in microvascular endothelial cells has not been studied. Hence, this study demonstrated the anti-angiogenic effects of α-mangostin in relation to ROS formation in bovine retinal endothelial cells (REC). α-mangostin significantly and dose-dependently reduced formation of ROS in hypoxia-treated REC. α-mangostin also significantly and dose-dependently suppressed VEGF-induced increases in permeability, proliferation, migration and tube formation in REC and blocked angiogenic sprouting in the ex vivo aortic ring assay. In addition, α-mangostin inhibited VEGF-induced phosphorylation of VEGFR2 and ERK1/2-MAPK. According to our results, α-mangostin reduces oxidative stress and limits VEGF-induced angiogenesis through a process involving abrogation of VEGFR2 and ERK1/2-MAPK activation. PMID:24721607

  20. Identification and biological activities of a new antiangiogenic small molecule that suppresses mitochondrial reactive oxygen species

    SciTech Connect

    Kim, Ki Hyun; Park, Ju Yeol; Jung, Hye Jin; Kwon, Ho Jeong

    2011-01-07

    Research highlights: {yields} YCG063 was screened as a new angiogenesis inhibitor which suppresses mitochondrial ROS generation in a phenotypic cell-based screening of a small molecule-focused library. {yields} The compound inhibited in vitro and in vivo angiogenesis in a dose-dependent manner. {yields} This new small molecule tool will provide a basis for a better understanding of angiogenesis driven under hypoxic conditions. -- Abstract: Mitochondrial reactive oxygen species (ROS) are associated with multiple cellular functions such as cell proliferation, differentiation, and apoptosis. In particular, high levels of mitochondrial ROS in hypoxic cells regulate many angiogenesis-related diseases, including cancer and ischemic disorders. Here we report a new angiogenesis inhibitor, YCG063, which suppressed mitochondrial ROS generation in a phenotypic cell-based screening of a small molecule-focused library with an ArrayScan HCS reader. YCG063 suppressed mitochondrial ROS generation under a hypoxic condition in a dose-dependent manner, leading to the inhibition of in vitro angiogenic tube formation and chemoinvasion as well as in vivo angiogenesis of the chorioallantoic membrane (CAM) at non-toxic doses. In addition, YCG063 decreased the expression levels of HIF-1{alpha} and its target gene, VEGF. Collectively, a new antiangiogenic small molecule that suppresses mitochondrial ROS was identified. This new small molecule tool will provide a basis for a better understanding of angiogenesis driven under hypoxic conditions.

  1. New insights into the antiangiogenic and proangiogenic properties of dietary polyphenols.

    PubMed

    Diniz, Carmen; Suliburska, Joanna; Ferreira, Isabel M P L V O

    2016-12-16

    Polyphenols can be found in natural products of plant origin, including vegetables, fruits, and beverages. A large number of these plant origin compounds are an integral part of the human diet and in the past decade evidence has shown their beneficial properties in human health, by acting in several cell signaling pathways. Among other beneficial effects, polyphenols have been associated with angiogenesis. Increasing evidence highlighting the ability of dietary polyphenols to influence angiogenesis by interfering with multiple signaling pathways is debated. Particular emphasis is given to the mechanisms that ultimately may induce the formation of capillary-like structures (by increasing endothelial cell proliferation, migration, and invasion) or, conversely, may inhibit the steps of angiogenesis leading to the inhibition/regress of vascular development. Dietary polyphenols can, therefore, be viewed as promising nutraceuticals but important aspects have still to be further investigated, to deep knowledge concerning their concentration-mediated effects, effect of specific polyphenols, and respective metabolites, to ensure their appropriate and effective usefulness as proangiogenic or antiangiogenic nutraceuticals.

  2. FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

    PubMed Central

    Haemmerle, Monika; Bottsford-Miller, Justin; Pradeep, Sunila; Taylor, Morgan L.; Hansen, Jean M.; Dalton, Heather J.; Stone, Rebecca L.; Cho, Min Soon; Nick, Alpa M.; Nagaraja, Archana S.; Gutschner, Tony; Gharpure, Kshipra M.; Mangala, Lingegowda S.; Han, Hee Dong; Zand, Behrouz; Armaiz-Pena, Guillermo N.; Wu, Sherry Y.; Pecot, Chad V.; Burns, Alan R.; Lopez-Berestein, Gabriel; Afshar-Kharghan, Vahid; Sood, Anil K.

    2016-01-01

    Recent studies in patients with ovarian cancer suggest that tumor growth may be accelerated following cessation of antiangiogenesis therapy; however, the underlying mechanisms are not well understood. In this study, we aimed to compare the effects of therapy withdrawal to those of continuous treatment with various antiangiogenic agents. Cessation of therapy with pazopanib, bevacizumab, and the human and murine anti-VEGF antibody B20 was associated with substantial tumor growth in mouse models of ovarian cancer. Increased tumor growth was accompanied by tumor hypoxia, increased tumor angiogenesis, and vascular leakage. Moreover, we found hypoxia-induced ADP production and platelet infiltration into tumors after withdrawal of antiangiogenic therapy, and lowering platelet counts markedly inhibited tumor rebound after withdrawal of antiangiogenic therapy. Focal adhesion kinase (FAK) in platelets regulated their migration into the tumor microenvironment, and FAK-deficient platelets completely prevented the rebound tumor growth. Additionally, combined therapy with a FAK inhibitor and the antiangiogenic agents pazopanib and bevacizumab reduced tumor growth and inhibited negative effects following withdrawal of antiangiogenic therapy. In summary, these results suggest that FAK may be a unique target in situations in which antiangiogenic agents are withdrawn, and dual targeting of FAK and VEGF could have therapeutic implications for ovarian cancer management. PMID:27064283

  3. Angiostatin regulates the expression of antiangiogenic and proapoptotic pathways via targeted inhibition of mitochondrial proteins

    PubMed Central

    Lee, Tong-Young; Muschal, Stefan; Pravda, Elke A.; Folkman, Judah; Abdollahi, Amir

    2009-01-01

    Angiostatin, a proteolytic fragment of plasminogen, is a potent endogenous antiangiogenic agent. The molecular mechanisms governing angiostatin's antiangiogenic and antitumor effects are not well understood. Here, we report the identification of mitochondrial compartment as the ultimate target of angiostatin. After internalization of angiostatin into the cell, at least 2 proteins within the mitochondria bind this molecule: malate dehydrogenase, a member of Krebs cycle, and adenosine triphosphate synthase. In vitro and in vivo studies revealed differential regulation of key prosurvival and angiogenesis-related proteins in angiostatin-treated tumors and tumor-endothelium. Angiostatin induced apoptosis via down-regulation of mitochondrial BCL-2. Angiostatin treatment led to down-regulation of c-Myc and elevated levels of another key antiangiogenic protein, thrombospondin-1, reinforcing its antitumor and antiangiogenic effects. Further evidence is provided for reduced recruitment and infiltration of bone marrow–derived macrophages in angiostatin-treated tumors. The observed effects of angiostatin were restricted to the tumor site and were not observed in other major organs of the mice, indicating unique tumor specific bioavailability. Together, our data suggest mitochondria as a novel target for antiangiogenic therapy and provide mechanistic insights to the antiangiogenic and antitumor effects of angiostatin. PMID:19465692

  4. Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer

    PubMed Central

    Mahner, Sven; Woelber, Linn; Mueller, Volkmar; Witzel, Isabell; Prieske, Katharina; Grimm, Donata; Keller-v Amsberg, Gunhild; Trillsch, Fabian

    2015-01-01

    In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated. PMID:26500886

  5. Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds

    PubMed Central

    Ebrahim, Hassan Y.; El Sayed, Khalid A.

    2016-01-01

    Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly’s Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds. PMID:26978377

  6. Discovery of Novel Antiangiogenic Marine Natural Product Scaffolds.

    PubMed

    Ebrahim, Hassan Y; El Sayed, Khalid A

    2016-03-11

    Marine natural products (MNPs) are recognized for their structural complexity, diversity, and novelty. The vast majority of MNPs are pharmacologically relevant through their ability to modulate macromolecular targets underlying human diseases. Angiogenesis is a fundamental process in cancer progression and metastasis. Targeting angiogenesis through selective modulation of linked protein kinases is a valid strategy to discover novel effective tumor growth and metastasis inhibitors. An in-house marine natural products mini-library, which comprises diverse MNP entities, was submitted to the Lilly's Open Innovation Drug Discovery platform. Accepted structures were subjected to in vitro screening to discover mechanistically novel angiogenesis inhibitors. Active hits were subjected to additional angiogenesis-targeted kinase profiling. Some natural and semisynthetic MNPs, including multiple members of the macrolide latrunculins, the macrocyclic oxaquinolizidine alkaloid araguspongine C, and the sesquiterpene quinone puupehenone, showed promising results in primary and secondary angiogenesis screening modules. These hits inhibited vascular endothelial growth factor (VEGF)-mediated endothelial tube-like formation, with minimal cytotoxicity at relevant doses. Secondary kinase profiling identified six target protein kinases, all involved in angiogenesis signaling pathways. Molecular modeling and docking experiments aided the understanding of molecular binding interactions, identification of pharmacophoric epitopes, and deriving structure-activity relationships of active hits. Marine natural products are prolific resources for the discovery of chemically and mechanistically unique selective antiangiogenic scaffolds.

  7. Advances in antiangiogenic treatment of small-cell lung cancer

    PubMed Central

    Lu, Hongyang; Jiang, Zhiming

    2017-01-01

    Small-cell lung cancer (SCLC), a poorly differentiated neuroendocrine malignancy, has a rapid growth rate, strong aggressiveness, early metastases, and poor prognosis. Angiogenesis greatly contributes to the metastatic process of SCLC, which has a higher vascularization compared with non-small-cell lung cancer (NSCLC). SCLC might constitute an ideal malignancy for assessing new antiangiogenic drugs and therapeutic strategies. Combining bevacizumab with paclitaxel has therapeutic benefits in chemoresistant, relapsed SCLC. The cisplatin–etoposide and bevacizumab combination, as the first-line treatment for extensive-stage SCLC, can improve progression-free survival (PFS), with an acceptable toxicity profile. Ziv-aflibercept combined with topotecan is promising for platinum-refractory SCLC. Chemotherapy combined with thalidomide cannot prolong survival. Maintenance sunitinib of 37.5 mg/day in extensive-stage SCLC patients following induction chemotherapy with platinum/etoposide improves median PFS by 1.6 months. Serum angiopoietin-2 concentrations and vascular endothelial growth factor levels correlate with poor prognosis. Bevacizumab, ziv-aflibercept, and sunitinib are worthy of further evaluation. Thalidomide, sorafenib, pomalidomide, and cediranib may not be suitable for SCLC. PMID:28138259

  8. Antiangiogenic factors and maternal hemodynamics during intensive hemodialysis in pregnancy.

    PubMed

    Cornelis, Tom; Spaanderman, Marc; Beerenhout, Charles; Perschel, Frank H; Verlohren, Stefan; Schalkwijk, Casper G; van der Sande, Frank M; Kooman, Jeroen P; Hladunewich, Michelle

    2013-10-01

    We report on a 21-year-old pregnant patient with IgA nephropathy who was initiated on intensive hemodialysis (8 hours of hemodialysis 3 times a week) at a gestational age of 26 weeks on the basis of worsening kidney function resulting in rapidly progressive fatigue and difficulties in metabolic control. Throughout the pregnancy, and while on intensive hemodialysis, 24-hour ambulatory blood pressure control was within the target, and results of weekly 24-hour measurement of central hemodynamics and pulse wave velocity, and of serial levels of circulating (anti-)angiogenic factors were comparable to normal pregnancies. Estimated fetal growth evolved along the 50th percentile, and no polyhydramnios was detected. After induction for a sudden, unexplained increase in blood pressure, she delivered a healthy boy of 2480 g at a gestational age of 36 weeks. This case adds to the expanding literature that supports the use of intensive hemodialysis in pregnant patients with end-stage renal disease and illustrates, for the first time, the potential use of serial (anti-) angiogenic factors and 24-hour measurements of blood pressure and hemodynamic indices in order to facilitate monitoring of these complicated patients.

  9. The role of antiangiogenic agents in the treatment of gastric cancer

    PubMed Central

    Lei, Xuefen; Wang, Feng; Ke, Yang; Wei, Dong; Gu, Hou; Zhang, Zhixian; Jiang, Lifeng; Lv, Li; Lin, Jie; Wang, Lin

    2017-01-01

    Abstract Background: The survival of advanced gastric cancer (GC) is dismal, and effects of antiangiogenic agents remain inconclusive. The purpose of this study is to assess combination of chemotherapy with antiangiogenic therapy versus traditional chemotherapy. Methods: To achieve the goal of scientific rigor, statistics from both referenced works and experiments were analyzed. We carefully searched for the referenced works by retrieving, as well as analyzing, literature databases for information on antiangiogenic therapy compared to other therapeutic approaches used to treat GC patients. Two groups were defined in the experiment: experimental and control groups. The experimental group was treated with antiangiogenic drug, and the control group was treated with standard chemotherapy or placebo. Results: The study included a total of 3240 participants. Overall, there was significant improvement in overall survival (hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.67–0.91, P = 0.002), progression-free survival (HR 0.65, 95% CI: 0.52–0.81, P = 0.0002), objective response rate (risk ratio [RR] = 1.58, 95% CI: 1.33–1.88, P < 0.00001), and disease control rate (RR 2.44, 95% CI: 1.57–3.78, P < 0.0001) in the group with antiangiogenic drug versus the group with standard chemotherapy or placebo. Moreover, this new treatment approach showed tolerable toxicity. Conclusion: This study confirms the superior efficacy of combination therapy with antiangiogenic agents in comparison to traditional chemotherapy regimens for patients with GC. Moreover, this new treatment approach showed tolerable toxicity. This meta-analysis provides important information for clinicians who are interested in using antiangiogenic therapies to treat GC patients. PMID:28272258

  10. Induction of the fibrinolytic system by cartilage extract mediates its antiangiogenic effect in mouse glioma.

    PubMed

    Simard, Bryan; Bouamrani, Ali; Jourdes, Peggy; Pernod, Gilles; Dimitriadou, Violetta; Berger, François

    2011-07-01

    Both the antiangiogenic and antitumoral activity of shark cartilage extracts (SCE) have been demonstrated in animal models and clinical trials. Studies reported that SCE induces the expression of tissue plasminogen activator gene (PLAT) in endothelial cells and increases the activity of the protein (t-PA) in vitro. The aim of this study was to demonstrate the crucial role of t-PA induction in the antiangiogenic and antitumor activity of SCE in experimental glioma. This study showed antiangiogenic and antitumoral effects of SCE in three mice glioma models (C6, HGD and GL26). Histological examination suggested perivascular proteolysis and edema as well as important intratumoral necrosis, which artefactually increased the tumor volume at high doses. Thus, the antiangiogenic effect of SCE correlated with the presence of t-PA and angiostatin in degenerating vessels. Functional in vivo experiments were conducted to modulate the plasminogen pathway. No antiangiogenic effect was observed on tumors overexpressing the plasminogen activator inhibitor-1 (PAI-1). Moreover, therapeutical effects were neutralized in mice that were cotreated with ε-aminocaproic acid (EACA, 120 mg/kg p.o.), an inhibitor that blocks the high-affinity lysine binding sites of both plasminogen and plasmin. In contrast, cotreatment with N-acetylcysteine (NAC, 7,5mg/kg i.p.), a sulfhydril donor that reduces plasmin into angiostatin or other antiangiogenic fragments, increased the benefit of SCE on mice survival. In subcutaneous models, NAC prevented the increase in tumor volume caused by high doses of cartilage extract. In conclusion, this study indicates that induction of t-PA by shark cartilage extract plays an essential role in its antiangiogenic activity, but that control of excessive proteolysis by a plasmin reductor could prevent edema and uncover the full benefit of shark cartilage extract in the treatment of intracranial tumors.

  11. Independent anti-angiogenic capacities of coagulation factors X and Xa.

    PubMed

    Lange, Soledad; Gonzalez, Ibeth; Pinto, Mauricio P; Arce, Maximiliano; Valenzuela, Rodrigo; Aranda, Evelyn; Elliot, Matias; Alvarez, Marjorie; Henriquez, Soledad; Velasquez, Ethel V; Orge, Felipe; Oliva, Barbara; Gonzalez, Pamela; Villalon, Manuel; Cautivo, Kelly M; Kalergis, Alexis M; Pereira, Karla; Mendoza, Camila; Saez, Claudia; Kato, Sumie; Cuello, Mauricio A; Parborell, Fernanda; Irusta, Griselda; Palma, Veronica; Allende, Miguel L; Owen, Gareth I

    2014-11-01

    Knockout models have shown that the coagulation system has a role in vascular development and angiogenesis. Herein, we report for the first time that zymogen FX and its active form (FXa) possess anti-angiogenic properties. Both the recombinant FX and FXa inhibit angiogenesis in vitro using endothelial EA.hy926 and human umbilical cord vascular endothelial cells (HUVEC). This effect is dependent on the Gla domain of FX. We demonstrate that FX and FXa use different mechanisms: the use of Rivaroxaban (RX) a specific inhibitor of FXa attenuated its anti-angiogenic properties but did not modify the anti-angiogenic effect of FX. Furthermore, only the anti-angiogenic activity of FXa is PAR-1dependent. Using in vivo models, we show that FX and FXa are anti-angiogenic in the zebrafish intersegmental vasculature (ISV) formation and in the chick embryo chorioallantoic membrane (CAM) assays. Our results provide further evidence for the non-hemostatic functions of FX and FXa and demonstrate for the first time a biological role for the zymogen FX.

  12. Assessment of anti-angiogenic and anti-tumoral potentials of Origanum onites L. essential oil.

    PubMed

    Bostancıoğlu, Rakibe Beklem; Kürkçüoğlu, Mine; Başer, Kemal Hüsnü Can; Koparal, Ayşe Tansu

    2012-06-01

    Medicinal plants and culinary herbs with anti-angiogenic and little toxicity properties have gained importance. Non-toxic anti-angiogenic phytochemicals are useful in combating cancer by preventing the formation of new blood vessels to support the tumor growth. We have investigated the essential oil of Origanum onites L. (OOEO), for a possible anti-angiogenic activity. OOEO was analyzed by gas chromatography (GC) and gas chromatography-mass spectrometry (GC/MS). The anti-proliferative activities (by MTT assay, 3-(4,5-dimethyl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide), anti-angiogenic activities (by tube formation assay), cell migration inhibiting capability (migration assay) and apoptotic potential (DAPI staining) of OOEO were evaluated on rat adipose tissue endothelial cells (RATECs) and 5RP7 (c-H-ras transformed rat embryonic fibroblasts) cells. Our results revealed that OOEO could markedly inhibit cell viability and induced apoptosis of 5RP7 cells and also could block in vitro tube formation and migration of RATEC. These results imply that OOEO having anti-angiogenic activity might be useful in preventing angiogenesis-related diseases and in combating cancer.

  13. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality

    PubMed Central

    McIntyre, Alan; Harris, Adrian L

    2015-01-01

    Anti-angiogenic therapy has increased the progression-free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table1). Many mechanisms of resistance to anti-VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti-angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia-inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre-clinical studies combining anti-angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti-angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre-clinical and clinical studies that have potential for producing synthetic lethality in combination with anti-angiogenic therapy as a future therapeutic strategy. PMID:25700172

  14. Hemorrhagic events in Hepatocellular Carcinoma patients treated with anti-angiogenic therapies

    PubMed Central

    Duffy, Austin; Wilkerson, Julia; Greten, Tim F.

    2012-01-01

    Background The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with anti-angiogenic agents. Patients and Methods We performed a systematic review and meta-analysis of anti-angiogenic studies in HCC from 1995 to 2011. For non-randomized studies we compared bleeding risk with other HCC single-arm studies which did not include an anti-angiogenic agent. To separate disease-specific factors we also performed a comparison analysis with renal cancer studies which evaluated sorafenib. Results Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (OR 1.77; 95% CI 1.04, 3.0) but not grade 3–5 events in both HCC and RCC ((OR1.46 95% CI 0.9, 2.36 [p=0.45]). When comparing the risk of bleeding in single-arm phase 2 studies evaluating anti-angiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. Conclusions This analysis of both randomized and non-randomized studies evaluating an anti-angiogenic agent in HCC showed that whilst the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower grade events and similar in magnitude to the risk encountered in RCC. PMID:23112096

  15. Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits

    PubMed Central

    Verheul, H M W; Panigrahy, D; Yuan, J; D'Amato, R J

    1999-01-01

    Neovascularization facilitates tumour growth and metastasis formation. In our laboratory, we attempt to identify clinically available oral efficacious drugs for antiangiogenic activity. Here, we report which non-steroidal anti-inflammatory drugs (NSAIDs) can inhibit corneal neovascularization, induced by basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF). This antiangiogenic activity may contribute to the known effects of NSAIDs on gastric ulcers, polyps and tumours. We found that sulindac was one of the most potent antiangiogenic NSAIDs, inhibiting bFGF-induced neovascularization by 50% and VEGF-induced neovascularization by 55%. Previously, we reported that thalidomide inhibited growth factor-induced corneal neovascularization. When we combined sulindac with thalidomide, we found a significantly increased inhibition of bFGF- or VEGF-induced corneal neovascularization (by 63% or 74% respectively) compared with either agent alone (P< 0.01). Because of this strong antiangiogenic effect, we tested the oral combination of thalidomide and sulindac for its ability to inhibit the growth of V2 carcinoma in rabbits. Oral treatment of thalidomide or sulindac alone inhibited tumour growth by 55% and 35% respectively. When given together, the growth of the V2 carcinoma was inhibited by 75%. Our results indicated that oral antiangiogenic combination therapy with thalidomide and sulindac may be a useful non-toxic treatment for cancer. © 1999 Cancer Research Campaign PMID:10408702

  16. Antiangiogenic Effects of Noscapine Enhance Radioresponse for GL261 Tumors

    SciTech Connect

    Newcomb, Elizabeth W. Lukyanov, Yevgeniy; Alonso-Basanta, Michelle; Esencay, Min; Smirnova, Iva; Schnee, Tona; Shao Yongzhao; Devitt, Mary Louise; Zagzag, David; McBride, William; Formenti, Silvia C.

    2008-08-01

    Purpose: To assess the effects of noscapine, a tubulin-binding drug, in combination with radiation in a murine glioma model. Methods and Materials: The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation, or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation, tumors were resected and immunostained to measure proliferation rate, apoptosis, and angiogenic activity. Results: Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, and 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, and a decrease in tumor vessel density compared with tumors treated with radiation alone. Conclusion: Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation, resulting in a significant tumor growth delay. An antiangiogenic mechanism contributed to the effect. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug.

  17. Antiangiogenic and Antitumor Effects of Src Inhibition in Ovarian Carcinoma

    PubMed Central

    Han, Liz Y.; Landen, Charles N.; Trevino, Jose G.; Halder, Jyotsnabaran; Lin, Yvonne G.; Kamat, Aparna A.; Kim, Tae-Jin; Merritt, William M.; Coleman, Robert L.; Gershenson, David M.; Shakespeare, William C.; Wang, Yihan; Sundaramoorth, Raji; Metcalf, Chester A.; Dalgarno, David C.; Sawyer, Tomi K.; Gallick, Gary E.; Sood, Anil K.

    2011-01-01

    Src, a nonreceptor tyrosine kinase, is a key mediator for multiple signaling pathways that regulate critical cellular functions and is often aberrantly activated in a number of solid tumors, including ovarian carcinoma. The purpose of this study was to determine the role of activated Src inhibition on tumor growth in an orthotopic murine model of ovarian carcinoma. In vitro studies on HeyA8 and SKOV3ip1 cell lines revealed that Src inhibition by the Src-selective inhibitor, AP23846, occurred within 1 hour and responded in a dose-dependent manner. Furthermore, Src inhibition enhanced the cytotoxicity of docetaxel in both chemosensitive and chemoresistant ovarian cancer cell lines, HeyA8 and HeyA8-MDR, respectively. In vivo, Src inhibition by AP23994, an orally bioavailable analogue of AP23846, significantly decreased tumor burden in HeyA8 (P = 0.02), SKOV3ip1 (P = 0.01), as well as HeyA8-MDR (P < 0.03) relative to the untreated controls. However, the greatest effect on tumor reduction was observed in combination therapy with docetaxel (P < 0.001, P = 0.002, and P = 0.01, for the above models, respectively). Proliferating cell nuclear antigen staining showed that Src inhibition alone (P = 0.02) and in combination with docetaxel (P = 0.007) significantly reduced tumor proliferation. In addition, Src inhibition alone and in combination with docetaxel significantly down-regulated tumoral production of vascular endothelial growth factor and interleukin 8, whereas combination therapy decreased the microvessel density (P = 0.02) and significantly affected vascular permeability (P < 0.05). In summary, Src inhibition with AP23994 has potent antiangiogenic effects and significantly reduces tumor burden in preclinical ovarian cancer models. Thus, Src inhibition may be an attractive therapeutic approach for patients with ovarian carcinoma. PMID:16951177

  18. ENMD-2076 is an orally active kinase inhibitor with antiangiogenic and antiproliferative mechanisms of action.

    PubMed

    Fletcher, Graham C; Brokx, Richard D; Denny, Trisha A; Hembrough, Todd A; Plum, Stacy M; Fogler, William E; Sidor, Carolyn F; Bray, Mark R

    2011-01-01

    ENMD-2076 is a novel orally active, small molecule kinase inhibitor with a mechanism of action involving several pathways key to tumor growth and survival: angiogenesis, proliferation, and the cell cycle. ENMD-2076 has selective activity against the mitotic kinase Aurora A, as well as kinases involved in angiogenesis (VEGFRs, FGFRs). ENMD-2076 inhibited the growth in vitro of a wide range of human solid tumor and hematopoietic cancer cell lines with IC(50) values ranging from 0.025 to 0.7 μmol/L. ENMD-2076 was also shown to induce regression or complete inhibition of tumor growth in vivo at well-tolerated doses in tumor xenograft models derived from breast, colon, melanoma, leukemia, and multiple myeloma cell lines. Pharmacodynamic experiments in vivo showed that in addition to inhibiting Aurora A, single doses of ENMD-2076 had sustained inhibitory effects on the activation of Flt3 as well as the angiogenic tyrosine kinases, VEGFR2/KDR and FGFR1 and 2. ENMD-2076 was shown to prevent the formation of new blood vessels and regress formed vessels in vivo at doses equivalent to those that gave substantial activity in tumor xenograft models. These results indicate that ENMD-2076 is a well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic/antiproliferative profile and provides strong preclinical support for use as a therapeutic for human cancers. Several phase 1 studies involving ENMD-2076 have been recently completed, and the compound is currently being evaluated in a phase 2 clinical trial in patients with platinum-resistant ovarian cancer.

  19. The antiangiogenic activities of ethanolic crude extracts of four Salvia species

    PubMed Central

    2013-01-01

    Background Angiogenesis is one of cancer hallmarks that are required for both cancer progression and metastasis. In this study we examined the antiangiogenic properties of the ethanolic crude extracts of four Salvia species grown in Jordan. Methods The direct antiangiogenic activity was evaluated using various models: ex vivo rat aortic ring assay, in vitro assessment of HUVEC proliferation and migration, and in vivo CAM assay, while we used the changes in the expression of HIF-1α and VEGF in breast cancer cells (MCF 7) as an indicative for the indirect antiangiogenic activity. Results All four crude extracts showed a potential antiangiogenic activity in the rat aortic assay, however two species were found to be cytotoxic against Fibroblast cell line (PLF); the finding that caused the exclusion of these two extracts from further studies. Of the two remaining extracts, S. triloba showed very promising direct and indirect antiangiogenic activities. S. triloba inhibited the HUVEC proliferation with an IC50 of 90 μg/mL and HUVEC migration by 82% at 150 μg/mL. Furthermore, the in vivo CAM assay also illustrated the high impact of S. triloba against the newly formed vessel in the chicken embryonic membrane. Interestingly, the S. triloba inhibited the expression of VEGF at the mRNA and protein and the HIF-1α mRNA in the MCF 7 breast cancer cells under both normoxic and hypoxic conditions. Conclusions Taken together, all these findings of the direct and indirect angiogenic investigations nominated S. triloba as a highly potent antiangiogenic plant that may have chemotherapeutic and/or chemoprevention potentials. PMID:24330494

  20. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies

    PubMed Central

    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-01-01

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development. PMID:26956051

  1. Biomarkers of evasive resistance predict disease progression in cancer patients treated with antiangiogenic therapies.

    PubMed

    Pircher, Andreas; Jöhrer, Karin; Kocher, Florian; Steiner, Normann; Graziadei, Ivo; Heidegger, Isabel; Pichler, Renate; Leonhartsberger, Nicolai; Kremser, Christian; Kern, Johann; Untergasser, Gerold; Gunsilius, Eberhard; Hilbe, Wolfgang

    2016-04-12

    Numerous antiangiogenic agents are approved for the treatment of oncological diseases. However, almost all patients develop evasive resistance mechanisms against antiangiogenic therapies. Currently no predictive biomarker for therapy resistance or response has been established. Therefore, the aim of our study was to identify biomarkers predicting the development of therapy resistance in patients with hepatocellular cancer (n = 11), renal cell cancer (n = 7) and non-small cell lung cancer (n = 2). Thereby we measured levels of angiogenic growth factors, tumor perfusion, circulating endothelial cells (CEC), circulating endothelial progenitor cells (CEP) and tumor endothelial markers (TEM) in patients during the course of therapy with antiangiogenic agents, and correlated them with the time to antiangiogenic progression (aTTP). Importantly, at disease progression, we observed an increase of proangiogenic factors, upregulation of CEC/CEP levels and downregulation of TEMs, such as Robo4 and endothelial cell-specific chemotaxis regulator (ECSCR), reflecting the formation of torturous tumor vessels. Increased TEM expression levels tended to correlate with prolonged aTTP (ECSCR high = 275 days vs. ECSCR low = 92.5 days; p = 0.07 and for Robo4 high = 387 days vs. Robo4 low = 90.0 days; p = 0.08). This indicates that loss of vascular stabilization factors aggravates the development of antiangiogenic resistance. Thus, our observations confirm that CEP/CEC populations, proangiogenic cytokines and TEMs contribute to evasive resistance in antiangiogenic treated patients. Higher TEM expression during disease progression may have clinical and pathophysiological implications, however, validation of our results is warranted for further biomarker development.

  2. AE-941, a multifunctional antiangiogenic compound: trials in renal cell carcinoma.

    PubMed

    Bukowski, Ronald M

    2003-08-01

    The therapy of renal cell carcinoma remains a challenge for medical oncologists and urologists. During the past 10 years, the molecular abnormalities occurring in various subtypes of renal cancer, such as clear cell renal carcinoma, have been well described. The genetic abnormalities found in clear cell tumours involve chromosome 3p and, additionally, hypermethylation of the von Hippel-Lindau (VHL) gene can be detected. The VHL protein is involved in the angiogenic cascade in non-hypoxic conditions, and the possible role of mutant or hypermethylated VHL protein in promoting angiogenesis is, therefore, of interest. The majority of patients with renal cell carcinoma who receive treatment, such as IL-2 and/or IFN, fail and develop progressive disease. Therapy is therefore inadequate and novel approaches, such as those inhibiting angiogenesis, are of interest. The agent AE-941 (Neovostat trade mark; AEterna) was developed based on the observation that shark cartilage may contain biologically active inhibitors of angiogenesis. A variety of in vitro and in vivo activities of this preparation have been identified. At the molecular level, AE-941 appears to exhibit four different potential mechanisms of action: modulation of matrix proteases; inhibition of vascular endothelial growth factor binding to its receptor; induction of endothelial cell apoptosis; and stimulation of angiostatin production. The antitumour effects of AE-941 are seen in multiple murine models and involve not only effects on primary tumour growth but also on development of metastases. AE-941 is administered orally and has an excellent toxicity profile. Of interest are the findings in patients with renal cell carcinoma. Preliminary trials in this setting have suggested that responses to AE-941 occur and that patients receiving higher doses of this agent may have improved survival. Based on these preliminary data, a large, multi-institutional, randomised, Phase III trial of this agent has now been conducted in patients with metastatic clear cell carcinoma of the kidney. Over 300 patients have been entered into this trial, accrual is complete and results still remain preliminary. The clinical studies in a malignancy such as renal cell carcinoma will provide sentinel and potentially important observations on the clinical effectiveness of this agent.

  3. Differential Growth Inhibition of Cerebral Metastases by Anti-angiogenic Compounds

    PubMed Central

    MARTIN, DANIEL K.; UCKERMANN, ORTRUD; BERTRAM, AIKO; LIEBNER, CORINA; HENDRUSCHK, SANDY; SITOCI-FICICI, KERIM HAKAN; SCHACKERT, GABRIELE; LORD, EDITH M.; TEMME, ACHIM; KIRSCH, MATTHIAS

    2015-01-01

    Background The formation of brain metastases is intrinsically linked to concomitant angiogenesis. The purpose of the present study was to investigate the combined effects of interleukin-12 (IL-12) and EMD121974 on the growth and distribution of melanoma brain metastases since both substances may interact with important steps in the cascade of brain metastases formation. Materials and Methods Brain metastases were induced by either stereotactic implantation of cells to the brain parenchyma or by injection of the melanoma cells into the internal carotid artery to mimic hematogenous metastatic spread in mice. Naive or IL-12-overexpressing murine K1735 melanoma cells were used either alone or in combination with intraperitoneal anti-integrin treatment using EMD121974. Results Solid melanoma metastases were more susceptible to daily low-dose treatment of EMD121974 than multiple hematogenous metastases. Interleukin-12 had a profound effect on both types of brain metastases. After 21 days, a marked reduction of vascularity was observed in both tumor types. Conclusion The combination of endogenous IL-12 production with integrin blockade resulted in additive effects for murine hematogenous brain metastases but not for focal brain metastases. PMID:24982333

  4. The Role of Antiangiogenic Therapy in the Development of Osteonecrosis of the Jaw.

    PubMed

    Fantasia, John E

    2015-11-01

    There is an increasing use of established and newer medications that have antiangiogenic properties. Inhibition of angiogenesis likely has either a primary or secondary role in the development of osteonecrosis of the jaw (ONJ). These medications are being used in the treatment of various cancers and in the treatment of several non-oncologic conditions. Antiangiogenic medications when used in combination with antiresorptive medications, such as nitrogen-containing bisphosphonates or denosumab, seem to increase the likelihood of osteonecrosis of the jaw. This review highlights the role of inhibitors of angiogenesis and their role in the development of osteonecrosis of the jaws.

  5. Evidence that nitric oxide is an endogenous antiangiogenic mediator.

    PubMed Central

    Pipili-Synetos, E.; Sakkoula, E.; Haralabopoulos, G.; Andriopoulou, P.; Peristeris, P.; Maragoudakis, M. E.

    1994-01-01

    1. The involvement of nitric oxide (NO) in the regulation of angiogenesis was examined in the in vivo system of the chorioallantoic membrane (CAM) of the chick embryo and in the matrigel tube formation assay. 2. Sodium nitroprusside (SNP) (0.37-28 nmol/disc), which releases NO spontaneously, caused a dose-dependent inhibition of angiogenesis in the CAM in vivo and reversed completely the angiogenic effects of alpha-thrombin (6.7 nmol/disc) and the protein kinase C (PKC) activator 4-beta-phorbol-12-myristate-13-acetate (PMA) (0.97 nmol/disc). In addition, SNP (28 x 10(-6) M) stimulated the release of guanosine 3'-5'-cyclic monophosphate (cyclic GMP) from the CAM in vitro. 3. In the matrigel tube formation assay, an in vitro assay of angiogenesis, both SNP (1-3 x 10(-6) M) and the cell permeable cyclic GMP analogue, Br-cGMP (0.3-1.0 x 10(-3) M) reduced tube formation. 4. The inhibitors of NO synthase, NG-monomethyl-L-arginine (L-NMMA) (3.8-102 nmol/disc) and NG-nitro-L-arginine methylester (L-NAME) (1.3-34.2 nmol/disc) stimulated angiogenesis in the CAM in vivo, in a dose-dependent fashion. D-NMMA and D-NAME on the other hand had no effect on angiogenesis in this system. 5. L-Arginine (10.9 nmol/disc), although it had a modest antiangiogenic effect by itself, was capable of abolishing the angiogenic effects of L-NMMA (34.2 nmol/disc) and of L-NAME (3.8 nmol/disc). 6. Dexamethasone, an inhibitor of the induction of NO synthase, at 0.2-116.1 nmol/disc, stimulated angiogenesis in the CAM, whereas at 348.4-1161 nmol/disc it inhibited this process. Combination of 38.7 nmol/disc dexamethasone with L-NAME (9.3 nmol/disc) resulted in a potentiation of the angiogenic effect of the former. It appears therefore that both the constitutive and the inducible NO synthase may contribute to the NO-mediated inhibition of angiogenesis.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 2 Figure 3 Figure 6 Figure 9 PMID:7517330

  6. Systemic antiangiogenic activity of cationic poly-L-lysine dendrimer delays tumor growth

    PubMed Central

    Al-Jamal, Khuloud T.; Al-Jamal, Wafa’ T.; Akerman, Simon; Podesta, Jennifer E.; Yilmazer, Açelya; Turton, John A.; Bianco, Alberto; Vargesson, Neil; Kanthou, Chryso; Florence, Alexander T.; Tozer, Gillian M.; Kostarelos, Kostas

    2010-01-01

    This study describes the previously unreported intrinsic capacity of poly-L-lysine (PLL) sixth generation (G6) dendrimer molecules to exhibit systemic antiangiogenic activity that could lead to solid tumor growth arrest. The PLL-dendrimer-inhibited tubule formation of SVEC4-10 murine endothelial cells and neovascularization in the chick embryo chick chorioallantoic membrane (CAM) assay. Intravenous administration of the PLL-dendrimer molecules into C57BL/6 mice inhibited vascularisation in Matrigel plugs implanted subcutaneously. Antiangiogenic activity was further evidenced using intravital microscopy of tumors grown within dorsal skinfold window chambers. Reduced vascularization of P22 rat sarcoma implanted in the dorsal window chamber of SCID mice was observed following tail vein administration (i.v.) of the PLL dendrimers. Also, the in vivo toxicological profile of the PLL-dendrimer molecules was shown to be safe at the dose regime studied. The antiangiogenic activity of the PLL dendrimer was further shown to be associated with significant suppression of B16F10 solid tumor volume and delayed tumor growth. Enhanced apoptosis/necrosis within tumors of PLL-dendrimer-treated animals only and reduction in the number of CD31 positive cells were observed in comparison to protamine treatment. This study suggests that PLL-dendrimer molecules can exhibit a systemic antiangiogenic activity that may be used for therapy of solid tumors, and in combination with their capacity to carry other therapeutic or diagnostic agents may potentially offer capabilities for the design of theranostic systems. PMID:20150514

  7. Antiangiogenic therapy for refractory colorectal cancer: current options and future strategies

    PubMed Central

    Riechelmann, Rachel; Grothey, Axel

    2016-01-01

    Even though significant improvements in the treatment of colorectal cancer (CRC) have been made in recent years, survival rates for metastatic colorectal cancer (mCRC) are poor. Effective treatment options for metastatic colorectal cancer remain limited, and new therapeutic strategies are desperately needed. Several tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) that target angiogenesis, a critical process for facilitating tumor cell growth, invasion, and metastasis, are either approved or in clinical development for the treatment of mCRC. Many of these agents have shown efficacy in mCRC, both as single agents and in combination with standard chemotherapy regimens. However, there is a need for predictive markers of response to identify those patients most likely to benefit from antiangiogenic therapy, and, to date, no markers of this type have been validated in patients. Additionally, because antiangiogenic agents typically cause cytostatic as opposed to cytotoxic antitumor effects, it is important to determine the best strategies for evaluating therapeutic response in mCRC to ensure maximum clinical benefit. In this review, we summarize the efficacy and tolerability of approved and investigational antiangiogenic agents for the treatment of mCRC. We also discuss potential markers of response to antiangiogenic agents and how these markers, along with appropriate endpoint selection, can improve clinical trial design. PMID:28203302

  8. Acrolein: unwanted side product or contribution to antiangiogenic properties of metronomic cyclophosphamide therapy?

    PubMed

    Günther, M; Wagner, E; Ogris, M

    2008-12-01

    Tumour therapy with cyclophosphamide (CPA), an alkylating chemotherapeutic agent, has been associated with reduced tumour blood supply and antiangiogenic effects when applied in a continuous, low-dose metronomic schedule. Compared to conventional high-dose scheduling, metronomic CPA therapy exhibits antitumoural activity with reduced side effects. We have studied potential antiangiogenic properties of acrolein which is released from CPA after hydroxylation. Acrolein adducts were found in tumour cells and tumour endothelial cells of CPA-treated mice, suggesting an in vivo relevance of acrolein. In vitro, acrolein inhibited endothelial cell proliferation, endothelial cell migration and tube formation. Moreover, acrolein caused disassembly of the F-actin cytoskeleton and inhibition of alphavbeta3 integrin clustering at focal adhesions points in endothelial cells. Acrolein treatment modulated expression of thrombospondin-1 (TSP-1), an endogenous inhibitor of angiogenesis known to be linked to antiangiogenic effects of metronomic CPA therapy. Further on, acrolein treatment of primary endothelial cells modified NF-(kappa)B activity levels. This is the first study that points at an antiangiogenic activity of acrolein in metronomically scheduled CPA therapy.

  9. Effects of 5HPP-33,an antiangiogenic thalidomide analog, in mouse whole embryo culture

    EPA Science Inventory

    Thalidomide is a well-known example of a teratogen which has been shown to have an inhibitory effect on angiogenesis. As a result of its targeted effect on immature blood vessels, anti-angiogenic specific chemical analogs were developed to maximize this mechanism of thalidomide e...

  10. [Experimental and morphological study of the effect of antiangiogenic therapy on corneal neovessels].

    PubMed

    Mamikonian, V R; Voevodina, T M; Fedorov, A A; Budzinskaia, M V; Balaian, M L

    2013-01-01

    The article presents the results of an experimental and morphological study of combined antiangiogenic effect of photodynamic therapy with Photosens photosensitizer and Avastin (bevacizumab) on neovascularization process in corneal stroma. The combined approach has demonstrated an advantage over separate application of these methods, what, however, has to be proved clinically.

  11. Structural Determinant and Its Underlying Molecular Mechanism of STPC2 Related to Anti-Angiogenic Activity

    PubMed Central

    Hu, Min; Cui, Ning; Bo, Zhixiang; Xiang, Feixiang

    2017-01-01

    In this study, we aimed to use different strategies to further uncover the anti-angiogenic molecular mechanism of a fucoidan-like polysaccharide STPC2, isolated from brown alga Sargassum thunbergii. A desulfated derivative, STPC2-DeS, was successfully prepared and identified. The native polysaccharide and desulfated product were subjected to evaluate their anti-angiogenic effects. In the tube formation assay, STPC2 showed dose-dependent inhibition. In addition, STPC2 could distinctly inhibit the permeation of HUVEC cells into the lower chamber. Moreover, a significant reduction of microvessel density was observed in chick chorioallantoic membrane assay treated with STPC2. Meanwhile, STPC2 was found to repress the VEGF-induced neovessel formation in the matrigel plug assay in vivo. However, STPC2-DeS failed to suppress the anti-angiogenic activity via these in vitro and in vivo strategies. In addition, we demonstrated that STPC2 could significantly downregulate the phosphorylation of VEGFR2 and its related downstream Src family kinase, focal adhesion kinase, and AKT kinase. Furthermore, surface plasmon resonance assay revealed that STPC2 bound strongly to VEGF to interfere with VEGF–VEGFR2 interaction. Taken together, these results evidently demonstrated that STPC2 exhibited a potent anti-angiogenic activity through binding to VEGF via sulfated groups to impede VEGF–VEGFR2 interaction, thus affected the downstream signaling molecules. PMID:28230794

  12. In vitro anti-proliferative and anti-angiogenic activities of thalidomide dithiocarbamate analogs.

    PubMed

    El-Aarag, Bishoy Y A; Kasai, Tomonari; Zahran, Magdy A H; Zakhary, Nadia I; Shigehiro, Tsukasa; Sekhar, Sreeja C; Agwa, Hussein S; Mizutani, Akifumi; Murakami, Hiroshi; Kakuta, Hiroki; Seno, Masaharu

    2014-08-01

    Inhibition of angiogenesis is currently perceived as a promising strategy in the treatment of cancer. The anti-angiogenicity of thalidomide has inspired a second wave of research on this teratogenic drug. The present study aimed to investigate the anti-proliferative and anti-angiogenic activities of two thalidomide dithiocarbamate analogs by studying their anti-proliferative effects on human umbilical vein endothelial cells (HUVECs) and MDA-MB-231 human breast cancer cell lines. Their action on the expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 was also assessed. Furthermore, their effect on angiogenesis was evaluated through wound healing, migration, tube formation, and nitric oxide (NO) assays. Results illustrated that the proliferation of HUVECs and MDA-MB-231 cells was not significantly affected by thalidomide at 6.25-100μM. Thalidomide failed to block angiogenesis at similar concentrations. By contrast, thalidomide dithiocarbamate analogs exhibited significant anti-proliferative action on HUVECs and MDA-MB-231 cells without causing cytotoxicity and also showed powerful anti-angiogenicity in wound healing, migration, tube formation, and NO assays. Thalidomide analogs 1 and 2 demonstrated more potent activity to suppress expression levels of IL-6, IL-8, TNF-α, VEGF165, and MMP-2 than thalidomide. Analog 1 consistently, showed the highest potency and efficacy in all the assays. Taken together, our results support further development and evaluation of novel thalidomide analogs as anti-tumor and anti-angiogenic agents.

  13. Molecular mechanisms of (R,R)ZX-5 on NO synthesis and its anti-angiogenic effect.

    PubMed

    Pan, Li; Hu, Jia-Liang; Wang, Wen-Jing; Zhang, Xiao-Juan; Wei, Jin; Liu, Zhen-Dong; Zhang, Yi-Hua; Xu, Han-Mei

    2012-01-01

    (R,R)ZX-5 is a NO regulatory compound, which could significantly increase choroidal blood flow in New Zealand rabbit. The aim of this paper is to investigate the molecular mechanism of (R,R)ZX-5 promoting NO production. Besides this, we also investigated the antiangiogenic activity of (R,R)ZX-5. Analysis of Western blot showed that (R,R)ZX-5 up-regulated the expression of Akt, p-Akt (Thr473), eNOS and p-eNOS (Ser1177), down-regulated the expression of Cyclin D1 in human retinal endothelial cells and escalated the intracellular free Ca(2+) concentration. Additionally, (R,R)ZX-5 inhibited the growth of blood vessels in the chick chorioallantoic membrane model. It is concluded that (R,R)ZX-5 promotes choroidal blood flow through PI3K/Akt-eNOS and Akt-Ca(2+)-eNOS pathways. Additionally, (R,R)ZX-5 can inhibit angiogenesis.

  14. Shark cartilage extracts as antiangiogenic agents: smart drinks or bitter pills?

    PubMed

    Gingras, D; Renaud, A; Mousseau, N; Béliveau, R

    2000-01-01

    The use of crude cartilage for the treatment of human cancers remains a subject of controversy. In this brief commentary, we reviewed the current knowledge on the anticancer properties of cartilage. We then presented the properties of AE-941, a novel standardized water-soluble extract derived from shark cartilage that represents less than 5% of the crude cartilage. It is a multifunctional antiangiogenic product that contains several biologically active molecules. EA-941 is one of the few antiangiogenic drugs that is under phase III clinical investigation. It is currently evaluated in Europe and North America for the treatment of refractory renal cell carcinoma and in North America for metastatic non small cell lung cancer.

  15. Evaluation of antiangiogenic and antoxidant properties of Parkia speciosa Hassk extracts.

    PubMed

    Aisha, Abdalrahim F A; Abu-Salah, Khalid M; Alrokayan, Salman A; Ismail, Zhari; Abdulmajid, Amin Malik Shah

    2012-01-01

    Parkia speciosa Hassk is a traditional medicinal plant with strong antioxidant and hypoglycemic properties. This study aims to investigate the total phenolic content, antioxidant, cytotoxic and antiangiogenic effect of eight extracts from P. speciosa empty pods. The extracts were found to contain high levels of total phenols and demonstrated strong antioxidant effect in DPPH scavenging test. In rat aortic rings, P. speciosa extracts significantly inhibited the microvessel outgrowth from aortic tissue explants by more than 50%. The antiangiogenic activity was further confirmed by tube formation on matrigel matrix involving human endothelial cells. Cytotoxic effect was evaluated by XTT test on endothelial cells as a model of angiogenesis versus a panel of human cancer and normal cell lines. Basically the extracts did not show acute cytotoxicity. Morphology examination of endothelial cells indicated induction of autophagy characterized by formation of plenty of cytoplasmic vacuoles. The extracts were found to work by decreasing expression of vascular endothelial growth factor in endothelial cells.

  16. Modeling Longitudinal Preclinical Tumor Size Data to Identify Transient Dynamics in Tumor Response to Antiangiogenic Drugs

    PubMed Central

    Mueller, H‐J; Gaffney, EA; Maini, PK; Wagg, J; Phipps, A; Boetsch, C; Byrne, HM; Ribba, B

    2016-01-01

    Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time‐course data in a breast cancer xenograft model. We used a mixed‐effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization. We estimated the characteristics of the window for mice treated with an anti‐VEGF antibody (bevacizumab) or with a bispecific anti‐VEGF/anti‐angiopoietin‐2 antibody (vanucizumab). We show how the mathematical model could theoretically be used to predict how to coordinate antiangiogenic therapy with radiotherapy or chemotherapy to maximize therapeutic effect, reducing the need for preclinical experiments that directly measure vessel normalization parameters. PMID:27863175

  17. Anti-angiogenic quassinoid-rich fraction from Eurycoma longifolia modulates endothelial cell function.

    PubMed

    Al-Salahi, Omar Saeed Ali; Kit-Lam, Chan; Majid, Amin Malik Shah Abdul; Al-Suede, Fouad Saleih R; Mohammed Saghir, Sultan Ayesh; Abdullah, Wan Zaidah; Ahamed, Mohamed B Khadeer; Yusoff, Narazah Mohd

    2013-11-01

    Targeting angiogenesis could be an excellent strategy to combat angiogenesis-dependent pathophysiological conditions such as cancer, rheumatoid arthritis, obesity, systemic lupus erythematosus, psoriasis, proliferative retinopathy and atherosclerosis. Recently a number of clinical investigations are being undertaken to assess the potential therapeutic application of various anti-angiogenic agents. Many of these angiogenesis inhibitors are directed against the functions of endothelial cells, which are considered as the building blocks of blood vessels. Similarly, roots of a traditional medicinal plant, Eurycoma longifolia, can be used as an alternative treatment to prevent and treat the angiogenesis-related diseases. In the present study, antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 was investigated in human umbilical vein endothelial cells (HUVEC). TAF273 caused significant suppression in sprouting of microvessels in rat aorta with IC50 11.5μg/ml. TAF273 (50μg/ml) showed remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of chick embryo. Tumor histology also revealed marked reduction in extent of vascularization. In vitro, TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Phytochemical analysis revealed high content of quassinoids in TAF273. Specially, HPLC characterization showed that TAF273 is enriched with eurycomanone, 13α(21)-epoxyeurycomanone and eurycomanol. These results demonstrated that the antiangiogenic activity of TAF273 may be due to its inhibitory effect on endothelial cell proliferation, differentiation and migration which could be attributed to the high content of quassinoids in E. longifolia.

  18. Platycodin D inhibits tumor growth by antiangiogenic activity via blocking VEGFR2-mediated signaling pathway

    SciTech Connect

    Luan, Xin; Gao, Yun-Ge; Guan, Ying-Yun; Xu, Jian-Rong; Lu, Qin; Zhao, Mei; Liu, Ya-Rong; Liu, Hai-Jun; Fang, Chao; Chen, Hong-Zhuan

    2014-11-15

    Platycodin D (PD) is an active component mainly isolated from the root of Platycodon grandiflorum. Recent studies proved that PD exhibited inhibitory effect on proliferation, migration, invasion and xenograft growth of diverse cancer cell lines. However, whether PD is suppressive for angiogenesis, an important hallmark in cancer development, remains unknown. Here, we found that PD could dose-dependently inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration and tube formation. PD also significantly inhibited angiogenesis in the chick embryo chorioallantoic membrane (CAM). Moreover, the antiangiogenic activity of PD contributed to its in vivo anticancer potency shown in the decreased microvessel density and delayed growth of HCT-15 xenograft in mice with no overt toxicity. Western blot analysis indicated that PD inhibited the phosphorylation of VEGFR2 and its downstream protein kinase including PLCγ1, JAK2, FAK, Src, and Akt in endothelial cells. Molecular docking simulation showed that PD formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic activity and the underlying molecular basis of PD, suggesting that PD may be a potential antiangiogenic agent for angiogenesis-related diseases. - Highlights: • Platycodin D inhibits HUVEC proliferation, motility, migration and tube formation. • Platycodin D inhibits the angiogenesis in chick embryo chorioallantoic membrane. • Platycodin D suppresses the angiogenesis and growth of HCT-15 xenograft in mice. • Platycodin D inhibits the phosphorylation of VEGFR2 and downstream kinases in HUVEC.

  19. NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.

    PubMed

    Broggini, Thomas; Wüstner, Marie; Harms, Christoph; Stange, Lena; Blaes, Jonas; Thomé, Carina; Harms, Ulrike; Mueller, Susanne; Weiler, Markus; Wick, Wolfgang; Vajkoczy, Peter; Czabanka, Marcus

    2016-10-01

    Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.

  20. Efficacy and Toxicity Assessment of Different Antibody Based Antiangiogenic Drugs by Computational Docking Method

    PubMed Central

    Mukherjee, Sayan; Chatterjee, Gopa; Ghosh, Moumita; Das, Bishwajit

    2016-01-01

    Bevacizumab and trastuzumab are two antibody based antiangiogenic drugs that are in clinical practice for the treatment of different cancers. Presently applications of these drugs are based on the empirical choice of clinical experts that follow towards population based clinical trials and, hence, their molecular efficacies in terms of quantitative estimates are not being explored. Moreover, different clinical trials with these drugs showed different toxicity symptoms in patients. Here, using molecular docking study, we made an attempt to reveal the molecular rationale regarding their efficacy and off-target toxicity. Though our study reinforces their antiangiogenic potentiality and, among the two, trastuzumab has much higher efficacy; however, this study also reveals that compared to bevacizumab, trastuzumab has higher toxicity effect, specially on the cardiovascular system. This study also reveals the molecular rationale of ocular dysfunction by antiangiogenic drugs. The molecular rationale of toxicity as revealed in this study may help in the judicious choice as well as therapeutic scheduling of these drugs in different cancers. PMID:27047544

  1. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance

    PubMed Central

    Depner, C.; zum Buttel, H.; Böğürcü, N.; Cuesta, A. M.; Aburto, M. R.; Seidel, S.; Finkelmeier, F.; Foss, F.; Hofmann, J.; Kaulich, K.; Barbus, S.; Segarra, M.; Reifenberger, G.; Garvalov, B. K.; Acker, T.; Acker-Palmer, A.

    2016-01-01

    Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1α induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies. PMID:27470974

  2. [Neovascularization in ocular tissues: mechanisms and role of proangiogenic and antiangiogenic factors].

    PubMed

    Nowak, Jerzy Z; Wiktorowska-Owczarek, Anna

    2004-01-01

    Blood vessel growth and stability are under precise control of an array of pro- and anti-angiogenic factors. Under physiological conditions, actions of particular regulatory factors, as well as their mutual interactions are harmonized and balanced. Disruption of the balance between these pro- and anti-angiogenic factors is characteristic of many vascular diseases, including those occurring within the eye. Functional dominancy of proangiogenic factors (e.g., vascular endothelial growth factor, VEGF) over antiangiogenic ones (e.g., pigment epithelium-derived growth factor, PEDF), which may occur under ischemic conditions, may initiate the process of retinal or choroidal neovascularization, representing a major threat to the eyesight. This article presents and discusses current ideas concerning molecular and cellular processes underlying aberrant growth on new blood vessels in ocular tissues, in relation to microvascular ocular complications associated mainly (but not only), with diabetes mellitus, age-related macular degeneration (AMD), and retinopathy of prematurity (ROP). This review also surveys latest achievements in the field of clinically more effective future therapeutic strategies, including gene therapy applicable to the neovascular eye diseases.

  3. Resistance to antiangiogenic therapy is directed by vascular phenotype, vessel stabilization, and maturation in malignant melanoma

    PubMed Central

    Scheffrahn, Inka; Bartling, Sönke; Weis, Joachim; von Felbert, Verena; Middleton, Mark; Kato, Masahi; Ergün, Süleyman; Augustin, Hellmut G.

    2010-01-01

    Angiogenesis is not only dependent on endothelial cell invasion and proliferation, it also requires pericyte coverage of vascular sprouts for stabilization of vascular walls. Clinical efficacy of angiogenesis inhibitors targeting the vascular endothelial growth factor (VEGF) signaling pathway is still limited to date. We hypothesized that the level of vessel maturation is critically involved in the response to antiangiogenic therapies. To test this hypothesis, we evaluated the vascular network in spontaneously developing melanomas of MT/ret transgenic mice after using PTK787/ZK222584 for anti-VEGF therapy but also analyzed human melanoma metastases taken at clinical relapse in patients undergoing adjuvant treatment using bevacizumab. Both experimental settings showed that tumor vessels, which are resistant to anti-VEGF therapy, are characterized by enhanced vessel diameter and normalization of the vascular bed by coverage of mature pericytes and immunoreactivity for desmin, NG-2, platelet-derived growth factor receptor β, and the late-stage maturity marker α smooth muscle actin. Our findings emphasize that the level of mural cell differentiation and stabilization of the vascular wall significantly contribute to the response toward antiangiogenic therapy in melanoma. This study may be useful in paving the way toward a more rational development of second generation antiangiogenic combination therapies and in providing, for the first time, a murine model to study this. PMID:20194633

  4. Antiangiogenic and antimetastatic properties of Neovastat (AE-941), an orally active extract derived from cartilage tissue.

    PubMed

    Dupont, Eric; Falardeau, Pierre; Mousa, Shaker A; Dimitriadou, Violetta; Pepin, Marie-Claude; Wang, Taiqi; Alaoui-Jamali, Moulay A

    2002-01-01

    A novel naturally occurring antiangiogenic agent isolated from cartilage, referred to as Neovastat (AE-941), was examined for its efficacy against tumor neovascularization and progression. Exposure to Neovastat results in ex ovo antiangiogenic properties in the chorioallantoid membrane of chicken embryo (71% decrease in the angiogenic index as compared to the basic fibroblast growth factor (bFGF) treated control embryos, P < 0.0001). Oral administration of Neovastat inhibits bFGF-induced angiogenesis in the Matrigel mouse model (87.5% decrease in hemoglobin as compared to the bFGF-treated control implants, P < 0.0001). Neovastat also induces a dose response decrease of lung metastases in the Lewis lung carcinoma model (oral administration; 69.1% of inhibition obtained at the maximal dose of 0.5 ml/day, P < 0.0001). Combined with a sub-optimal dose of cisplatinum (2 mg/kg, i.p.), Neovastat (0.5 ml/day) improved the therapeutic index by increasing the antimetastatic efficacy and by exerting a protective activity against cisplatinum-induced body weight loss and myelosuppression. In summary, our experimental data provide evidence of antiangiogenic and antimetastatic properties of Neovastat, following oral administration.

  5. Antiangiogenic activity of low-temperature lysozyme from a marine bacterium in vivo and in vitro

    NASA Astrophysics Data System (ADS)

    Wang, Zhenhua; Liu, Jincheng; Su, Ai; Sun, Mi; Wang, Chunbo

    2009-11-01

    We extracted marine low-temperature lysozyme (MLTL), a novel lysozyme, from a marine microorganism through fermentation. Our previous study suggested that a low molecular weight (16 kDa) may exert anti-tumor activity through antiangiogenesis. In this study, we extracted a high weight (39 kDa) and investigated its antiangiogenic activity in vivo and in vitro. Using zebrafish embryos as an in vivo study model, we found that treatment with MLTL significantly inhibited the growth of subintestinal vessels (SIVs) in a dose-dependent manner and that 400 µg/ml MLTL was sufficient to block the growth of SIVs. An in vitro study conducted using human umbilical vein endothelial cells (HUVECs) revealed that MLTL suppressed the proliferation, migration and tube formation of HUVECs in a dose-dependent manner. Interestingly, assays by flow cytometry and DNA electrophoresis indicated that MLTL was able to induce apoptosis of HUVECs. Moreover, further study demonstrated that the disruption of intracellular Ca2+ homeostasis may play an important role in MLTL induced apoptosis of HUVECs. Taken together, the results of this study demonstrate for the first time that MLTL inhibits angiogenesis through its pleiotropic effects on vascular endothelial cells and induces apoptosis through regulation of cellular Ca2+ levels. The results of this study also revealed a possible mechanism underlying the antiangiogenic effect of MLTL and suggested that MLTL may be a promising new antiangiogenic agent for use in cancer therapy.

  6. Antiangiogenic mechanisms of PJ-8, a novel inhibitor of vascular endothelial growth factor receptor signaling.

    PubMed

    Huang, Shiu-Wen; Lien, Jin-Cherng; Kuo, Sheng-Chu; Huang, Tur-Fu

    2012-05-01

    Angiogenesis occurs not only during tissue growth and development but also during wound healing and tumor progression. Angiogenesis is a balanced process controlled by proangiogenic and antiangiogenic molecules. As a critical factor in the induction of angiogenesis, vascular endothelial growth factor (VEGF) has become an attractive target for antiangiogenic and cancer therapeutic agents. In an effort to develop novel inhibitors to block VEGF signaling, we selected Pj-8, a benzimidazole derivative, and investigated its inhibitory mechanisms in human umbilical vascular endothelial cells (HUVECs). Pj-8 concentration-dependently inhibited VEGF-induced proliferation, migration and tube formation of HUVECs. Pj-8 also suppressed VEGF-induced microvessel sprouting from aortic rings ex vivo and suppressed neovascularization of implanted matrigel plugs in vivo. Pj-8 inhibited VEGF-induced phosphorylation of VEGF receptor (VEGFR) 2 and the downstream protein kinases, including Akt, focal adhesion kinase, extracellular signal-regulated kinases and Src. Results from in vitro kinase assay further demonstrated that Pj-8 suppressed the kinase activity of 3-phosphoinositide-dependent kinase 1 (PDK1). Using xenograft tumor angiogenesis model, Pj-8 markedly eliminated tumor-associated angiogenesis. Taken together, our findings suggest that Pj-8 inhibits VEGF and tumor cells MDA-MB-231-induced angiogenesis, and it may be a potential drug candidate in anticancer therapy. Downregulation of VEGFR2-mediated signaling may contribute to its antiangiogenic actions.

  7. Role of the antiangiogenic agent bevacizumab in the treatment of elderly patients with metastatic colorectal cancer.

    PubMed

    Di Bartolomeo, Maria; Pietrantonio, Filippo; Martinetti, Antonia; Buzzoni, Roberto; Gevorgyan, Arpine; Bajetta, Emilio

    2011-02-01

    Although major progress has been achieved in the treatment of metastatic colorectal cancer with the employment of biological antiangiogenic agents, several questions remain open for discussion regarding the use of this therapy in elderly patients with metastatic colorectal cancer. In Western countries, the total number of elderly patients with colorectal cancer is expected to increase in the future. As adverse physical or socioeconomic conditions are more common in the elderly, an assessment of the patient's suitability for this therapy should be performed before a treatment decision is made. Most patients in clinical trials of the antiangiogenic drug bevacizumab were aged <65 years and thus the efficacy and tolerability of this agent in older patients has been less well explored. However, this article shows that older and younger patients with metastatic colorectal cancer appeared to derive similar survival benefit from bevacizumab treatment. Elderly patients were also found to have significant prolongation of median progression-free survival with the addition of bevacizumab to their treatment, with a similar magnitude of improvement in this outcome being observed in younger and older patients. It should be emphasized that the patients included in the studies discussed in this article were eligible for clinical trials and therefore may not be representative of a more general elderly population. Careful selection of patients and monitoring of treatment effects are required to optimize use of the antiangiogenic agent bevacizumab in older patients.

  8. Anti-angiogenic Therapy in Patients with Advanced Gastric and Gastroesophageal Junction Cancer: A Systematic Review.

    PubMed

    Chen, Li-Tzong; Oh, Do-Youn; Ryu, Min-Hee; Yeh, Kun-Huei; Yeo, Winnie; Carlesi, Roberto; Cheng, Rebecca; Kim, Jongseok; Orlando, Mauro; Kang, Yoon-Koo

    2017-01-03

    Despite advancements in therapy for advanced gastric and gastroesophageal junction cancers, their prognosis remains dismal. Tumor angiogenesis plays a key role in cancer growth and metastasis, and recent studies indicate that pharmacologic blockade of angiogenesis is a promising approach to therapy. In this systematic review, we summarize current literature on the clinical benefit of anti-angiogenic agents in advanced gastric cancer. We conducted a systematic search of PubMed and conference proceedings including the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. Included studies aimed to prospectively evaluate the efficacy and safety of anti-angiogenic agents in advanced gastric or gastroesophageal junction cancer. Each trial investigated at least one of the following endpoints: overall survival, progression-free survival/time to progression, and/or objective response rate. Our search yielded 139 publications. Forty-two met the predefined inclusion criteria. Included studies reported outcomes with apatinib, axitinib, bevacizumab, orantinib, pazopanib, ramucirumab, regorafenib, sorafenib, sunitinib, telatinib, and vandetanib. Second-line therapy with ramucirumab and third-line therapy with apatinib are the only anti-angiogenic agents so far shown to significantly improve survival of patients with advanced gastric cancer. Overall, agents that specifically target the vascular endothelial growth factor ligand or receptor have better safety profile compared to multi-target tyrosine kinase inhibitors.

  9. Myopodin methylation is a prognostic biomarker and predicts antiangiogenic response in advanced kidney cancer.

    PubMed

    Pompas-Veganzones, N; Sandonis, V; Perez-Lanzac, Alberto; Beltran, M; Beardo, P; Juárez, A; Vazquez, F; Cozar, J M; Alvarez-Ossorio, J L; Sanchez-Carbayo, Marta

    2016-10-01

    Myopodin is a cytoskeleton protein that shuttles to the nucleus depending on the cellular differentiation and stress. It has shown tumor suppressor functions. Myopodin methylation status was useful for staging bladder and colon tumors and predicting clinical outcome. To our knowledge, myopodin has not been tested in kidney cancer to date. The purpose of this study was to evaluate whether myopodin methylation status could be clinically useful in renal cancer (1) as a prognostic biomarker and 2) as a predictive factor of response to antiangiogenic therapy in patients with metastatic disease. Methylation-specific polymerase chain reactions (MS-PCR) were used to evaluate myopodin methylation in 88 kidney tumors. These belonged to patients with localized disease and no evidence of disease during follow-up (n = 25) (group 1), and 63 patients under antiangiogenic therapy (sunitinib, sorafenib, pazopanib, and temsirolimus), from which group 2 had non-metastatic disease at diagnosis (n = 32), and group 3 showed metastatic disease at diagnosis (n = 31). Univariate and multivariate Cox analyses were utilized to assess outcome and response to antiangiogenic agents taking progression, disease-specific survival, and overall survival as clinical endpoints. Myopodin was methylated in 50 out of the 88 kidney tumors (56.8 %). Among the 88 cases analyzed, 10 of them recurred (11.4 %), 51 progressed (57.9 %), and 40 died of disease (45.4 %). Myopodin methylation status correlated to MSKCC Risk score (p = 0.050) and the presence of distant metastasis (p = 0.039). Taking all patients, an unmethylated myopodin identified patients with shorter progression-free survival, disease-specific survival, and overall survival. Using also in univariate and multivariate models, an unmethylated myopodin predicted response to antiangiogenic therapy (groups 2 and 3) using progression-free survival, disease-specific, and overall survival as clinical endpoints. Myopodin was revealed

  10. Antiangiogenic drugs used with chemotherapy for patients with recurrent ovarian cancer: a meta-analysis

    PubMed Central

    Yi, SuYi; Zeng, LongJia; Kuang, Yan; Cao, ZhiJuan; Zheng, ChengJun; Zhang, Yue; Liao, Meng; Yang, Lu

    2017-01-01

    Objective The value of antiangiogenic inhibitors for patients with recurrent ovarian cancer has not been completely affirmed. Therefore, we aimed to assess the effectiveness and toxicities of various antiangiogenic drugs for the treatment of recurrent ovarian cancer. Methods In this meta-analysis, we searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for complete randomized controlled trials. The searches were extended to May 15, 2016. The risk of bias of the included studies was evaluated via a Cochrane systematic evaluation, and the statistical analyses were performed using RevMan 5.2 software. Results In total, we included 8 randomized controlled trials involving 3,211 patients and divided them into 3 groups, vascular endothelial growth factor receptor inhibitors (VEGFRIs), vascular endothelial growth factor (VEGF) inhibitors (bevacizumab), and angiopoietin inhibitors (trebananib). The progression-free survival improved significantly in all the groups being given antiangiogenic drugs (hazard ratio [HR]: 0.55, 95% confidence interval [CI]: 0.45–0.67, I2=0%, P<0.00001 for the VEGFRI group; HR: 0.53, 95% CI: 0.45–0.63, I2=51%, P<0.00001 for the VEGF inhibitor group; HR: 0.67, 95% CI: 0.58–0.77, I2=0%, P<0.00001 for the trebananib group). Overall survival was obviously prolonged in the VEGFRI (HR: 0.76, 95% CI: 0.59–0.97, I2=0%, P=0.03), the VEGF inhibitor (HR: 0.87, 95% CI: 0.77–0.99, I2=0%, P=0.03), and trebananib groups (HR: 0.81, 95% CI: 0.67–0.99, I2=0%, P=0.04). The incidence of grade 3/4 side effects was different among the 3 groups, for example, proteinuria, hypertension, gastrointestinal perforation, and arterial thromboembolism were presented in the VEGF inhibitor group. Increased incidences of fatigue, diarrhea, and hypertension were seen in the VEGFRI group, and the trebananib group had a higher incidence of hypokalemia. Conclusion This meta-analysis showed that antiangiogenic drugs improved the

  11. Screening of antiangiogenic potential of twenty two marine invertebrate extracts of phylum Mollusca from South East Coast of India

    PubMed Central

    Gupta, Pankaj; Arumugam, Muthuvel; Azad, Raj Vardhan; Saxena, Rohit; Ghose, Supriyo; Biswas, Nihar Ranjan; Velpandian, Thirumurthy

    2014-01-01

    Objective To evaluate the antiangiogenic potential of twenty two marine invertebrate species of Phylum Mollusca from south east coast of India. Methods Live specimens of molluscan species were collected and their methanolic extracts were evaluated for preliminary antiangiogenic activity using the in ovo chick chorio-allantoic membrane assay. The extracts were further evaluated for in vivo antiangiogenic activity using chemical cautery induced corneal neovascularization assay in rats and oxygen induced retinopathy assay in rat pups. Results In the chick chorio-allantoic membrane assay, four methanolic extracts of marine molluscan species viz. Meretrix meretrix, Meretrix casta, Telescopium telescopium and Bursa crumena methanolic extracts exhibited noticeable antiangiogenic activity at the tested concentration of 200 µg whereby they significantly inhibited the VEGF induced proliferation of new blood vessels. Among these four extracts, the methanolic extract of Meretrix casta exhibited relatively higher degree of antiangiogenic activity with an inhibitiory percentage (64.63%) of the VEGF induced neovascularization followed by the methanolic extracts of Telescopium telescopium (62.02%), Bursa crumena (60.48%) and Meretrix meretrix (47.01%). These four methanolic extracts were further evaluated for in vivo antiangiogenic activity whereby the methanolic extract of Telescopium telescopium exhibited most noticeable inhibition (42.58%) of the corneal neovascularization in rats in comparison to the sham treated group, and also exhibited most noticeable inhibition (31.31%) of the oxygen induced retinal neovascularization in rat pups in comparison to the hyperoxia group that was observed for considerable retinal neovascularization. Conclusions The significant antiangiogenic activity evinced by the extract of Telescopium telescopium merits further investigation for ocular neovascular diseases. PMID:25183067

  12. Anti-angiogenic effect of a Palladium(II)-Saccharinate Complex of Terpyridine in vitro and in vivo.

    PubMed

    Ikitimur-Armutak, Elif I; Gurel-Gurevin, Ebru; Kiyan, H Tuba; Aydinlik, Seyma; Yilmaz, Veysel Turan; Dimas, Konstantinos; Ulukaya, Engin

    2017-01-01

    Anti-angiogenic activity of palladium (Pd)(II)-based complexes is unknown despite their quite powerful anticancer activity. This study was therefore carried out to evaluate both in vivo anti-angiogenic effect and in vitro cytotoxic activity of a Pd(II)-based complex. ([Pd(sac)(terpy)](sac)·4H2O(sac=saccharinate and terpy=2,2':6',2″-terpyridine)) on HUVEC cells. The anti-angiogenic activity of the complex was evaluated in vivo using the chick embryo chorioallantoic membrane (CAM) assay, tube formation assay and the cytotoxicity was screened using the MTT viability assays. The CAM treated with the complex (50μg/pellet) showed a strikingly high anti-angiogenic effect (score 1.1±0.2) compared to the positive controls cortisone, prednisone and (±)-thalidomide (e.g. (±)-thalidomide score 0.9±0.2) tested at the same concentration. Furthermore, the complex showed neither membrane toxicity nor irritation at the tested concentration. According to the MTT assays, the human umbilical vein endothelial cell (HUVEC) viability was inhibited in a dose-dependent manner at tested concentrations (1.56-100μM). Pd(II) complex also reduced the tube network at the lower dose than the compared with thalidomide. These results suggest that the Pd(II)-complex has strong anti-angiogenic activity, which adds an important feature to the previously-described anticancer activity of the complex.

  13. Collagen IV and CXC chemokine derived anti-angiogenic peptides suppress glioma xenograft growth

    PubMed Central

    Rosca, Elena V.; Lal, Bachchu; Koskimaki, Jacob E.; Popel, Aleksander S.; Laterra, John

    2012-01-01

    Peptides are receiving increased attention as therapeutic agents, due to their high binding specificity and versatility to be modified as targeting or carrier molecules. Particularly, peptides with anti-angiogenic activity are of high interest due to their applicability to a wide range of cancers. In this study we investigate the biological activity of two novel antiangiogenic peptides in pre-clinical glioma models. One peptide SP2000 is derived from collagen IV and the other peptide SP3019 belongs to the CXC family. We previously characterized the capacity of SP2000 and SP3019 to inhibit multiple biological endpoints linked to angiogenesis in human endothelial cells in several assays. Here we report additional studies using endothelial cells and focus on the activity of these peptides against human glioma cell growth, migration and adhesion in vitro and growth as tumor xenografts in vivo. We found that SP2000 completely inhibits migration of the glioma cells at 50 μM and SP3019 produced 50% inhibition at 100 μM. Their relative anti-adhesion activities were similar with SP2000 and SP3019 generating 50% adhesion inhibition at 4.9 ± 0.82 μM and 21.3 ± 5.92 μM respectively. In vivo glioma growth inhibition was 63 % for SP2000 and 76% for SP3019 after 2 weeks of administration at daily doses of 10mg/kg and 20 mg/kg, respectively. The direct activity of these peptides against glioma cells in conjunction with their anti-angiogenic activities warrants their further development as either stand-alone agents or in combination with standard cytotoxic or emerging targeted therapies in malignant brain tumors. PMID:22495619

  14. Characterization of the conformational alterations, reduced anticoagulant activity, and enhanced antiangiogenic activity of prelatent antithrombin.

    PubMed

    Richard, Benjamin; Swanson, Richard; Schedin-Weiss, Sophia; Ramirez, Ben; Izaguirre, Gonzalo; Gettins, Peter G W; Olson, Steven T

    2008-05-23

    A conformationally altered prelatent form of antithrombin that possesses both anticoagulant and antiangiogenic activities is produced during the conversion of native to latent antithrombin (Larsson, H., Akerud, P., Nordling, K., Raub-Segall, E., Claesson-Welsh, L., and Björk, I. (2001) J. Biol. Chem. 276, 11996-12002). Here, we show that the previously characterized prelatent antithrombin is a mixture of native antithrombin and a modified, true prelatent antithrombin that are resolvable by heparin-agarose chromatography. Kinetic analyses revealed that prelatent antithrombin is an intermediate in the conversion of native to latent antithrombin whose formation is favored by stabilizing anions of the Hofmeister series. Purified prelatent antithrombin had reduced anticoagulant function compared with native antithrombin, due to a reduced heparin affinity and consequent impaired ability of heparin to either bridge prelatent antithrombin and coagulation proteases in a ternary complex or to induce full conformational activation of the serpin. Significantly, prelatent antithrombin possessed an antiangiogenic activity more potent than that of latent antithrombin, based on the relative abilities of the two forms to inhibit endothelial cell growth. The prelatent form was conformationally altered from native antithrombin as judged from an attenuation of tryptophan fluorescence changes following heparin activation and a reduced thermal stability. The alterations are consistent with the limited structural changes involving strand 1C observed in a prelatent form of plasminogen activator inhibitor-1 (Dupont, D. M., Blouse, G. E., Hansen, M., Mathiasen, L., Kjelgaard, S., Jensen, J. K., Christensen, A., Gils, A., Declerck, P. J., Andreasen, P. A., and Wind, T. (2006) J. Biol. Chem. 281, 36071-36081), since the (1)H NMR spectrum, electrophoretic mobility, and proteolytic susceptibility of prelatent antithrombin most resemble those of native rather than those of latent antithrombin

  15. Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials.

    PubMed

    Falardeau, P; Champagne, P; Poyet, P; Hariton, C; Dupont, E

    2001-12-01

    Recent studies have indicated that bone marrow angiogenesis is increased in multiple myeloma, suggesting that treatment with an antiangiogenic agent might be useful. Among the new antiangiogenic drugs in development, Neovastat (AE-941; Aeterna Laboratories, Quebec City, Canada) can be classified as a naturally occurring multifunctional antiangiogenic agent. It has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. Furthermore, in vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antitumor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in tumor volume. Neovastat also decreased the number of lung metastases in the Lewis lung carcinoma model. Interestingly, the effect of Neovastat was additive to cisplatin in this model. Furthermore, no treatment-related mortality or loss of body weight was observed. Also, toxicology studies in rats and monkeys demonstrate no dose-limiting toxicity or target organ damage after 1 year of chronic exposure, thus suggesting that Neovastat could be safely administered in humans. Four clinical studies have been conducted to establish the dosing, safety, and early efficacy of Neovastat administered orally. In the oncology field, 482 patients have received Neovastat, of which 146 with solid tumors were exposed to the drug for

  16. Gorham-Stout Disease of the Skull Base With Hearing Loss: Dramatic Recovery and Antiangiogenic Therapy.

    PubMed

    Nozawa, Akifumi; Ozeki, Michio; Kuze, Bunya; Asano, Takahiko; Matsuoka, Kentaro; Fukao, Toshiyuki

    2016-05-01

    Gorham-Stout disease (GSD) is a rare disorder of unknown etiology. We present a 6-year-old male with GSD involving the skull base who presented with recurrent cerebrospinal fluid (CSF) rhinorrhea, severe hearing loss, and facial palsy secondary to cerebellar herniation into the internal auditory canal. After 2 months of treatment with pegylated interferon (IFN) α-2b (50 μg/week), his hearing recovered dramatically. Two years later, new bone formation appeared radiologically and IFN was switched to sirolimus. One year after the switch, CSF rhinorrhea disappeared. Antiangiogenic therapy might inhibit proliferation of vascular endothelial cells in osteolytic lesions and lead to new bone formation.

  17. Antiangiogenic immunotherapy targeting Flk-1, DNA vaccine and adoptive T cell transfer, inhibits ocular neovascularization

    SciTech Connect

    Zhang, Han; Sonoda, Koh-Hei; Hijioka, Kuniaki; Qiao, Hong; Oshima, Yuji; Ishibashi, Tatsuro

    2009-04-17

    Ocular neovascularization (NV) is the primary cause of blindness in a wide range of ocular diseases. The exact mechanism underlying the pathogenesis of ocular NV is not yet well understood, and so there is no satisfactory therapy for ocular NV. Here, we describe a strategy targeting Flk-1, a self-antigen overexpressed on proliferating endothelial cells in ocular NV, by antiangiogenic immunotherapy-DNA vaccine and adoptive T cell therapy. An oral DNA vaccine encoding Flk-1 carried by attenuated Salmonella typhimurium markedly suppressed development of laser-induced choroidal NV. We further demonstrated that adoptive transfer of vaccine-induced CD8{sup +} T cells reduced pathological preretinal NV, with a concomitant facilitation of physiological revascularization after oxygen-induced retinal vessel obliteration. However, physiological retinal vascular development was unaffected in neonatal mice transferred with vaccine-induced CD8{sup +} T cells. These findings suggested that antiangiogenic immunotherapy targeting Flk-1 such as vaccination and adoptive immunotherapy may contribute to future therapies for ocular NV.

  18. Antitumor and antiangiogenic activity of Schisandra chinensis polysaccharide in a renal cell carcinoma model.

    PubMed

    Qu, Hai-Ming; Liu, Shi-Jian; Zhang, Chun-Ying

    2014-05-01

    The aim of this study was to determine the antitumor and antiangiogenic effects of the Schisandra chinensis polysaccharides (SCP) in selected renal cell carcinoma (RCC) cells and evaluate its potential mechanism of action. In vitro, endothelial growth factor (VEGF) secretion by Caki-1 was blockaded in response to SCP treatment for 48h. In vivo, a significant tumor growth inhibition effect was observed after SCP administration for 4 weeks. Moreover, SCP treatment decreased the level of VEGF, CD31 and CD34 in RCC tumor tissues. Further analysis of the tumor inhibition mechanism indicated that the number of apoptotic tumor cells increased significantly; the expression of Bax and p53 increased; and the expression of Bcl-2 decreased dramatically in transplanted tumor tissues following SCP administration. These results indicated that the potential mechanisms involved by which SCP exerted its antitumor and antiangiogenic activity might be associated with the up-regulation of Bax and p53, downregulation of Bcl-2, as well as the reduction of VEGF, CD31 and CD34 in xenografted tumors. These findings demonstrated that the SCP is a potential antitumor agent for RCC treatment.

  19. A novel polypeptide from shark cartilage with potent anti-angiogenic activity.

    PubMed

    Zheng, Lanhong; Ling, Peixue; Wang, Zheng; Niu, Rongli; Hu, Chaoxin; Zhang, Tianmin; Lin, Xiukun

    2007-05-01

    Using guanidine-HCl extraction, acetone precipitation, ultra-filtration and chromatography, a novel polypeptide with potent anti-angiogenic activity was purified from cartilage of the shark, Prionace glauca. N-terminal amino acid sequence analysis and SDS-PAGE revealed that the substance is a novel polypeptide with MW 15500 (PG155). The anti-angiogenic effects of PG155 were evaluated using zebrafish embryos model in vivo. Treatment of the embryos with 20 microg/ml PG155 resulted in a significant reduction in the growth of subintestinal vessels (SIVs). A higher dose resulted in almost complete inhibition of SIV growth, as observed by endogenous alkaline phosphatase (EAP) staining assay. An in vitro transwell experiment revealed that the polypeptide inhibited vascular endothelial growth factor (VEGF) induced migration and tubulogenesis of human umbilical vein endothelial cells (HUVECs). Exposure of HUVECs in 20 microg/ml PG155 significantly decreased the density of migrated cells. Almost complete inhibition of cell migration was found when HUVECs were treated with 40-80 microg/ml PG155. PG155 (20 microg/ml) markedly inhibited the tube formation of HUVECs and a dose-dependent effect was also found when treatment of HUVECs with PG155 at the concentration from 20-160 microg/ml.

  20. Acquired resistance with epigenetic alterations under long-term anti-angiogenic therapy for hepatocellular carcinoma.

    PubMed

    Ohata, Yoshiteru; Shimada, Shu; Akiyama, Yoshimitsu; Mogushi, Kaoru; Nakao, Keisuke; Matsumura, Satoshi; Aihara, Arihiro; Mitsunori, Yusuke; Ban, Daisuke; Ochiai, Takanori; Kudo, Atsushi; Arii, Shigeki; Tanabe, Minoru; Tanaka, Shinji

    2017-02-28

    Anti-angiogenic therapy is initially effective for several solid tumors including hepatocellular carcinoma (HCC); however, they finally relapse and progress, resulting in poor prognosis. We here established in vivo drug-tolerant subclones of human HCC cells by long-term treatment with vascular endothelial growth factor receptor (VEGFR) inhibitor and serial transplantation in immunocompromised mice (total 12 months), and then compared them with the parental cells in molecular and biological features. Gene expression profiles elucidated a G-actin monomer binding protein thymosin β 4 (Tβ4) as one of the genes enriched in the resistant cancer cells relative to the initially sensitive ones. Highlighting epigenetic alterations involved in drug resistance, we revealed that Tβ4 could be aberrantly expressed following demethylation of DNA and active modification of histone H3 at the promoter region. Ectopic overexpression of Tβ4 in HCC cells could significantly enhance sphere-forming capacities and infiltrating phenotypes in vitro, and promote growth of tumors refractory to the VEGFR mutltikinase inhibitor sorafenib in vivo. Clinically, sorafenib failed to improve the progression-free survival in patients with Tβ4-high HCC, indicating that Tβ4 expression could be available as a surrogate marker of susceptibility to this drug. This study suggests that Tβ4 expression triggered by epigenetic alterations could contribute to the development of resistance to anti-angiogenic therapy by the acquisition of stemness, and that epigenetic control might be one of the key targets to regulate the resistance in HCC.

  1. Neoadjuvant antiangiogenic therapy reveals contrasts in primary and metastatic tumor efficacy.

    PubMed

    Ebos, John M L; Mastri, Michalis; Lee, Christina R; Tracz, Amanda; Hudson, John M; Attwood, Kristopher; Cruz-Munoz, William R; Jedeszko, Christopher; Burns, Peter; Kerbel, Robert S

    2014-10-31

    Thousands of cancer patients are currently in clinical trials evaluating antiangiogenic therapy in the neoadjuvant setting, which is the treatment of localized primary tumors prior to surgical intervention. The rationale is that shrinking a tumor will improve surgical outcomes and minimize growth of occult micrometastatic disease-thus delaying post-surgical recurrence and improving survival. But approved VEGF pathway inhibitors have not been tested in clinically relevant neoadjuvant models that compare pre- and post-surgical treatment effects. Using mouse models of breast, kidney, and melanoma metastasis, we demonstrate that primary tumor responses to neoadjuvant VEGFR TKI treatment do not consistently correlate with improved post-surgical survival, with survival worsened in certain settings. Similar negative effects did not extend to protein-based VEGF pathway inhibitors and could be reversed with altered dose, surgical timing, and treatment duration, or when VEGFR TKIs are combined with metronomic 'anti-metastatic' chemotherapy regimens. These studies represent the first attempt to recapitulate the complex clinical parameters of neoadjuvant therapy in mice and identify a novel tool to compare systemic antiangiogenic treatment effects on localized and disseminated disease.

  2. Pharmacogenetics of antiangiogenic and antineovascular therapies of age-related macular degeneration.

    PubMed

    Agosta, Elisa; Lazzeri, Stefano; Orlandi, Paola; Figus, Michele; Fioravanti, Anna; Di Desidero, Teresa; Sartini, Maria Sole; Nardi, Marco; Danesi, Romano; Bocci, Guido

    2012-07-01

    Age-related macular degeneration (AMD), the most common age-related disease causing irreversible visual loss in industrialized countries, is a complex and multifactorial illness. Researchers have found components of the complement alternative pathway inside drusen and Bruch's membrane of AMD patients, underlying a possible important role of complement factor H in the pathogenesis of AMD. The neovascular (wet) AMD is the most destructive form and it is characterized by invasion of new blood vessels into subretinal spaces with subsequent exudation and bleeding, resulting in scarring of the macular region and loss of the central vision. The hallmark of the neovascular form is the choroidal neovascularization, where VEGF-A has an important role in the pathogenesis of the disease. SNPs of these genes have recently been investigated as potential pharmacogenetic markers of the antiangiogenic and antineovascular therapy of AMD, which includes verteporfin photodynamic therapy and anti-VEGF-A drugs, such as pegaptanib, bevacizumab and ranibizumab. The CFH rs1061170 CT and TT genotypes have been associated with an improvement of visual acuity in bevacizumab or ranibizumab treated patients, whereas patients harboring VEGF-A rs699946 G allele responded better to bevacizumab-based therapy if compared with patients carrying the A allele. In conclusion, the discovery of pharmacogenetic markers for the personalization of the antiangiogenic and/or antineovascular therapy could be, in the future, a key issue in ophthalmology to obtain a personalization of the therapy and to avoid unnecessary costs and adverse drug reactions.

  3. Predictive biomarker candidates to delineate efficacy of antiangiogenic treatment in renal cell carcinoma.

    PubMed

    Romero-Laorden, N; Doger, B; Hernandez, M; Hernandez, C; Rodriguez-Moreno, J F; Garcia-Donas, J

    2016-01-01

    Antiangiogenic therapy is currently considered as the cornerstone of treatment in metastatic kidney cancer. A monoclonal antibody against the vascular endothelial growth factor (VEGF) and several tyrosine kinase inhibitors targeting the VEGF receptors demonstrated, 7 years ago, to deeply impact the outcome of this tumor and became a model of integration of molecular knowledge into clinical practice. Unfortunately, no further improvement in survival has been made and 20-25 % of cases remain primary refractory to these drugs, with an overall dismal prognosis. Since biomarker predictors of activity are lacking, their development could highly help in the process of making clinical decisions when choosing the best option for every patient or prompting the inclusion in clinical trials. This unmet medical need could become even more relevant if new immunotherapy confirms its initial promising results in this pathology. In this article, we provide an insight of current state of the art regarding the prediction of antiangiogenic efficacy in kidney cancer and propose new strategies for the implementation of such markers in clinical practice.

  4. Age-Related Macular Degeneration: Clinical Findings following Treatment with Antiangiogenic Drugs.

    PubMed

    Casaroli-Marano, Ricardo; Gallego-Pinazo, Roberto; Fernández-Blanco, Clemencia Torrón; Figueroa, Marta S; Pina Marín, Begoña; Fernández-Baca Vaca, Gustavo; Piñero-Bustamante, Antonio; Donate López, Juan; García-Arumí, José; Farrés Martí, Jordi

    2014-01-01

    Purpose. To survey the management of patients with neovascular age-related macular degeneration (nvAMD) in Spain. Methods. An observational retrospective multicenter study was conducted. The variables analyzed were sociodemographic characteristics, foveal and macular thickness, visual acuity (VA), type of treatment, number of injections, and the initial administration of a loading dose of an antiangiogenic drug. Results. 208 patients were followed up during 23.4 months in average. During the first and second years, patients received a mean of 4.5 ± 1.8 and 1.6 ± 2.1 injections of antiangiogenic drugs, and 5.4 ± 2.8 and 3.6 ± 2.2 follow-up visits were performed, respectively. The highest improvement in VA was observed at 3 months of follow-up, followed by a decrease in the response that stabilized above baseline values until the end of the study. Patients who received an initial loading dose presented greater VA gains than those without. Conclusions. Our results suggest the need for a more standardized approach in the management and diagnosis of nvAMD receiving VEGF inhibitors. To achieve the visual outcomes reported in pivotal trials, an early diagnosis, proactive approach (more treating than follow-up visits), and a close monitoring might be the key to successfully manage nvAMD.

  5. Anticancer and antiangiogenic activity of HPMA copolymer-aminohexylgeldanamycin-RGDfK conjugates for prostate cancer therapy.

    PubMed

    Greish, Khaled; Ray, Abhijit; Bauer, Hillevi; Larson, Nate; Malugin, Alexander; Pike, Daniel; Haider, Mohamed; Ghandehari, Hamidreza

    2011-05-10

    Tumor progression is dependent on neoangiogenesis for blood supply. Neovasculature over-express α(v)β(3) integrins which recognize the Arg-Gly-Asp (RGD) sequence in the extracellular matrix. N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing side chains terminated in cyclic RGD analogs such as RGDfK show increased accumulation in prostate tumors. Geldanamycin and their derivatives (e.g., aminohexylgeldanamycin (AH-GDM)) are benzoquinone ansamycins that have both antiangiogenic and antitumor activity. In this work the antiangiogenic and antitumor activities of targetable HPMA copolymer-RGDfK-AH-GDM conjugates were compared with non-targetable systems in vitro and in vivo. Copolymer-drug conjugates containing RGDfK in the side chains showed superior activity against endothelial and prostate cancer cell lines in vitro, as well as higher inhibition of angiogenesis in vivo. At equimolar doses of the drug, the RGDfK containing conjugates showed significantly higher antitumor activity in nude mice bearing DU-145 human prostate cancer xenografts. These findings suggest the utility of HPMA copolymer-RGDfK conjugates for targeted delivery of geldanamycin analogs with a dual mode of action.

  6. GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance

    PubMed Central

    Kuang, Ruby; Jahangiri, Arman; Mascharak, Smita; Nguyen, Alan; Flanigan, Patrick M.; Yagnik, Garima; Wagner, Jeffrey R.; De Lay, Michael; Carrera, Diego; Castro, Brandyn A.; Hayes, Josie; Sidorov, Maxim; Garcia, Jose Luiz Izquierdo; Eriksson, Pia; Ronen, Sabrina; Phillips, Joanna; Koliwad, Suneil; Aghi, Manish K.

    2017-01-01

    Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, 13C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α–dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation–selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3β inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments. PMID:28138554

  7. Antiangiogenic and tumour inhibitory effects of downregulating tumour endothelial FABP4

    PubMed Central

    Harjes, U; Bridges, E; Gharpure, K M; Roxanis, I; Sheldon, H; Miranda, F; Mangala, L S; Pradeep, S; Lopez-Berestein, G; Ahmed, A; Fielding, B; Sood, A K; Harris, A L

    2017-01-01

    Fatty acid binding protein 4 (FABP4) is a fatty acid chaperone, which is induced during adipocyte differentiation. Previously we have shown that FABP4 in endothelial cells is induced by the NOTCH1 signalling pathway, the latter of which is involved in mechanisms of resistance to antiangiogenic tumour therapy. Here, we investigated the role of FABP4 in endothelial fatty acid metabolism and tumour angiogenesis. We analysed the effect of transient FABP4 knockdown in human umbilical vein endothelial cells on fatty acid metabolism, viability and angiogenesis. Through therapeutic delivery of siRNA targeting mouse FABP4, we investigated the effect of endothelial FABP4 knockdown on tumour growth and blood vessel formation. In vitro, siRNA-mediated FABP4 knockdown in endothelial cells led to a marked increase of endothelial fatty acid oxidation, an increase of reactive oxygen species and decreased angiogenesis. In vivo, we found that increased NOTCH1 signalling in tumour xenografts led to increased expression of endothelial FABP4 that decreased when NOTCH1 and VEGFA inhibitors were used in combination. Angiogenesis, growth and metastasis in ovarian tumour xenografts were markedly inhibited by therapeutic siRNA delivery targeting mouse endothelial FABP4. Therapeutic targeting of endothelial FABP4 by siRNA in vivo has antiangiogenic and antitumour effects with minimal toxicity and should be investigated further. PMID:27568980

  8. Substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamides as antimitotics. Antiproliferative, antiangiogenic and antitumoral activity, and quantitative structure-activity relationships.

    PubMed

    Fortin, Sébastien; Wei, Lianhu; Moreau, Emmanuel; Lacroix, Jacques; Côté, Marie-France; Petitclerc, Eric; Kotra, Lakshmi P; Gaudreault, René C

    2011-11-01

    The importance of the bridge linking the two phenyl moieties of substituted phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs) was assessed using a sulfonamide group, which is a bioisostere of sulfonate and ethenyl groups. Forty one phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonamide (PIB-SA) derivatives were prepared and biologically evaluated. PIB-SAs exhibit antiproliferative activities at the nanomolar level against sixteen cancer cell lines, block the cell cycle progression in G(2)/M phase, leading to cytoskeleton disruption and anoikis. These results were subjected to CoMFA and CoMSIA analyses to establish quantitative structure-activity relationships. These results evidence that the sulfonate and sulfonamide moieties are reciprocal bioisosteres and that phenylimidazolidin-2-one could mimic the trimethoxyphenyl moiety found in the structure of numerous potent antimicrotubule agents. Finally, compounds 16 and 17 exhibited potent antitumor and antiangiogenic activities on HT-1080 fibrosarcoma cells grafted onto chick chorioallantoic membrane similar to CA-4 without significant toxicity for the chick embryos, making this class of compounds a promising class of anticancer agents.

  9. Thrombospondin-1 as a Paradigm for the Development of Antiangiogenic Agents Endowed with Multiple Mechanisms of Action

    PubMed Central

    Rusnati, Marco; Urbinati, Chiara; Bonifacio, Silvia; Presta, Marco; Taraboletti, Giulia

    2010-01-01

    Uncontrolled neovascularization occurs in several angiogenesis-dependent diseases, including cancer. Neovascularization is tightly controlled by the balance between angiogenic growth factors and antiangiogenic agents. The various natural angiogenesis inhibitors identified so far affect neovascularization by different mechanisms of action. Thrombospondin-1 (TSP-1) is a matricellular modular glycoprotein that acts as a powerful endogenous inhibitor of angiogenesis. It acts both indirectly, by sequestering angiogenic growth factors and effectors in the extracellular environment, and directly, by inducing an antiangiogenic program in endothelial cells following engagement of specific receptors including CD36, CD47, integrins and proteoglycans (all involved in angiogenesis ). In view of its central, multifaceted role in angiogenesis, TSP-1 has served as a source of antiangiogenic tools, including TSP-1 fragments, synthetic peptides and peptidomimetics, gene therapy strategies, and agents that up-regulate TSP-1 expression. This review discusses TSP-1-based inhibitors of angiogenesis, their mechanisms of action and therapeutic potential, drawing our experience with angiogenic growth factor-interacting TSP-1 peptides, and the possibility of exploiting them to design novel antiangiogenic agents. PMID:27713299

  10. Antiangiogenic therapy using endostatin increases the number of ALDH+ lung cancer stem cells by generating intratumor hypoxia

    PubMed Central

    Yu, Yang; Wang, Yu-yi; Wang, Yi-qin; Wang, Xia; Liu, Yan-Yang; Wang, Jian-Tao; Du, Chi; Wang, Li; Li, Mei; Luo, Feng; Jiang, Ming

    2016-01-01

    Antiangiogenic therapy is becoming a promising option for cancer treatment. However, many investigations have recently indicated that these therapies may have limited efficacy, and the cancers in most patients eventually develop resistance to these therapies. There is considerable recently acquired evidence for an association of such resistance with cancer stem-like cells (CSLCs). Here, we used xenograft tumor murine models to further suggest that antiangiogenic agents actually increase the invasive and metastatic properties of lung cancer cells. In our experiments with murine lung cancer xenografts, we found that the antiangiogenic agent endostatin increased the population of ALDH+ cells, and did so by generating intratumoral hypoxia in the xenografts. We further showed endostatin to cause an increase in the CSLC population by accelerating the generation of tumor hypoxia and by recruiting TAMs, MDSCs and Treg cells, which are inflammatory and immunosuppressive cells and which can secrete cytokines and growth factors such as IL-6, EGF, and TGF-β into the tumor microenvironment. All these factors are related with increased CSLC population in tumors. These results imply that improving the clinical efficacy of antiangiogenic treatments will require the concurrent use of CSLC-targeting agents. PMID:27703219

  11. Antiangiogenic gene therapy of solid tumor by systemic injection of polyplex micelles loading plasmid DNA encoding soluble flt-1.

    PubMed

    Oba, Makoto; Vachutinsky, Yelena; Miyata, Kanjiro; Kano, Mitsunobu R; Ikeda, Sorato; Nishiyama, Nobuhiro; Itaka, Keiji; Miyazono, Kohei; Koyama, Hiroyuki; Kataoka, Kazunori

    2010-04-05

    In this study, a polyplex micelle was developed as a potential formulation for antiangiogenic gene therapy of subcutaneous pancreatic tumor model. Poly(ethylene glycol)-poly(l-lysine) block copolymers (PEG-PLys) with thiol groups in the side chain of the PLys segment were synthesized and applied for preparation of disulfide cross-linked polyplex micelles through ion complexation with plasmid DNA (pDNA) encoding the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sFlt-1), which is a potent antiangiogenic molecule. Antitumor activity and gene expression of polyplex micelles with various cross-linking rates were evaluated in mice bearing subcutaneously xenografted BxPC3 cell line, derived from human pancreatic adenocarcinoma, and polyplex micelles with optimal cross-linking rate achieved effective suppression of tumor growth. Significant gene expression of this micelle was detected selectively in tumor tissue, and its antiangiogenic effect was confirmed by decreased vascular density inside the tumor. Therefore, the disulfide cross-linked polyplex micelle loading sFlt-1 pDNA has a great potential for antiangiogenic therapy against subcutaneous pancreatic tumor model by systemic application.

  12. Anticancer and antiangiogenic activity of surfactant-free nanoparticles based on self-assembled polymeric derivatives of vitamin E: structure-activity relationship.

    PubMed

    Palao-Suay, Raquel; Aguilar, María Rosa; Parra-Ruiz, Francisco J; Fernández-Gutiérrez, Mar; Parra, Juan; Sánchez-Rodríguez, Carolina; Sanz-Fernández, Ricardo; Rodrigáñez, Laura; Román, Julio San

    2015-05-11

    α-Tocopheryl succinate (α-TOS) is a well-known mitochondrially targeted anticancer compound, however, it is highly hydrophobic and toxic. In order to improve its activity and reduce its toxicity, new surfactant-free biologically active nanoparticles (NP) were synthesized. A methacrylic derivative of α-TOS (MTOS) was prepared and incorporated in amphiphilic pseudoblock copolymers when copolymerized with N-vinylpyrrolidone (VP) by free radical polymerization (poly(VP-co-MTOS)). The selected poly(VP-co-MTOS) copolymers formed surfactant-free NP by nanoprecipitation with sizes between 96 and 220 nm and narrow size distribution, and the in vitro biological activity was tested. In order to understand the structure-activity relationship three other methacrylic monomers were synthesized and characterized: MVE did not have the succinate group, SPHY did not have the chromanol ring, and MPHY did not have both the succinate group and the chromanol ring. The corresponding families of copolymers (poly(VP-co-MVE), poly(VP-co-SPHY), and poly(VP-co-MPHY)) were synthesized and characterized, and their biological activity was compared to poly(VP-co-MTOS). Both poly(VP-co-MTOS) and poly(VP-co-MVE) presented triple action: reduced cell viability of cancer cells with little or no harm to normal cells (anticancer), reduced viability of proliferating endothelial cells with little or no harm to quiescent endothelial cells (antiangiogenic), and efficiently encapsulated hydrophobic molecules (nanocarrier). The anticancer and antiangiogenic activity of the synthesized copolymers is demonstrated as the active compound (vitamin E or α-tocopheryl succinate) do not need to be cleaved to trigger the biological action targeting ubiquinone binding sites of complex II. Poly(VP-co-SPHY) and poly(VP-co-MPHY) also formed surfactant-free NP that were also endocyted by the assayed cells; however, these NP did not selectively reduce cell viability of cancer cells. Therefore, the chromanol ring of the

  13. Anti-angiogenic treatment promotes triple-negative breast cancer invasion via vasculogenic mimicry.

    PubMed

    Sun, Huizhi; Zhang, Danfang; Yao, Zhi; Lin, Xian; Liu, Jiameng; Gu, Qiang; Dong, Xueyi; Liu, Fang; Wang, Yi; Yao, Nan; Cheng, Siqi; Li, Linqi; Sun, Shuya

    2017-02-21

    Agents that target angiogenesis have shown limited efficacy for human triple-negative breast cancer (TNBC) in clinical trials. Along with endothelium-dependent vessels, there is also vasculogenic mimicry (VM) in the microcirculation of malignant tumors. The role of VM is not completely understood regarding anti-angiogenic treatment. In this study, human TNBC MDA-MB-231 and Hs578T and non-TNBC MCF-7 and BT474 tumor-bearing mice were treated with sunitinib, an anti-angiogenic drug, using a clinically relevant schedule. The drug was administered for one week and then discontinued. Tumor growth and invasion were observed, and the microcirculation patterns were detected with PAS/endomucin staining. Moreover, hypoxia and VM-associated proteins were evaluated with Hypoxyprobe kits and immunohistochemistry, respectively. Sunitinib significantly inhibited tumor growth in the TNBC and non-TNBC tumors. However, MDA-MB-231 and Hs578T tumors regrew and were more aggressive when the treatment was stopped. The discontinuation had no significant effect on the behavior of the non-TNBC MCF-7 and BT474 tumors. The growth of endothelium-dependent vessels in the TNBC MDA-MB-231 and Hs578T tumors were blocked by sunitinib, during which the number of VM channels significantly increased and resulted in a rebound of endothelium-dependent vessels after sunitinib discontinuation. Moreover, the VM-associated proteins VE-cadherin and Twist1 upregulated in the sunitinib-treated MDA-MB-231 and Hs578T tumors. Furthermore, the clinical significance of this upregulation was validated in 174 human breast cancers. The results from human breast cancer specimens indicated that there were more VM-positive TNBC cases than those in non-TNBC cases. HIF-1α, MMP2, VE-cadherin, and Twist1 were also expressed in a higher level in human TNBC compared with non-TNBC. In aconclusion, sunitinib promoted TNBC invasion by VM. The VM status could be helpful to predict the efficacy of anti-angiogenic therapy in

  14. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor

    PubMed Central

    Hawkins-Daarud, Andrea; Rockne, Russell C.; Anderson, Alexander R. A.; Swanson, Kristin R.

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  15. Modeling Tumor-Associated Edema in Gliomas during Anti-Angiogenic Therapy and Its Impact on Imageable Tumor.

    PubMed

    Hawkins-Daarud, Andrea; Rockne, Russell C; Anderson, Alexander R A; Swanson, Kristin R

    2013-01-01

    Glioblastoma, the most aggressive form of primary brain tumor, is predominantly assessed with gadolinium-enhanced T1-weighted (T1Gd) and T2-weighted magnetic resonance imaging (MRI). Pixel intensity enhancement on the T1Gd image is understood to correspond to the gadolinium contrast agent leaking from the tumor-induced neovasculature, while hyperintensity on the T2/FLAIR images corresponds with edema and infiltrated tumor cells. None of these modalities directly show tumor cells; rather, they capture abnormalities in the microenvironment caused by the presence of tumor cells. Thus, assessing disease response after treatments impacting the microenvironment remains challenging through the obscuring lens of MR imaging. Anti-angiogenic therapies have been used in the treatment of gliomas with spurious results ranging from no apparent response to significant imaging improvement with the potential for extremely diffuse patterns of tumor recurrence on imaging and autopsy. Anti-angiogenic treatment normalizes the vasculature, effectively decreasing vessel permeability and thus reducing tumor-induced edema, drastically altering T2-weighted MRI. We extend a previously developed mathematical model of glioma growth to explicitly incorporate edema formation allowing us to directly characterize and potentially predict the effects of anti-angiogenics on imageable tumor growth. A comparison of simulated glioma growth and imaging enhancement with and without bevacizumab supports the current understanding that anti-angiogenic treatment can serve as a surrogate for steroids and the clinically driven hypothesis that anti-angiogenic treatment may not have any significant effect on the growth dynamics of the overall tumor cell populations. However, the simulations do illustrate a potentially large impact on the level of edematous extracellular fluid, and thus on what would be imageable on T2/FLAIR MR. Additionally, by evaluating virtual tumors with varying growth kinetics, we see tumors

  16. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy.

    PubMed

    Tartour, Eric; Pere, H; Maillere, B; Terme, M; Merillon, N; Taieb, J; Sandoval, F; Quintin-Colonna, F; Lacerda, K; Karadimou, A; Badoual, C; Tedgui, A; Fridman, W H; Oudard, S

    2011-03-01

    The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor-associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF…), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17…) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFβ), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells…) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy.

  17. Surgical implantation of steroids with antiangiogenic characteristics for treating neovascular age-related macular degeneration

    PubMed Central

    Geltzer, Arthur; Turalba, Angela; Vedula, Satyanarayana S

    2014-01-01

    Background Neovascular age-related macular degeneration (AMD) is associated with rapid vision loss due to choroidal neovascularization (CNV), leakage, and scarring. Steroids have gained attention in their role for the treatment of neovascular AMD for their antiangiogenic and anti-inflammatory properties. Objectives This review aims to examine effects of steroids with antiangiogenic properties in the treatment of neovascular AMD. Search methods We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 11), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to November 2012), EMBASE (January 1980 to November 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2012), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 21 November 2012. Selection criteria We included randomized controlled clinical trials of intra- and peri-ocular antiangiogenic steroids in people diagnosed with neovascular AMD. Data collection and analysis Two authors independently screened abstracts and full-text articles, assessed risk of bias in the included trials, and extracted data. We did not conduct a meta-analysis. Main results We included three trials after screening a total of 1503 abstracts and 21 full-text articles. The three trials included a total of 809 participants. One trial compared different doses of acetonide anecortave acetate with placebo, a second trial compared triamcinolone acetonide versus placebo, and the third trial compared anecortave acetate against photodynamic therapy (PDT). We did not conduct a

  18. Optimal biologic dose of metronomic chemotherapy regimens is associated with maximum antiangiogenic activity.

    PubMed

    Shaked, Yuval; Emmenegger, Urban; Man, Shan; Cervi, Dave; Bertolini, Francesco; Ben-David, Yaacov; Kerbel, Robert S

    2005-11-01

    Low-dose metronomic chemotherapy is a promising therapeutic cancer treatment strategy thought to have an antiangiogenic basis. However, the advantages of reduced toxicity, increased efficacy in some cases, and ability to combine chemotherapy administered long term in this way with targeted therapies can be compromised by the empiricism associated with determining the optimum biologic dose (OBD). Using 4 distinct metronomic chemotherapy regimens in 4 different preclinical tumor models, including a hematologic malignancy, we established the OBD by determining the maximum efficacy associated with minimum or no toxicity. We then found each OBD to be strikingly correlated with the maximum reduction in viable peripheral blood circulating vascular endothelial growth factor receptor 2-positive (VEGFR-2+) endothelial precursors (CEPs). These results suggest that CEPs may serve as a pharmacodynamic biomarker to determine the OBD of metronomic chemotherapy regimens.

  19. Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis

    PubMed Central

    Pàez-Ribes, Marta; Allen, Elizabeth; Hudock, James; Takeda, Takaaki; Okuyama, Hiroaki; Viñals, Francesc; Inoue, Masahiro; Bergers, Gabriele; Hanahan, Douglas; Casanovas, Oriol

    2009-01-01

    SUMMARY Multiple angiogenesis inhibitors have been therapeutically validated in preclinical cancer models, and several in clinical trials. Here we report that angiogenesis inhibitors targeting the VEGF pathway demonstrate antitumor effects in mouse models of pancreatic neuroendocrine carcinoma and glioblastoma but concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness and in some cases increased lymphatic and distant metastasis. Increased invasiveness is also seen by genetic ablation of the Vegf-A gene in both models, substantiating the results of the pharmacological inhibitors. The realization that potent angiogenesis inhibition can alter the natural history of tumors by increasing invasion and metastasis warrants clinical investigation, as the prospect has important implications for the development of enduring antiangiogenic therapies. PMID:19249680

  20. Anti-angiogenic activity of a novel synthetic agent, 9alpha-fluoromedroxyprogesterone acetate.

    PubMed

    Yamaji, T; Tsuboi, H; Murata, N; Uchida, M; Kohno, T; Sugino, E; Hibino, S; Shimamura, M; Oikawa, T

    1999-10-18

    9Alpha-fluoromedroxyprogesterone acetate (FMPA) is a novel synthetic analog of medroxyprogesterone acetate (MPA), widely used as therapeutic agent for breast and endometrium cancers. FMPA showed almost the same binding affinities to the progesterone and glucocorticoid receptors as MPA. In the rabbit corneal assay, FMPA, MPA and fumagillin significantly inhibited the angiogenic response induced by rat mammary tumor at doses of 0. 1, 1 and 50 microg/pellet, respectively, so FMPA showed greater anti-angiogenic activity than MPA and fumagillin. In the mouse dorsal air sac method, FMPA inhibited the mouse sarcoma 180 cell-induced angiogenesis by oral administration at a dose of 200 mg/kg. FMPA inhibited the activity of plasminogen activator (PA) in bovine endothelial cells. These results suggest that FMPA may be useful for diseases associated with angiogenesis by oral administration.

  1. IL-20, an anti-angiogenic cytokine that inhibits COX-2 expression.

    PubMed

    Heuzé-Vourc'h, Nathalie; Liu, Ming; Dalwadi, Harnisha; Baratelli, Felicita E; Zhu, Li; Goodglick, Lee; Põld, Mehis; Sharma, Sherven; Ramirez, Ruben D; Shay, Jerry W; Minna, John D; Strieter, Robert M; Dubinett, Steven M

    2005-07-29

    COX-2 overexpression and subsequent PGE(2) production are frequently associated with non-small cell lung cancer and are implicated in tumor-mediated angiogenesis. Here, we report for the first time that IL-20 downregulates COX-2 and PGE(2) in human bronchial epithelial and endothelial cells. Flow cytometry analysis suggests that IL-20-dependent inhibition of COX-2/PGE(2) occurs through the IL-22R1/IL-20R2 dimers. In addition, we report that IL-20 exerts anti-angiogenic effects, inhibiting experimental angiogenesis. IL-20-mediated inhibition of PMA-induced angiogenesis occurs through the COX-2 regulatory pathway. Altogether our findings revealed that IL-20 is a negative modulator of COX-2/PGE(2) and inhibits angiogenesis.

  2. A new phenylacetate-bisphosphonate inhibits breast cancer cell growth by proapoptotic and antiangiogenic effects.

    PubMed

    Sebbah-Louriki, Malika; Colombo, Bruno M; el Manouni, Driss; Martin, Antoine; Salzmann, Jean-Loup; Leroux, Yves; Perret, Gérard Y; Crépin, Michel

    2002-01-01

    Sodium phenylacetate (NaPa) and some bisphosphonates demonstrated antiproliferative and proapoptotic properties against cancer. We have previously shown that NaPa inhibited cell proliferation of MCF7-ras tumor breast cells both in vitro and in vivo. On the other hand, bisphosphonate activities have only been demonstrated in vitro. Here we evaluated the antitumor effects of a new bisphosphonate, the phenylacetate-bisphosphonate (PaBp), on human breast cancer MCF7 and MCF7-ras cell lines, both in vitro and in vivo. To our knowledge, this is the first report indicating the use of a bisphosphonate derivative as a powerful cytostatic and cytotoxic agent, with proapoptotic and antiangiogenic properties on human breast cancer cells lines, with no animal toxicity.

  3. NI-23BRAIN BREAST METASTASES RESPOND TO ANTI-ANGIOGENIC THERAPY BY MODES OF VASCULAR NORMALIZATION

    PubMed Central

    Emblem, Kyrre; Pinho, Marco; Chandra, Vyshak; Gerstner, Elizabeth; Stufflebeam, Steve; Sorenson, Greg; Harris, Gordon; Freedman, Rachel; Sohl, Jessica; Younger, Jerry; Krop, Ian; Winer, Eric; Lin, Nancy

    2014-01-01

    INTRODUCTION: As systemic therapy improves, brain metastases are increasingly common in patients with breast cancer. Unfortunately, effective therapy with durable control has remained elusive [1]. Combining bevacizumab and cyototoxic chemotherapy is an appealing approach as the anti-angiogenic effect of bevicizumab may improve delivery of cytotoxic drugs to brain tumors. METHODS: We conducted a Phase II study of patients with parenchymal brain metastasis treated with bevacizumab and carboplatin [2]. Patients could have any hormone receptor status or any number of prior therapies. Patients with HER2+ breast cancer also received trastuzamab. Correlative perfusion MRI scans to look at tumor perfusion, blood volume, vessel calibers and relative oxygen saturation (ΔSO2) levels were performed at baseline, day 1, and after 2 months of therapy [3, 4]. For consistency, the largest contrast-enhancing lesion in each patient visible on all three MR visits was selected for analysis. RESULTS: Thirty-eight patients were enrolled in the study of which 32 had, paired evaluable imaging datasets. Compared to baseline, 12/32 patients were identified as responders by a durable increase in ΔSO2 levels at day 1 and at 2 months above a 5% measurement error threshold. The remaining patients were identified by stable (15/32) or reduced (5/32) ΔSO2 levels. Patients responding to therapy showed increased tumor perfusion (Mann-Whitney; P<0.01) and prolonged survival (625 versus 400 days, Cox regression; P<0.05) Fig. 1B). A collective and selective pruning of macroscopic tumor vessels (>10 µm) were seen across all patients. CONCLUSIONS: Similar to primary brain tumors [2, 3], perfusion MRI demonstrates that anti-angiogenic therapy can induce vascular normalization in a subset of patients with metastatic breast cancer to the brain. Our data indicate that the vascular response may also be associated with improved survival. [1] Lin NU, Lancet Oncol 2013 [2] Sorensen AG, Cancer Res 2012 [3

  4. Antenatal corticosteroids impact the inflammatory rather than the antiangiogenic profile of women with preeclampsia.

    PubMed

    Nayeri, Unzila A; Buhimschi, Irina A; Laky, Christine A; Cross, Sarah N; Duzyj, Christina M; Ramma, Wenda; Sibai, Baha M; Funai, Edmund F; Ahmed, Asif; Buhimschi, Catalin S

    2014-06-01

    Circulating antiangiogenic factors and proinflammatory cytokines are implicated in the pathogenesis of preeclampsia. This study was performed to test the hypothesis that steroids modify the balance of inflammatory and proangiogenic and antiangiogenic factors that potentially contribute to the patient's evolving clinical state. Seventy singleton women, admitted for antenatal corticosteroid treatment, were enrolled prospectively. The study group consisted of 45 hypertensive women: chronic hypertension (n=6), severe preeclampsia (n=32), and superimposed preeclampsia (n=7). Normotensive women with shortened cervix (<2.5 cm) served as controls (n=25). Maternal blood samples of preeclampsia cases were obtained before steroids and then serially up until delivery. A clinical severity score was designed to clinically monitor disease progression. Serum levels of angiogenic factors (soluble fms-like tyrosine kinase-1 [sFlt-1], placental growth factor [PlGF], soluble endoglin [sEng]), endothelin-1 (ET-1), and proinflammatory markers (IL-6, C-reactive protein [CRP]) were assessed before and after steroids. Soluble IL-2 receptor (sIL-2R) and total immunoglobulins (IgG) were measured as markers of T- and B-cell activation, respectively. Steroid treatment coincided with a transient improvement in clinical manifestations of preeclampsia. A significant decrease in IL-6 and CRP was observed although levels of sIL-2R and IgG remained unchanged. Antenatal corticosteroids did not influence the levels of angiogenic factors but ET-1 levels registered a short-lived increase poststeroids. Although a reduction in specific inflammatory mediators in response to antenatal steroids may account for the transient improvement in clinical signs of preeclampsia, inflammation is unlikely to be the major contributor to severe preeclampsia or useful for therapeutic targeting.

  5. Anti-angiogenic activities of CRBGP from buccal glands of lampreys (Lampetra japonica).

    PubMed

    Jiang, Qi; Liu, Yu; Duan, Dandan; Gou, Meng; Wang, Hao; Wang, Jihong; Li, Qingwei; Xiao, Rong

    2016-04-01

    Cysteine-rich secretory proteins (CRISPs), characterized by 16 conserved cysteines, are distributed in a wide range of organisms, such as secernenteas, amphibians, reptiles and mammals. In the previous studies, a novel CRISP family member (cysteine-rich buccal gland protein, CRBGP) was separated from the buccal gland of lampreys (Lampetra japonica, L. japonica). Lamprey CRBGP could not only suppress depolarization-induced contraction of rat tail arterial smooth muscle, but also block voltage-gated sodium channels (VGSCs). In the present study, the anti-angiogenic activities of lamprey CRBGP were investigated using endothelial cells and chick chorioallantoic membrane (CAM) models. In vitro assays, lamprey CRBGP is able to induce human umbilical vein endothelial cells (HUVECs) apoptosis by disturbing the calcium homeostasis and mitochondria functions. In addition, lamprey CRBGP could inhibit proliferation, adhesion, migration, invasion and tube formation of HUVECs by affecting the organization of F-actin and expression level of matrix metallo-proteinase 2 (MMP-2), matrix metallo-proteinase 9 (MMP-9) and vascular endothelial growth factor A (VEGFA) which are related to angiogenesis. In vivo assays, lamprey CRBGP could suppress the blood vessel formation in CAM models. Therefore, lamprey CRBGP is an important protein present in the buccal gland of lampreys and might help lampreys suppress the contraction of blood vessels, nociceptive responses and wound healing of host fishes during their feeding time. In addition, lamprey CRBGP might have the potential to act as an effective anti-angiogenic factor for the treatment of abnormal angiogenesis induced diseases.

  6. Total alkaloids of Rubus alceifolius Poir shows anti-angiogenic activity in vivo and in vitro.

    PubMed

    Zhao, Jinyan; Lin, Wei; Zhuang, Qunchuan; Zhong, Xiaoyong; Cao, Zhiyun; Hong, Zhenfeng; Peng, Jun

    2014-11-01

    Total alkaloids is an active ingredient of the natural plant Rubus alceifolius Poir, commonly used for the treatment of various cancers. Antitumor effects may be mediated through anti-angiogenic mechanisms. As such, the goal of the present study was to investigate and evaluate the effect of total alkaloids in Rubus alceifolius Poir (TARAP) on tumor angiogenesis and investigate the underlying molecular mechanisms of TARAP action in vivo and in vitro. A chick embryo chorioallantoic membrane (CAM) assay was used to assess angiogenesis in vivo. An MTT assay was performed to determine the viability of human umbilical vein endothelial cells (HUVECs) with and without treatment. Cell cycle progression of HUVECs was examined by FACS analysis with propidium iodide staining. HUVEC migration was determined using a scratch wound method. Tube formation of HUVECs was assessed with an ECMatrix gel system, and mRNA and protein expression of VEGF-A in both HUVECs and HepG2 human hepatocellular carcinoma cells were examined by RT-PCR and ELISA, respectively. Our results showed that TARAP inhibited angiogenesis in the CAM model in vivo and inhibited HUVEC proliferation via blocking cell cycle G1 to S progression in a dose- and time-dependent manners in vitro. Moreover, TARAP inhibited HUVEC migration and tube formation and downregulated mRNA and protein expression of VEGF-A in both HepG2 cells and HUVECs. Our findings suggest that the anti-angiogenic activity of TARAP may partly contribute to its antitumor properties and may be valuable for the treatment of diseases involving pathologic angiogenesis such as cancer.

  7. Zingiber officinale attenuates retinal microvascular changes in diabetic rats via anti-inflammatory and antiangiogenic mechanisms

    PubMed Central

    Dongare, Shirish; Mathur, Rajani; Saxena, Rohit; Mathur, Sandeep; Agarwal, Renu; Nag, Tapas C.; Srivastava, Sushma; Kumar, Pankaj

    2016-01-01

    Purpose Diabetic retinopathy is a common microvascular complication of long-standing diabetes. Several complex interconnecting biochemical pathways are activated in response to hyperglycemia. These pathways culminate into proinflammatory and angiogenic effects that bring about structural and functional damage to the retinal vasculature. Since Zingiber officinale (ginger) is known for its anti-inflammatory and antiangiogenic properties, we investigated the effects of its extract standardized to 5% 6-gingerol, the major active constituent of ginger, in attenuating retinal microvascular changes in rats with streptozotocin-induced diabetes. Methods Diabetic rats were treated orally with the vehicle or the ginger extract (75 mg/kg/day) over a period of 24 weeks along with regular monitoring of bodyweight and blood glucose and weekly fundus photography. At the end of the 24-week treatment, the retinas were isolated for histopathological examination under a light microscope, transmission electron microscopy, and determination of the retinal tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and vascular endothelial growth factor (VEGF) levels. Results Oral administration of the ginger extract resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and vascular basement membrane thickness. Improvement in the architecture of the retinal vasculature was associated with significantly reduced expression of NF-κB and reduced activity of TNF-α and VEGF in the retinal tissue in the ginger extract–treated group compared to the vehicle-treated group. Conclusions The current study showed that ginger extract containing 5% of 6-gingerol attenuates the retinal microvascular changes in rats with streptozotocin-induced diabetes through anti-inflammatory and antiangiogenic actions. Although precise molecular targets remain to be determined, 6-gingerol seems to be a potential candidate for further investigation. PMID:27293376

  8. Dimethyl sulfoxide-caused changes in pro- and anti-angiogenic factor levels could contribute to an anti-angiogenic response in HeLa cells.

    PubMed

    Şimşek, Ece; Aydemir, Esra Arslan; İmir, Nilüfer; Koçak, Orhan; Kuruoğlu, Aykut; Fışkın, Kayahan

    2015-10-01

    Dimethyl sulfoxide (DMSO) is widely used in biological research as a general solvent. While it has been previously demonstrated that DMSO possesses a wide range of pharmacological effects, there is no published work regarding the effects of DMSO on pro-angiogenic factor levels. This study was designed to investigate the possible effects of DMSO on the levels of three pro-angiogenic factors released from HeLa cells in vitro. Cells were treated with two different and previously determined concentrations of DMSO. The cytotoxic effects of DMSO concentrations on HeLa cells were determined via MTT. Survival rates of DMSO-treated cells were determined by Invitrogen live/dead viability/cytotoxicity kit and trypan blue exclusion assay. Changes in the pro-angiogenic levels in media were evaluated by Cayman's Substance P Enzyme Immunoassay ELISA kit. Vascular endothelial growth factor ELISA kit and interferon gamma ELISA kit for substance P, VEGF and IFNγ respectively. Changes in substance P levels were corrected by standard western blotting. Changes in VEGF and IFNγ levels were corrected both by western blot and real time PCR. Treatment with 1.4 μM DMSO caused a time-dependent inhibition of cell proliferation at 24, 48 and 72 h. 1.4 μM DMSO caused a significant reduction in VEGF levels at 72 h of incubation and sharp increases in IFNγ levels at both 48 and 72 h of incubation. According to real time PCR analyses, DMSO (1.4 μM) exhibited an inhibitory effect on VEGF but acted as an augmenter of IFNγ release on HeLa cells in vitro. This is the first report showing that the general solvent DMSO suppressed HeLa cell proliferation, decreased the levels of two pro-angiogenic factors (substance P and VEGF) and increased the release of an anti-angiogenic factor IFNγ in vitro.

  9. Toxicity and Intraocular Properties of a Novel Long-Acting Anti-Proliferative and Anti-Angiogenic Compound IMS2186

    PubMed Central

    Falkenstein, Iryna A.; Cheng, Lingyun; Wong-Staal, Flossie; Tammewar, Ajay M.; Barron, Erin C.; Silva, Gabriel A.; Li, Qi-Xiang; Yu, Dehua; Hysell, Michelle; Liu, Guohong; Ke, Ning; Macdonald, James E.; Freeman, William R.

    2009-01-01

    Purpose To investigate the intraocular properties and toxicity of IMS2186, a small molecule developed as an anti-choroidal neovascularization (anti-CNV) drug. Materials and Methods Cellular toxicity and mechanism of action was tested on cell lines in vitro. Intraocular studies used rabbits for drug dissolution as well as toxicity and rats for the treatment study as well as the toxicity confirmation study. Rabbits' eyes were injected with 2.5 mg of IMS2186 and observed for 36 weeks. Laser-induced CNV in rats was treated with IMS2186, Kenalog, or phosphate-buffered saline (pBS). Fluorescein angiography (FA) and immunohistochemical processing of the globes was performed. Results The anti-proliferative IC50 of IMS2186 for human fibroblast cells was 1.0–3.0 μM and 0.3–3.0 μM for human cancer cells; the IC50 of IMS2186 to inhibit endothelial tube formation was 0.1–0.3 μM. The IC50 of IMS2186 for inhibiting the production of pro-inflammatory cytokines was 0.3–1 μM. The IC50 of IMS2186 for inhibiting macrophage migration was 1 μM. These biological properties were not species specific. IMS2186 can be formulated as a suspension for long-lasting release and when delivered intraocularly, no intraocular toxicity was observed by slit lamp exam, fundus exam, intraocular pressure measurements, or by electroretinography. FA showed a reduction in the leakage in eyes treated with IMS2186 and triamcinolone acetonide; DAPI staining also showed significantly less cellularity in IMS2186-treated lesions as compared to PBS (p = 0.0025). Conclusion IMS2186 may be a safe intraocular therapeutic agent for intraocular proliferation and angiogenesis. PMID:18600493

  10. Anti-Angiogenic Properties of BDDPM, a Bromophenol from Marine Red Alga Rhodomela confervoides, with Multi Receptor Tyrosine Kinase Inhibition Effects

    PubMed Central

    Wang, Shuaiyu; Wang, Li-Jun; Jiang, Bo; Wu, Ning; Li, Xiangqian; Liu, Shaofang; Luo, Jiao; Shi, Dayong

    2015-01-01

    Bis-(2,3-dibromo-4,5-dihydroxy-phenyl)-methane (BDDPM) is a bromophenol first isolated from Rhodomelaceae confervoides. Our previous studies showed that BDDPM exerts PTP1B-inhibiting activity and anti-cancer activity against a wide range of tumor cells while it also showed lower cytotoxicity against normal cells. In the present study, we found that BDDPM exhibits significant activities toward angiogenesis in vitro. BDDPM inhibits multiple angiogenesis processes, including endothelial cell sprouting, migration, proliferation, and tube formation. Further kinase assays investigations found that BDDPM is a potent selective, but multi-target, receptor tyrosine kinase (RTKs) inhibitor. BDDPM (10 μM) inhibits the activities of fibroblast growth factor receptor 2 and 3 (FGFR2, 3), vascular endothelial growth factor receptor 2 (VEGFR2) and platelet-derived growth factor receptor α (PDGFRα) (inhibition rate: 57.7%, 78.6%, 78.5% and 71.1%, respectively). Moreover, BDDPM also decreases the phosphorylation of protein kinase B (PKB/Akt) and endothelial nitric oxide synthase (eNOS), as well as nitric oxide (NO) production in a dose dependent manner. These results indicate that BDDPM can be exploited as an anti-angiogenic drug, or as a lead compound for the development of novel multi-target RTKs inhibitors. PMID:26075871

  11. Synthesis, Physicochemical Studies, Molecular Dynamics Simulations, and Metal-Ion-Dependent Antiproliferative and Antiangiogenic Properties of Cone ICL670-Substituted Calix[4]arenes

    PubMed Central

    Rouge, Pascal; Dassonville-Klimpt, Alexandra; Cézard, Christine; Boudesocque, Stéphanie; Ourouda, Roger; Amant, Carole; Gaboriau, François; Forfar, Isabelle; Guillon, Jean; Guillon, Emmanuel; Vanquelef, Enguerran; Cieplak, Piotr; Dupradeau, François-Yves; Dupont, Laurent

    2014-01-01

    Iron chelators, through their capacity to modulate the iron concentration in cells, are promising molecules for cancer chemotherapy. Chelators with high lipophilicity easily enter into cells and deplete the iron intracellular pool. Consequently, iron-dependent enzymes, such as ribonucleotide reductase, which is over-expressed in cancer cells, become nonfunctional. A series of calix[4]arene derivatives substituted at the lower rim by ICL670, a strong FeIII chelator, have been synthesized. Physicochemical properties and antiproliferative, angiogenesis, and tumorigenesis effects of two calix[4]arenes mono- (5a) or disubstituted (5b) with ICL670 have been studied. These compounds form metal complexes in a ratio of one to two ligands per FeIII atom as shown by combined analyses of the protometric titration curves and ESIMS spectra. The grafting of an ICL670 group on a calix[4]arene core does not significantly alter the acid–base properties, but improves the iron-chelating and lipophilicity properties. The best antiproliferative and anti-angiogenic results were obtained with calix[4]arene ligand 5a, which possesses the highest corresponding properties. Analyses of molecular dynamics simulations performed on the two calix[4]arenes provide three-dimensional structures of the complexes and proved 5a to be the most stable upon complexation. PMID:25599014

  12. Anti-angiogenic drugs for second-line treatment of NSCLC patients: just new pawns on the chessboard?

    PubMed

    Bronte, Giuseppe; Passiglia, Francesco; Galvano, Antonio; Russo, Antonio

    2016-01-01

    Tumor angiogenesis is one of the main pathways targeted to treat cancer. Bevacizumab added survival benefit when combined with platinum-based chemotherapy in NSCLC. Recently, Phase III trials showed survival benefit when anti-angiogenic drugs are added to docetaxel as second-line treatment for NSCLC. These anti-angiogenic agents include nintedanib and ramucirumab, a tyrosine-kinase inhibitor and a monoclonal antibody, respectively, which target receptors involved in angiogenesis. These studies have some similarities and differences. We propose a new algorithm for treatment sequences in performance status 0-1 patients with non-oncogene-addicted NSCLC type adenocarcinoma. Indeed clearer scientific evidences are available for this subgroup of patients.

  13. Separation of anti-angiogenic and cytotoxic activities of borrelidin by modification at the C17 side chain.

    PubMed

    Wilkinson, Barrie; Gregory, Matthew A; Moss, Steven J; Carletti, Isabelle; Sheridan, Rose M; Kaja, Andrew; Ward, Michael; Olano, Carlos; Mendez, Carmen; Salas, José A; Leadlay, Peter F; vanGinckel, Rob; Zhang, Ming-Qiang

    2006-11-15

    A set of novel borrelidin analogues have been prepared by precursor-directed biosynthesis. Structure-activity relationship analysis suggests that steric structural arrangement within the C17 side chain is important for differentiating cytotoxic and anti-angiogenic activities. A C17-cyclobutyl analogue 3 was found to have markedly increased selectivity for in vitro angiogenesis inhibition over cytotoxicity and is therefore potentially useful as an anticancer agent.

  14. Antiangiogenic Treatment Diminishes Renal Injury and Dysfunction via Regulation of Local AKT in Early Experimental Diabetes

    PubMed Central

    Zhou, Zhanmei

    2014-01-01

    In view of increased vascular endothelial growth factor-A (VEGF-A) expression and renal dysfunction in early diabetes, we designed a study to test whether VEGF-A inhibition can prevent early renal injury and dysfunction. We investigated the relationship and mechanism between VEGF-A and AKT regulation. In vitro, VEGF-A small interfering RNA (siRNA) and AKT inhibitor MK-2206 were employed to podocytes and NRK-52 cells cultured in high glucose (30 mM). In vivo, the antiangiogenic drug endostatin was administered in 12 week-old streptozotocin-induced male Sprague Dawley rats. The levels of VEGF-A, AKT, phosphorylated Ser473-AKT, phosphorylated Thr308-AKT, nephrin, angiotensin II (Ang II), angiotensin type II receptor 1 (ATR1) were examined using quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemistry. Interactions between phosphorylated Thr308-AKT and either nephrin in podocytes or Ang II in renal tubules were studied, respectively, using confocal immunofluorescence microscopy and immunoprecipitation. Silencing VEGF-A in podocytes upregulated phosphorylated Thr308-AKT and nephrin. Silencing VEGF-A in NRK-52E cells upregulated phosphorylated Thr308-AKT while downregulated Ang II and ATR1. MK-2206 enhanced VEGF-A expression in both podocytes and NRK-52E cells by inhibiting AKT activities. In diabetic rat kidneys, VEGF-A was upregulated and phosphorylated Thr308-AKT colocalized with either nephrin in podocytes or Ang II in renal tubules. With the endostatin treatment, the level of VEGF-A decreased while phosphorylated Thr308-AKT increased in both glomeruli and renal tubules. Treatment with endostatin upregulated nephrin in podocytes while downregulated Ang II and AT1R in renal tubules. Glomerular mesangial expansion was attenuated by the endostatin treatment, however, differences did not reach statistical significance. Endostatin ameliorated the interstitial fibrosis, urine albumin excretion rate

  15. Anti-Inflammatory, Antioxidant, Anti-Angiogenic and Skin Whitening Activities of Phryma leptostachya var. asiatica Hara Extract

    PubMed Central

    Jung, Hyun-Joo; Cho, Young-Wook; Lim, Hye-Won; Choi, Hojin; Ji, Dam-Jung; Lim, Chang-Jin

    2013-01-01

    This work aimed to assess some pharmacological activities of P. leptostachya var. asiatica Hara. The dried roots of P. leptostachya var. asiatica Hara were extracted with 70% ethanol to generate the powdered extract, named PLE. Anti-angiogenic activity was detected using chick chorioallantoic membrane (CAM) assay. In vitro anti-inflammatory activity was evaluated via analyzing nitric oxide (NO) content, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Antioxidant activity was determined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and reactive oxygen species (ROS) level in the stimulated macrophage cells. Matrix metalloproteinase-9 (MMP-9) and -2 (MMP-2) activities in the culture media were detected using zymography. PLE exhibits an anti-angiogenic activity in the CAM assay, and displays an inhibitory action on the generation of NO in the LPS-stimulated macrophage cells. In the stimulated macrophage cells, it is able to diminish the enhanced ROS level. It can potently scavenge the stable DPPH free radical. It suppresses the induction of iNOS and COX-2 and the enhanced MMP-9 activity in the stimulated macrophage cells. Both monooxygenase and oxidase activities of tyrosinase were strongly inhibited by PLE. Taken together, the dried roots of P. leptostachya var. asiatica Hara possess anti-angiogenic, anti-inflammatory, antioxidant and skin whitening activities, which might partly provide its therapeutic efficacy in traditional medicine. PMID:24009862

  16. Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy.

    PubMed

    Priceman, Saul J; Sung, James L; Shaposhnik, Zory; Burton, Jeremy B; Torres-Collado, Antoni X; Moughon, Diana L; Johnson, Mai; Lusis, Aldons J; Cohen, Donald A; Iruela-Arispe, M Luisa; Wu, Lily

    2010-02-18

    Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6C(hi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers.

  17. Markers of Response to Antiangiogenic Therapies in Colorectal Cancer: Where Are We Now and What Should Be Next?

    PubMed Central

    Cidon, E. Una; Alonso, P.; Masters, B.

    2016-01-01

    Despite advances in the treatment of colorectal cancer (CRC), it remains the second most common cause of cancer-related death in the Western world. Angiogenesis is a complex process that involves the formation of new blood vessels from preexisting vessels. It is essential for promoting cancer survival, growth, and dissemination. The inhibition of angiogenesis has been shown to prevent tumor progression experimentally, and several chemotherapeutic targets of tumor angiogenesis have been identified. These include anti-vascular endothelial growth factor (VEGF) treatments, such as bevacizumab (a VEGF-specific binding antibody) and anti-VEGF receptor tyrosine kinase inhibitors, although antiangiogenic therapy has been shown to be effective in the treatment of several cancers, including CRC. However, it is also associated with its own side effects and financial costs. Therefore, the identification of biomarkers that are able to identify patients who are more likely to benefit from antiangiogenic treatment is very important. This article intends to be a concise summary of the potential biomarkers that can predict or prognosticate the benefit of antiangiogenic treatments in CRC, and also what we can expect in the near future. PMID:27147901

  18. In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways

    PubMed Central

    Lei, Xueping; Chen, Minfeng; Nie, Qiulin; Hu, Jianyang; Zhuo, Zhenjian; Yiu, Anita; Chen, Heru; Xu, Nanhui; Huang, Maohua; Ye, Kaihe; Bai, Liangliang; Ye, Wencai; Zhang, Dongmei

    2016-01-01

    Tumor angiogenic process is regulated by multiple proangiogenic pathways, such as vascular endothelial growth factor receptor 2 (VEGFR2) and Axl receptor tyrosine kinase (Axl). Axl is one of many important factors involved in anti-VEGF resistance. Inhibition of VEGF/VEGFR2 signaling pathway alone fails to block tumor neovascularization. Therefore, discovery of novel agents targeting multiple angiogenesis pathways is in demand. Desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB), has been reported exhibit an anticancer activity via its cytotoxic effect. However, little attention has been paid to the antiangiogenic properties of DAVLBH. Here, we firstly reported that DAVLBH exerted a more potent antiangiogenic effect than VLB in vitro and in vivo, which was associated with inactivation of VEGF/VEGFR2 and Gas6/Axl signaling pathways. We found that DAVLBH inhibited VEGF- and Gas6-induced HUVECs proliferation, migration, tube formation and vessel sprouts formation in vitro and ex vivo. It significantly inhibited in vivo tumor angiogenesis and tumor growth in HeLa xenografts. It also inhibited Gas6-induced pericytes recruitment to endothelial tubes accompanied with a decrease in expression and activation of Axl. Besides, it could block the compensatory up-regulating expression and activation of Axl in response to bevacizumab treatment in HUVECs. Taken together, our results suggest that DAVLBH potently inhibits angiogenesis-mediated tumor growth through blockage of the activation of VEGF/VEGFR2 and Gas6/Axl pathways and it might serve as a promising antiangiogenic agent for the cancer therapy. PMID:27186435

  19. Twin-to-twin transfusion syndrome: an anti-angiogenic state?

    PubMed Central

    KUSANOVIC, Juan Pedro; ROMERO, Roberto; ESPINOZA, Jimmy; NIEN, Jyh Kae; KIM, Chong Jai; MITTAL, Pooja; EDWIN, Sam; EREZ, Offer; GOTSCH, Francesca; MAZAKI-TOVI, Shali; THAN, Nandor G.; SOTO, Eleazar; CAMACHO, Natalia; GOMEZ, Ricardo; QUINTERO, Ruben; HASSAN, Sonia S.

    2008-01-01

    Objective An imbalanced chronic blood flow between the donor and recipient twin through placental vascular anastomoses is the accepted pathophysiology of twin-to-twin transfusion syndrome (TTTS). Vascular endothelial growth factor receptor-1 (VEGFR-1) mRNA is overexpressed only in the syncytiotrophoblast of the donor twin in some cases of TTTS. This study was conducted to determine maternal plasma concentrations of placental growth factor (PlGF), soluble VEGFR-1, and soluble endoglin (s-Eng) in monochorionic-diamniotic pregnancies with and without TTTS. Study design This case-control study included monochorionic-diamniotic pregnancies between 16–26 weeks with and without TTTS. Maternal plasma concentrations of PlGF, sVEGFR-1 and s-Eng were determined with ELISA. A p-value <.05 was considered statistically significant. Results Patients with TTTS had higher median plasma concentrations of s-Eng [14.8 ng/ml vs. 7.8 ng/ml; p<0.001] and sVEGFR-1 [6383.1 pg/ml vs. 3220.1 pg/ml; p<0.001]; and lower median plasma concentrations of PlGF [115.5 pg/ml vs. 359.3 pg/ml; p=0.002] than those without TTTS. Conclusions We propose that an anti-angiogenic state may be present in some cases of TTTS. PMID:18395032

  20. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma.

    PubMed

    Kessler, Tobias; Sahm, Felix; Blaes, Jonas; Osswald, Matthias; Rübmann, Petra; Milford, David; Urban, Severino; Jestaedt, Leonie; Heiland, Sabine; Bendszus, Martin; Hertenstein, Anne; Pfenning, Philipp-Niclas; Ruiz de Almodóvar, Carmen; Wick, Antje; Winkler, Frank; von Deimling, Andreas; Platten, Michael; Wick, Wolfgang; Weiler, Markus

    2015-10-13

    Loss of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a prerequisite for tumor cell-specific expression of vascular endothelial growth factor receptor (VEGFR)-2 in glioblastoma defining a subgroup prone to develop evasive resistance towards antiangiogenic treatments. Immunohistochemical analysis of human tumor tissues showed VEGFR-2 expression in glioma cells in 19% of specimens examined, mainly in the infiltration zone. Glioma cell VEGFR-2 positivity was restricted to PTEN-deficient tumor specimens. PTEN overexpression reduced VEGFR-2 expression in vitro, as well as knock-down of raptor or rictor. Genetic interference with VEGFR-2 revealed proproliferative, antiinvasive and chemoprotective functions for VEGFR-2 in glioma cells. VEGFR-2-dependent cellular effects were concomitant with activation of 'kappa-light-chain-enhancer' of activated B-cells, protein kinase B, and N-myc downstream regulated gene 1. Two-photon in vivo microscopy revealed that expression of VEGFR-2 in glioma cells hampers antiangiogenesis. Bevacizumab induces a proinvasive response in VEGFR-2-positive glioma cells. Patients with PTEN-negative glioblastomas had a shorter survival after initiation of bevacizumab therapy compared with PTEN-positive glioblastomas. Conclusively, expression of VEGFR-2 in glioma cells indicates an aggressive glioblastoma subgroup developing early resistance to temozolomide or bevacizumab. Loss of PTEN may serve as a biomarker identifying those tumors upfront by routine neuropathological methods.

  1. Assessment of the anti-angiogenic, anti-inflammatory and antinociceptive properties of ethyl vanillin.

    PubMed

    Jung, Hyun-Joo; Song, Yun Seon; Kim, Kyunghoon; Lim, Chang-Jin; Park, Eun-Hee

    2010-02-01

    The present work aimed to assess novel pharmacological properties of ethyl vanillin (EVA) which is used as a flavoring agent for cakes, dessert, confectionary, etc. EVA exhibited an inhibitory activity in the chorioallantoic membrane angiogenesis. Anti-inflammatory activity of EVA was convinced using the two in vivo models, such as vascular permeability and air pouch models in mice. Antinociceptive activity of EVA was assessed using acetic acid-induced writhing model in mice. EVA suppressed production of nitric oxide and induction of inducible nitric oxide synthase in the lipopolysaccharide (LPS)-activated RAW264.7 macrophage cells. However, EVA could not suppress induction of cyclooxygenase-2 in the LPS-activated macrophages. EVA diminished reactive oxygen species level in the LPS-activated macrophages. EVA also suppressed enhanced matrix metalloproteinase-9 gelatinolytic activity in the LPSactivated RAW264.7 macrophage cells. EVA at the used concentrations couldn't diminish viability of the macrophage cells. Taken together, the anti-angiogenic, anti-inflammatory and anti-nociceptive properties of EVA are based on its suppressive effect on the production of nitric oxide possibly via decreasing the reactive oxygen species level.

  2. Anti-angiogenic treatment of breast cancer using metronomic low-dose chemotherapy.

    PubMed

    Munoz, Raquel; Shaked, Yuval; Bertolini, Francesco; Emmenegger, Urban; Man, Shan; Kerbel, Robert S

    2005-12-01

    We have been studying the molecular and cellular basis of chronic low-dose, frequently administered, metronomic chemotherapy regimens for the treatment of cancer in a variety of preclinical models, including human breast cancer xenografts. The advantages of metronomic-maintenance-type chemotherapy regimens include significantly reduced host toxicity, potentially reduced costs, increased convenience for patients when oral chemotherapy drugs are used, and the possibility of adopting chronic combination therapies involving conventional chemotherapy drugs and cytostatic molecularly targeted therapies. However, a disadvantage is the empiricism associated with determining the optimal biologic dose (OBD). Recently, we have developed a surrogate biomarker approach involving measurement of circulating endothelial progenitor cells (CEPs) in peripheral blood to help determine the OBD of anti-angiogenic drugs or treatments, including metronomic chemotherapy. Using this approach we determined the OBD for different metronomic chemotherapy regimens and then tested the effect of such drugs for the treatment of established, advanced (high volume) and widespread human breast cancer metastases in immunodeficient mice. This treatment strategy, which was maintained for over 6 months, with no breaks, resulted in marked prolongation of survival and was devoid of overt toxicity. These results suggest the possibility of using metronomic chemotherapy regimens as an adjuvant therapy for early-stage disease, including breast cancer, as was demonstrated recently using long-term daily low-dose UFT for the treatment of early-stage resected non-small cell lung cancer or UFT in combination for early stage breast cancer combined with tamoxifen.

  3. Optical tomographic monitoring of vascular responses to anti-angiogenic drugs in preclinical tumor models

    NASA Astrophysics Data System (ADS)

    Flexman, Molly L.; Kim, Hyun K.; Hernandez, Sonia L.; Huang, Jianzhong; Johung, Tessa J.; Lee, Jonghwan; Yamashiro, Darrell J.; Kandel, Jessica J.; Hielscher, Andreas H.

    2011-02-01

    It is well acknowledged that treatment efficacy could be increased and unnecessary toxicities reduced if a rapid assessment strategy were available to allow individual tailoring of cancer therapy. In this work we focus on using optical tomographic imaging to detect tumor response to anti-angiogenic treatment within the first 5 days of therapy. For this study we used two models with well-characterized and divergent responses to inhibition of vascular endothelial growth factor (VEGF). SK-NEP and NGP cells were implanted intrarenally into NCR nude mice and the resulting tumors were monitored until a threshold of 1-2 g was reached. Optical tomographic imaging with a dual-wavelength (λ = 765nm and 830nm) continuous wave system, was performed prior to the first treatment with the anti-VEGF bevacizumab (BV), as well as 1, 3, and 5 days later. We found that the SK-NEP tumor model, known to be responsive to BV treatment, shows a decrease in hemoglobin levels over the 5 days. Mice implanted with the NGP tumor model, known to be less responsive to treatment, do not show such decreases. These results were further validated with histopathological findings that showed a decrease in tumor vascularization in treated SK-NEP mice. These results suggest that optical tomography is a promising tool for monitoring early tumor response to drug therapy.

  4. Anti-Oxidant, Anti-Inflammatory and Anti-Angiogenic Properties of Resveratrol in Ocular Diseases.

    PubMed

    Lançon, Allan; Frazzi, Raffaele; Latruffe, Norbert

    2016-03-02

    Resveratrol (3,4',5 trihydroxy-trans-stilbene) is one of the best known phytophenols with pleiotropic properties. It is a phytoalexin produced by vine and it leads to the stimulation of natural plant defenses but also exhibits many beneficial effects in animals and humans by acting on a wide range of organs and tissues. These include the prevention of cardiovascular diseases, anti-cancer potential, neuroprotective effects, homeostasia maintenance, aging delay and a decrease in inflammation. Age-related macular degeneration (AMD) is one of the main causes of deterioration of vision in adults in developed countries This review deals with resveratrol and ophthalmology by focusing on the antioxidant, anti-inflammatory, and anti-angiogenic effects of this molecule. The literature reports that resveratrol is able to act on various cell types of the eye by increasing the level of natural antioxidant enzymatic and molecular defenses. Resveratrol anti-inflammatory effects are due to its capacity to limit the expression of pro-inflammatory factors, such as interleukins and prostaglandins, and also to decrease the chemo-attraction and recruitment of immune cells to the inflammatory site. In addition to this, resveratrol was shown to possess anti-VEGF effects and to inhibit the proliferation and migration of vascular endothelial cells. Resveratrol has the potential to be used in a range of human ocular diseases and conditions, based on animal models and in vitro experiments.

  5. A Novel Noninvasive Model of Endometriosis for Monitoring the Efficacy of Antiangiogenic Therapy

    PubMed Central

    Becker, Christian M.; Wright, Renee D.; Satchi-Fainaro, Ronit; Funakoshi, Tae; Folkman, Judah; Kung, Andrew L.; D’Amato, Robert J.

    2006-01-01

    Endometriosis, the presence of ectopic endometrial tissue, is a common disease associated with high morbidity and socioeconomic problems. Angiogenesis, the formation of new blood vessels, plays an important role in the formation and growth of endometriotic lesions. We have created a novel, noninvasive model to monitor the growth of these lesions and the associated angiogenesis in vivo. First, we generated luciferase-expressing transgenic mice by inserting the human ubiquitin C promoter coupled to the firefly luciferase reporter. Injection of luciferin in these mice causes full-body bioluminescence, which can be detected using a low-light CCD camera. Endometrial tissue from these transgenic mice was surgically implanted into nonluminescent recipients. Bioluminescence of lesions was noninvasively imaged after intravenous or intraperitoneal injection of luciferin. Transabdominal luminescence compared well with the location of the transgenic endometriotic lesions, and lesion size correlated with the intensity of luminescence. Systemic treatment with the angiogenesis inhibitors caplostatin and endostatin peptide mP-1 delayed and suppressed the onset and intensity of the luminescent signal. Caplostatin suppressed the growth of endometriotic lesions by 59% compared with controls. This novel, noninvasive model of endometriosis provides a means to study early angiogenesis in vivo and to monitor endometriotic growth and the efficacy of systemic antiangiogenic therapy. PMID:16723720

  6. Topical Antiangiogenic SRPK1 Inhibitors Reduce Choroidal Neovascularization in Rodent Models of Exudative AMD

    PubMed Central

    Gammons, Melissa V.; Fedorov, Oleg; Ivison, David; Du, Chunyun; Clark, Tamsyn; Hopkins, Claire; Hagiwara, Masatoshi; Dick, Andrew D.; Cox, Russell; Harper, Steven J.; Hancox, Jules C.; Knapp, Stefan; Bates, David O.

    2013-01-01

    Purpose. Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. We tested the hypothesis that topical (eye drop) SRPK1-selective inhibitors could be generated that reduce pro-angiogenic isoforms, and prevent choroidal neovascularization in vivo. Methods. Novel inhibitors were tested for SRPK inhibition in vitro, pro-angiogenic VEGF production in RPE cells by PCR and ELISA, and for inhibition of choroidal neovascularisation in mice and rats. Results. A novel disubstituted furan inhibitor was selective for the SRPK family of kinases and reduced expression of pro-angiogenic but not antiangiogenic VEGF isoforms. This inhibitor and previously identified SRPK inhibitors significantly reduced choroidal neovascularisation in vivo. Topical administration of SRPK inhibitors dose-dependently blocked CNV with an EC50 of 9 μM. Conclusions. These results indicate that novel SRPK1 selective inhibitors could be a potentially novel topical (eye drop) therapeutic for wet AMD. PMID:23887803

  7. Antitumor Activity of VB-111, a Novel Antiangiogenic Virotherapeutic, in Thyroid Cancer Xenograft Mouse Models

    PubMed Central

    Reddi, H. V.; Madde, P.; Cohen, Y. C.; Bangio, L.; Breitbart, E.; Harats, D.; Bible, K. C.

    2011-01-01

    VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing. PMID:22701765

  8. Computational modelling of anti-angiogenic therapies based on multiparametric molecular imaging data

    PubMed Central

    Kozak, Kevin R.; Jeraj, Robert

    2013-01-01

    Computational tumour models have emerged as powerful tools for the optimization of cancer therapies; ideally, these models should incorporate patient-specific imaging data indicative of therapeutic response. The purpose of this study was to develop a tumour modelling framework in order to simulate the therapeutic effects of anti-angiogenic agents based upon clinical molecular imaging data. The model was applied to positron emission tomography (PET) data of cellular proliferation and hypoxia from a phase I clinical trial of bevacizumab, an antibody that neutralizes the vascular endothelial growth factor (VEGF). When using pre-therapy PET data in combination with literature-based dose response parameters, simulated follow-up hypoxia data yielded good qualitative agreement with imaged hypoxia levels. Improving the quantitative agreement with follow-up hypoxia and proliferation PET data required tuning of the maximum vascular growth fraction (VGFmax) and the tumour cell cycle time to patient-specific values. VGFmax was found to be the most sensitive model parameter (CV=22%). Assuming availability of patient-specific, intratumoural VEGF levels, we show how bevacizumab dose levels can potentially be ‘tailored’ to improve levels of tumour hypoxia while maintaining proliferative response, both of which are critically important in the context of combination therapy. Our results suggest that, upon further validation, the application of image-driven computational models may afford opportunities to optimize dosing regimens and combination therapies in a patient-specific manner. PMID:22972469

  9. Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine.

    PubMed

    Lupo, Gabriella; Caporarello, Nunzia; Olivieri, Melania; Cristaldi, Martina; Motta, Carla; Bramanti, Vincenzo; Avola, Roberto; Salmeri, Mario; Nicoletti, Ferdinando; Anfuso, Carmelina D

    2016-01-01

    Primary solid tumors originate close to pre-existing tissue vasculature, initially growing along such tissue blood vessels, and this phenomenon is important for the metastatic potential which frequently occurs in highly vascularized tissues. Unfortunately, preclinic and clinic anti-angiogenic approaches have not been very successful, and multiple factors have been found to contribute to toxicity and tumor resistance. Moreover, tumors can highlight intrinsic or acquired resistances, or show adaptation to the VEGF-targeted therapies. Furthermore, different mechanisms of vascularization, activation of alternative signaling pathways, and increased tumor aggressiveness make this context even more complex. On the other hand, it has to be considered that the transitional restoration of normal, not fenestrated, microvessels allows the drug to reach the tumor and act with the maximum efficiency. However, these effects are time-limited and different, depending on the various types of cancer, and clearly define a specific "normalization window." So, new horizons in the therapeutic approaches consist on the treatment of the tumor with pro- (instead of anti-) angiogenic therapies, which could strengthen a network of well-structured blood vessels that facilitate the transport of the drug.

  10. Anti-angiogenic Therapy in Cancer: Downsides and New Pivots for Precision Medicine

    PubMed Central

    Lupo, Gabriella; Caporarello, Nunzia; Olivieri, Melania; Cristaldi, Martina; Motta, Carla; Bramanti, Vincenzo; Avola, Roberto; Salmeri, Mario; Nicoletti, Ferdinando; Anfuso, Carmelina D.

    2017-01-01

    Primary solid tumors originate close to pre-existing tissue vasculature, initially growing along such tissue blood vessels, and this phenomenon is important for the metastatic potential which frequently occurs in highly vascularized tissues. Unfortunately, preclinic and clinic anti-angiogenic approaches have not been very successful, and multiple factors have been found to contribute to toxicity and tumor resistance. Moreover, tumors can highlight intrinsic or acquired resistances, or show adaptation to the VEGF-targeted therapies. Furthermore, different mechanisms of vascularization, activation of alternative signaling pathways, and increased tumor aggressiveness make this context even more complex. On the other hand, it has to be considered that the transitional restoration of normal, not fenestrated, microvessels allows the drug to reach the tumor and act with the maximum efficiency. However, these effects are time-limited and different, depending on the various types of cancer, and clearly define a specific “normalization window.” So, new horizons in the therapeutic approaches consist on the treatment of the tumor with pro- (instead of anti-) angiogenic therapies, which could strengthen a network of well-structured blood vessels that facilitate the transport of the drug. PMID:28111549

  11. Anti-angiogenic therapy (bevacizumab) in the management of oral lichen planus.

    PubMed

    Mahmoud, Maha M; Afifi, Marwa M

    2016-04-01

    Oral lichen planus (OLP), a mucocutaneous chronic inflammatory disease, is conventionally managed using topical corticosteroid therapy. Given the fact that OLP is strongly linked to angiogenesis, anti-angiogenic drugs, such as bevacizumab, might be introduced as an alternative treatment for contraindicated, non-responsive patients. The aim of the present study was to report the short-term effectiveness and safety of intralesional bevacizumab injection in the management of atrophic/erosive OLP. A case series study was conducted in patients with atrophic/erosive OLP in the buccal mucosa, assigned to receive either 2.5 mg of bevacizumab, by intralesional injection (n = 20, test), or topical 0.1% triamcinolone acetonide ointment (n = 20, control). The size, score, and pain intensity of the lesions were assessed pre- and post-treatment. Tissue biopsies were collected for histopathologic, immunohistochemical, and ultrastructural examination. After 1 wk, the test group had significant reductions both in lesion seize and in pain scores compared with controls. A marked decrease in vascular endothelial growth factor (VEGF) and interleukin-8 immunoexpression was noted in tissue biopsies from bevacizumab-treated lesions compared with control lesions. Furthermore, ultrastructural examination of OLP tissue specimens revealed significant healing signs associated with bevacizumab treatment. Short-term data suggest that intralesional bevacizumab injection effectively and safely achieved resolution of atrophic/erosive OLP lesions without disease exacerbations during a 3-month follow-up period.

  12. Computational modelling of anti-angiogenic therapies based on multiparametric molecular imaging data

    NASA Astrophysics Data System (ADS)

    Titz, Benjamin; Kozak, Kevin R.; Jeraj, Robert

    2012-10-01

    Computational tumour models have emerged as powerful tools for the optimization of cancer therapies; ideally, these models should incorporate patient-specific imaging data indicative of therapeutic response. The purpose of this study was to develop a tumour modelling framework in order to simulate the therapeutic effects of anti-angiogenic agents based upon clinical molecular imaging data. The model was applied to positron emission tomography (PET) data of cellular proliferation and hypoxia from a phase I clinical trial of bevacizumab, an antibody that neutralizes the vascular endothelial growth factor (VEGF). When using pre-therapy PET data in combination with literature-based dose response parameters, simulated follow-up hypoxia data yielded good qualitative agreement with imaged hypoxia levels. Improving the quantitative agreement with follow-up hypoxia and proliferation PET data required tuning of the maximum vascular growth fraction (VGFmax) and the tumour cell cycle time to patient-specific values. VGFmax was found to be the most sensitive model parameter (CV = 22%). Assuming availability of patient-specific, intratumoural VEGF levels, we show how bevacizumab dose levels can potentially be ‘tailored’ to improve levels of tumour hypoxia while maintaining proliferative response, both of which are critically important in the context of combination therapy. Our results suggest that, upon further validation, the application of image-driven computational models may afford opportunities to optimize dosing regimens and combination therapies in a patient-specific manner.

  13. Raman spectral study of anti-angiogenic drugs on the role of chick vascular

    NASA Astrophysics Data System (ADS)

    Huang, Ruixiang; Chen, Rong; Chen, Qisong; Lin, Juqiang; Pan, Jianji; Lin, Shaojun; Li, Chao; Li, Yongzeng; Feng, Shangyuan

    2009-08-01

    Inhibit angiogenesis is one of the important tumor therapy. If the mechanism of vascular changes can be detected at molecular level, it will have therapeutic significance. Raman spectroscopy, which can be applied to the structural analysis of solid, liquid or solution of biological molecules, is a non-destructive spectral technology holding very rich information. Basing on Confocal Raman Microscope, a unique system is developed for obtaining the different Raman spectra of the chick embryo vascular with the anti-angiogenic drugs - thalidomide and without. In the study, the location and shape of the average Raman spectra of vessels in drug 5h were very similar to the ones without medicine, and the intensity of some characteristic peaks changed, such as 1441cm-1,1527cm-1 and 1657cm-1 showing markedly increasing, while the 971cm-1 and 1081cm-1 decreasing. This change was due to anti- angiogenic drugs that caused the nucleic acid, protein, phospholipids, and other important biological molecules of the vessels on the structure or content tovary. PCA was used to distinguish between the two kinds of vascular with the result that they were accurately partitioned.The study indicated that Raman spectroscopy could be an effective tool for detection of the mechanism of vascular changes.

  14. Antiangiogenic effects of p-coumaric acid in human endothelial cells.

    PubMed

    Kong, Chang-Seok; Jeong, Chul-Ho; Choi, Jae-Sun; Kim, Kil-Jung; Jeong, Joo-Won

    2013-03-01

    p-Coumaric acid, a hydroxy derivative of cinnamic acid, has been known to possess antioxidant and anticancer activities. Despite its potential contribution to chemopreventive effects, the mechanism by which p-coumaric acid exerts its antiangiogenic actions remains elusive. In this study, we revealed that p-coumaric acid inhibited the sprouting of endothelial cells in rat aortic rings and inhibited the tube formation and migration of endothelial cells. We observed that p-coumaric acid could downregulate mRNA expression levels of the key angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor. Also, we demonstrated that p-coumaric acid inhibited both the AKT and ERK signaling pathways, which are known to be crucial for angiogenesis. Using a mouse model, we also showed that p-coumaric acid effectively suppressed tumor growth in vivo by lowering hemoglobin contents. Collectively, these findings indicate that p-coumaric acid possesses potent anticancer properties due to the inhibition of angiogenesis in vivo.

  15. Discovery of mixed type thymidine phosphorylase inhibitors endowed with antiangiogenic properties: synthesis, pharmacological evaluation and molecular docking study of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones. Part II.

    PubMed

    Bera, Hriday; Ojha, Probir kumar; Tan, Bee Jen; Sun, Lingyi; Dolzhenko, Anton V; Chui, Wai-Keung; Chiu, Gigi Ngar Chee

    2014-05-06

    In our drug discovery program, a series of 2-thioxo-pyrazolo[1,5-a][1,3,5]triazin-4-ones were designed, synthesized and evaluated for their TP inhibitory potential. All the synthesized analogues conferred a varying degree of TP inhibitory activity, comparable or better than positive control, 7-deazaxanthine (7-DX, 2) (IC50 value = 42.63 μM). A systematic approach to the lead optimization identified compounds 3c and 4a as the most promising TP inhibitors, exhibiting mixed mode of enzyme inhibition. Moreover, selected compounds demonstrated the ability to attenuate the expression of the angiogenic markers (viz. MMP-9 and VEGF) in MDA-MB-231 cells at sublethal concentrations. In addition, molecular docking studies revealed the plausible binding orientation of these inhibitors towards TP, which was in accordance with the experimental results. Taken as a whole, these compounds would constitute a new direction for the design of novel TP inhibitors with promising antiangiogenic properties.

  16. Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development--A Systematic Review.

    PubMed

    Martić-Kehl, Marianne Isabelle; Wernery, Jannis; Folkers, Gerd; Schubiger, Pius August

    2015-01-01

    Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill

  17. Quality of Animal Experiments in Anti-Angiogenic Cancer Drug Development – A Systematic Review

    PubMed Central

    Martić-Kehl, Marianne Isabelle; Wernery, Jannis; Folkers, Gerd; Schubiger, Pius August

    2015-01-01

    Translation from preclinical animal research to clinical bedside has proven to be difficult to impossible in many fields of research (e.g. acute stroke, ALS and HIV vaccination development) with oncology showing particularly low translation rates (5% vs. 20% for cardiovascular diseases). Several investigations on published preclinical animal research have revealed that apart from plain species differences, translational problems can arise from low study quality (e.g. study design) or non-representative experimental conditions (e.g. treatment schedule). This review assessed the published experimental circumstances and quality of anti-angiogenic cancer drug development in 232 in vivo studies. The quality of study design was often insufficient; at least the information published about the experiments was not satisfactory in most cases. There was no quality improvement over time, with the exception of conflict of interest statements. This increase presumably arose mainly because journal guidelines request such statements more often recently. Visual inspection of data and a cluster analysis confirmed a trend described in literature that low study quality tends to overestimate study outcome. It was also found that experimental outcome was more favorable when a potential drug was investigated as the main focus of a study, compared to drugs that were used as comparison interventions. We assume that this effect arises from the frequent neglect of blinding investigators towards treatment arms and refer to it as hypothesis bias. In conclusion, the reporting and presumably also the experimental performance of animal studies in drug development for oncology suffer from similar shortcomings as other fields of research (such as stroke or ALS). We consider it necessary to enforce experimental quality and reporting that corresponds to the level of clinical studies. It seems that only clear journal guidelines or guidelines from licensing authorities, where failure to fulfill

  18. Optical Coherence Tomography and the Development of Antiangiogenic Therapies in Neovascular Age-Related Macular Degeneration

    PubMed Central

    Rosenfeld, Philip J.

    2016-01-01

    Purpose To explain the pivotal role optical coherence tomography (OCT) imaging had in the development of antiangiogenic therapies for the treatment of neovascular age-related macular degeneration (nvAMD). Methods A historical literature review was combined with personal perspectives from the introduction of OCT imaging and the early clinical use of vascular endothelial growth factor (VEGF) inhibitors. Results At the time that OCT emerged, the gold standard for imaging of nvAMD was fluorescein angiography (FA), a time-consuming, dye-based, invasive technique that provided en face images of the retina and was used to characterize leakage, perfusion status, and the types of macular neovascularization (MNV). In comparison, OCT imaging was a fast, safe, noninvasive technique that complemented FA imaging by providing cross-sectional images of the macula. OCT was able to visualize and quantify the macular fluid that was associated with the presence of excess VEGF, which was identified by intraretinal fluid, subretinal fluid, and fluid under the retinal pigment epithelium (RPE). Clinicians quickly appreciated the benefits of OCT imaging for following macular fluid after anti-VEGF therapy. By observing the qualitative and quantitative changes in macular fluid depicted by OCT imaging, clinicians were empowered to compare anti-VEGF drugs and move from fixed-dosing regimens to patient-specific dosing strategies requiring fewer injections. Conclusions Optical coherence tomography imaging was adopted as a VEGF-meter, a method to detect excess VEGF, and evolved to become the gold standard imaging strategy for diagnosing nvAMD, assessing treatment responses to anti-VEGF drugs, deciding when to re-treat, and evaluating disease progression. PMID:27409464

  19. Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

    SciTech Connect

    Narayana, Ashwatha; Kunnakkat, Saroj D.; Medabalmi, Praveen; Golfinos, John; Parker, Erik; Knopp, Edmond; Zagzag, David; Eagan, Patricia; Gruber, Deborah; Gruber, Michael L.

    2012-01-01

    Purpose: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. Methods and Materials: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. Results: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R{sup 2} = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). Conclusion: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials.

  20. Anti-angiogenic effects of pterogynidine alkaloid isolated from Alchornea glandulosa

    PubMed Central

    Lopes, Flávia CM; Rocha, Ana; Pirraco, Ana; Regasini, Luis O; Silva, Dulce HS; Bolzani, Vanderlan S; Azevedo, Isabel; Carlos, Iracilda Z; Soares, Raquel

    2009-01-01

    Background Angiogenesis, a complex multistep process that comprehends proliferation, migration and anastomosis of endothelial cells (EC), has a major role in the development of pathologic conditions such as inflammatory diseases, tumor growth and metastasis. Brazilian flora, the most diverse in the world, is an interesting spot to prospect for new chemical leads, being an important source of new anticancer drugs. Plant-derived alkaloids have traditionally been of interest due to their pronounced physiological activities. We investigated the anti-angiogenic potential of the naturally occurring guanidine alkaloid pterogynidine (Pt) isolated from the Brazilian plant Alchornea glandulosa. The purpose of this study was to examine which features of the angiogenic process could be disturbed by Pt. Methods Human umbilical vein endothelial cells (HUVEC) were incubated with 8 μM Pt and cell viability, proliferation, apoptosis, invasion and capillary-like structures formation were addressed. Nuclear factor κB (NFκB), a transcription factor implicated in these processes, was also evaluated in HUVEC incubated with Pt. Quantifications were expressed as mean ± SD of five independent experiments and one-way analysis of variance (ANOVA) followed by the Dunnet test was used. Results A significant decrease in proliferation and invasion capacity and an effective increase in apoptosis as assessed by bromodeoxyuridine (BrdU), double-chamber and terminal transferase dUTP nick end labeling (TUNEL) assay, respectively, have been found. Pt also led to a drastic reduction in the number of capillary-like structures formation when HUVEC were cultured on growth factor reduced-Matrigel (GFR-Matrigel) coated plates. In addition, incubation of HUVEC with Pt resulted in reduced NFκB activity. Conclusion These findings emphasize the potential use of Pt against pathological situations where angiogenesis is stimulated as tumor development. PMID:19463163

  1. Imaging Biomarker Dynamics in an Intracranial Murine Glioma Study of Radiation and Antiangiogenic Therapy

    SciTech Connect

    Chung, Caroline; Jalali, Shahrzad; Foltz, Warren; Burrell, Kelly; Wildgoose, Petra; Lindsay, Patricia; Graves, Christian; Camphausen, Kevin; Milosevic, Michael; Jaffray, David; Zadeh, Gelareh; Ménard, Cynthia

    2013-03-01

    Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). Methods and Materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K{sub trans}, K{sub ep}). Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K{sub trans} reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K{sub ep} reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of −0.878 (P=.002) and −0.80 (P=.01), respectively. Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.

  2. Vascular mimicry in glioblastoma following anti-angiogenic and anti-20-HETE therapies.

    PubMed

    Angara, Kartik; Rashid, Mohammad H; Shankar, Adarsh; Ara, Roxan; Iskander, Asm; Borin, Thaiz F; Jain, Meenu; Achyut, Bhagelu R; Arbab, Ali S

    2016-12-19

    Glioblastoma (GBM) is one hypervascular and hypoxic tumor known among solid tumors. Antiangiogenic therapeutics (AATs) have been tested as an adjuvant to normalize blood vessels and control abnormal vasculature. Evidence of relapse exemplified in the progressive tumor growth following AAT reflects development of resistance to AATs. Here, we identified that GBM following AAT (Vatalanib) acquired an alternate mechanism to support tumor growth, called vascular mimicry (VM). We observed that Vatalanib induced VM vessels are positive for periodic acid-Schiff (PAS) matrix but devoid of any endothelium on the inner side and lined by tumor cells on the outer-side. The PAS+ matrix is positive for basal laminae (laminin) indicating vascular structures. Vatalanib treated GBM displayed various stages of VM such as initiation (mosaic), sustenance, and full-blown VM. Mature VM structures contain red blood cells (RBC) and bear semblance to the functional blood vessel-like structures, which provide all growth factors to favor tumor growth. Vatalanib treatment significantly increased VM especially in the core of the tumor, where HIF-1α was highly expressed in tumor cells. VM vessels correlate with hypoxia and are characterized by co-localized MHC-1+ tumor and HIF-1α expression. Interestingly, 20-HETE synthesis inhibitor HET0016 significantly decreased GBM tumors through decreasing VM structures both at the core and at periphery of the tumors. In summary, AAT induced resistance characterized by VM is an alternative mechanism adopted by tumors to make functional vessels by transdifferentiation of tumor cells into endothelial-like cells to supply nutrients in the event of hypoxia. AAT induced VM is a potential therapeutic target of the novel formulation of HET0016. Our present study suggests that HET0016 has a potential to target therapeutic resistance and can be combined with other antitumor agents in preclinical and clinical trials.

  3. Deep sequencing reveals microRNAs predictive of antiangiogenic drug response

    PubMed Central

    García-Donas, Jesús; Beuselinck, Benoit; Inglada-Pérez, Lucía; Graña, Osvaldo; Schöffski, Patrick; Wozniak, Agnieszka; Bechter, Oliver; Apellániz-Ruiz, Maria; Leandro-García, Luis Javier; Esteban, Emilio; Castellano, Daniel E.; González del Alba, Aranzazu; Climent, Miguel Angel; Hernando, Susana; Arranz, José Angel; Morente, Manuel; Pisano, David G.; Robledo, Mercedes

    2016-01-01

    The majority of metastatic renal cell carcinoma (RCC) patients are treated with tyrosine kinase inhibitors (TKI) in first-line treatment; however, a fraction are refractory to these antiangiogenic drugs. MicroRNAs (miRNAs) are regulatory molecules proven to be accurate biomarkers in cancer. Here, we identified miRNAs predictive of progressive disease under TKI treatment through deep sequencing of 74 metastatic clear cell RCC cases uniformly treated with these drugs. Twenty-nine miRNAs were differentially expressed in the tumors of patients who progressed under TKI therapy (P values from 6 × 10–9 to 3 × 10–3). Among 6 miRNAs selected for validation in an independent series, the most relevant associations corresponded to miR–1307-3p, miR–155-5p, and miR–221-3p (P = 4.6 × 10–3, 6.5 × 10–3, and 3.4 × 10–2, respectively). Furthermore, a 2 miRNA–based classifier discriminated individuals with progressive disease upon TKI treatment (AUC = 0.75, 95% CI, 0.64–0.85; P = 1.3 × 10–4) with better predictive value than clinicopathological risk factors commonly used. We also identified miRNAs significantly associated with progression-free survival and overall survival (P = 6.8 × 10–8 and 7.8 × 10–7 for top hits, respectively), and 7 overlapped with early progressive disease. In conclusion, this is the first miRNome comprehensive study, to our knowledge, that demonstrates a predictive value of miRNAs for TKI response and provides a new set of relevant markers that can help rationalize metastatic RCC treatment. PMID:27699216

  4. Experimental study of antiangiogenic gene therapy targeting VEGF in oral cancer.

    PubMed

    Okada, Yasuo; Ueno, Hikaru; Katagiri, Masataka; Oneyama, Takahiro; Shimomura, Kana; Sakurai, Satoshi; Mataga, Izumi; Moride, Michiko; Hasegawa, Hitoshi

    2010-02-01

    It is well known that tumor angiogenesis plays an important role in local growth and metastasis of oral cancer; therefore, inhibiting angiogenesis is considered to be effective for treating oral cancer. This study aimed to investigate the effectiveness of systemically available antiangiogenic gene therapy targeting vascular endothelial growth factor (VEGF), which is one of the most important angiogenesis accelerators. We administered a soluble form of VEGF receptor-expressing gene incorporated into adenovirus (AdVEGF-ExR) intraperitoneally to nude mice to which oral cancer cell lines (SAS, HSC-3, and Ca9-22) had been transplanted subcutaneously in vivo to inhibit angiogenesis and tumor proliferation. Then, we measured tumor volumes over time, and tumors were enucleated and examined histopathologically and immunohistologically at 28 days after AdVEGF-ExR administration. Compared to the controls to which we administered AdLacZ or saline, significant antiproliferative effects were observed (P < 0.05) in the AdVEGF-ExR administration group, and extensive tumor necrosis was found histopathologically. Immunohistochemical analysis with CD34 (NU-4A1) revealed tumor angiogenesis was suppressed significantly (P < 0.05), and that with ssDNA revealed apoptosis induction was significantly high (P < 0.05) in the AdVEGF-ExR group. However, analysis with Ki-67 (MIB-1) revealed tumor proliferative capacity was not significantly different between the groups. Consequently, we consider that AdVEGF-ExR administration achieved tumor growth suppression by inhibiting angiogenesis and inducing apoptosis, but not by inhibiting the proliferative capacity of tumor cells. Neither topical administration of a soluble form of VEGF receptor (sVEGFR) to the tumor nor a megadose was needed to achieve this inhibition effect. These results suggest gene therapy via sVEGFR would be an effective oral cancer therapy and benefit future clinical applications.

  5. FKBPL Is a Critical Antiangiogenic Regulator of Developmental and Pathological Angiogenesis

    PubMed Central

    Yakkundi, Anita; Bennett, Rachel; Hernández-Negrete, Ivette; Delalande, Jean-Marie; Hanna, Mary; Lyubomska, Oksana; Arthur, Kenneth; Short, Amy; McKeen, Hayley; Nelson, Laura; McCrudden, Cian M.; McNally, Ross; McClements, Lana; McCarthy, Helen O.; Burns, Alan J.; Bicknell, Roy; Kissenpfennig, Adrien

    2015-01-01

    Objective— The antitumor effects of FK506-binding protein like (FKBPL) and its extracellular role in angiogenesis are well characterized; however, its role in physiological/developmental angiogenesis and the effect of FKBPL ablation has not been evaluated. This is important as effects of some angiogenic proteins are dosage dependent. Here we evaluate the regulation of FKBPL secretion under angiogenic stimuli, as well as the effect of FKBPL ablation in angiogenesis using mouse and zebrafish models. Approach and Results— FKBPL is secreted maximally by human microvascular endothelial cells and fibroblasts, and this was specifically downregulated by proangiogenic hypoxic signals, but not by the angiogenic cytokines, VEGF or IL8. FKBPL’s critical role in angiogenesis was supported by our inability to generate an Fkbpl knockout mouse, with embryonic lethality occurring before E8.5. However, whilst Fkbpl heterozygotic embryos showed some vasculature irregularities, the mice developed normally. In murine angiogenesis models, including the ex vivo aortic ring assay, in vivo sponge assay, and tumor growth assay, Fkbpl+/− mice exhibited increased sprouting, enhanced vessel recruitment, and faster tumor growth, respectively, supporting the antiangiogenic function of FKBPL. In zebrafish, knockdown of zFkbpl using morpholinos disrupted the vasculature, and the phenotype was rescued with hFKBPL. Interestingly, this vessel disruption was ineffective when zcd44 was knocked-down, supporting the dependency of zFkbpl on zCd44 in zebrafish. Conclusions— FKBPL is an important regulator of angiogenesis, having an essential role in murine and zebrafish blood vessel development. Mouse models of angiogenesis demonstrated a proangiogenic phenotype in Fkbpl heterozygotes. PMID:25767277

  6. Nuclear magnetic resonance imaging of tumour growth and neovasculature performance in vivo reveals Grb7 as a novel antiangiogenic target.

    PubMed

    García-Palmero, Irene; López-Larrubia, Pilar; Cerdán, Sebastián; Villalobo, Antonio

    2013-09-01

    Development of neovasculature is a necessary requirement for tumour growth and it provides additional opportunities for therapeutic intervention. However, current antiangiogenic therapies have limited efficacy, mostly because of the development of resistance. Hence, characterization of new antiangiogenic molecular targets is of considerable clinical interest. We report that a calmodulin-binding domain (CaM-BD) deletion mutant of the growth factor receptor bound protein 7 (Grb7) (denoted Grb7Δ) impairs tumour growth and associated angiogenesis in vivo. We implanted glioma C6 cells in rat brains transfected with an enhanced yellow fluorescent protein (EYFP) chimera of Grb7∆, its EYFP-Grb7 wild type counterpart, and EYFP alone. We systematically followed intracerebral growth of the tumours, their cellularity and the functional performance of tumour-associated microvasculature using magnetic resonance imaging, including anatomical T1W and T2W images and functional diffusion and perfusion parameters. Tumours grown from implanted C6 cells expressing EYFP-Grb7Δ developed slower, became smaller and presented lower apparent cellularity than those derived from cells expressing EYFP-Grb7 and EYFP. Vascular perfusion measurements within tumours derived from EYFP-Grb7∆-expressing cells showed significantly lower cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) values. These findings were independently validated by histological and immunohistochemical techniques. Taken together, these findings confirm that the CaM-BD of Grb7 plays an important role in tumour growth and associated angiogenesis in vivo, thus identifying this region of the protein as a novel target for antiangiogenic treatment.

  7. Molecular features of interaction between VEGFA and anti-angiogenic drugs used in retinal diseases: a computational approach

    PubMed Central

    Platania, Chiara B. M.; Di Paola, Luisa; Leggio, Gian M.; Romano, Giovanni L.; Drago, Filippo; Salomone, Salvatore; Bucolo, Claudio

    2015-01-01

    Anti-angiogenic agents are biological drugs used for treatment of retinal neovascular degenerative diseases. In this study, we aimed at in silico analysis of interaction of vascular endothelial growth factor A (VEGFA), the main mediator of angiogenesis, with binding domains of anti-angiogenic agents used for treatment of retinal diseases, such as ranibizumab, bevacizumab and aflibercept. The analysis of anti-VEGF/VEGFA complexes was carried out by means of protein-protein docking and molecular dynamics (MD) coupled to molecular mechanics-Poisson Boltzmann Surface Area (MM-PBSA) calculation. Molecular dynamics simulation was further analyzed by protein contact networks. Rough energetic evaluation with protein-protein docking scores revealed that aflibercept/VEGFA complex was characterized by electrostatic stabilization, whereas ranibizumab and bevacizumab complexes were stabilized by Van der Waals (VdW) energy term; these results were confirmed by MM-PBSA. Comparison of MM-PBSA predicted energy terms with experimental binding parameters reported in literature indicated that the high association rate (Kon) of aflibercept to VEGFA was consistent with high stabilizing electrostatic energy. On the other hand, the relatively low experimental dissociation rate (Koff) of ranibizumab may be attributed to lower conformational fluctuations of the ranibizumab/VEGFA complex, higher number of contacts and hydrogen bonds in comparison to bevacizumab and aflibercept. Thus, the anti-angiogenic agents have been found to be considerably different both in terms of molecular interactions and stabilizing energy. Characterization of such features can improve the design of novel biological drugs potentially useful in clinical practice. PMID:26578958

  8. FDA Approval Summary: Nivolumab in Advanced Renal Cell Carcinoma After Anti-Angiogenic Therapy and Exploratory Predictive Biomarker Analysis.

    PubMed

    Xu, James Xunhai; Maher, V Ellen; Zhang, Lijun; Tang, Shenghui; Sridhara, Rajeshwari; Ibrahim, Amna; Kim, Geoffrey; Pazdur, Richard

    2017-03-01

    On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol-Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open-label, randomized study of 821 patients with advanced RCC who progressed after at least one anti-angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross-over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60-0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression-free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune-mediated nephritis appeared to be higher in patients with RCC. The Oncologist 2017;22:311-317 IMPLICATIONS FOR PRACTICE: The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti-angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor-targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

  9. Targeted concurrent and sequential delivery of chemotherapeutic and antiangiogenic agents to the brain by using drug-loaded nanofibrous membranes

    PubMed Central

    Tseng, Yuan-Yun; Yang, Tao-Chieh; Wang, Yi-Chuan; Lee, Wei-Hwa; Chang, Tzu-Min; Kau, Yi-Chuan; Liu, Shih-Jung

    2017-01-01

    Glioblastoma is the most frequent and devastating primary brain tumor. Surgery followed by radiotherapy with concomitant and adjuvant chemotherapy is the standard of care for patients with glioblastoma. Chemotherapy is ineffective, because of the low therapeutic levels of pharmaceuticals in tumor tissues and the well-known tumor-cell resistance to chemotherapy. Therefore, we developed bilayered poly(d,l)-lactide-co-glycolide nanofibrous membranes that enabled the sequential and sustained release of chemotherapeutic and antiangiogenic agents by employing an electrospinning technique. The release characteristics of embedded drugs were determined by employing an in vitro elution technique and high-performance liquid chromatography. The experimental results showed that the fabricated nanofibers showed a sequential drug-eluting behavior, with the release of high drug levels of chemotherapeutic carmustine, irinotecan, and cisplatin from day 3, followed by the release of high concentrations of the antiangiogenic combretastatin from day 21. Biodegradable multidrug-eluting nanofibrous membranes were then dispersed into the cerebral cavity of rats by craniectomy, and the in vivo release characteristics of the pharmaceuticals from the membranes were investigated. The results suggested that the nanofibrous membranes released high concentrations of pharmaceuticals for more than 8 weeks in the cerebral parenchyma of rats. The result of histological analysis demonstrated developmental atrophy of brains with no inflammation. Biodegradable nanofibrous membranes can be manufactured for long-term sequential transport of different chemotherapeutic and anti-angiogenic agents in the brain, which can potentially improve the treatment of glioblastoma multiforme and prevent toxic effects due to systemic administration. PMID:28243088

  10. Anti-tumor efficacy of ultrasonic cavitation is potentiated by concurrent delivery of anti-angiogenic drug in colon cancer.

    PubMed

    Zhang, Chao; Huang, Pintong; Zhang, Ying; Chen, Jian; Shentu, Weihui; Sun, Yu; Yang, Zhijian; Chen, Shuyuan

    2014-05-28

    This study investigated the efficacy of concurrent delivery of an anti-angiogenic drug and ultrasonic cavitation therapy in a mouse model of human colon cancer. A biotinylated form of the anti-angiogenic drug Endostar was conjugated to a streptavidin-coated microbubble (MB). Mice bearing subcutaneous tumors (HT29) were divided into 4 groups. Group 1 served as an untreated control. Group 2 served as a cavitation control and received naked microbubbles and sham ultrasonic cavitation (MB+sham cavitation). Group 3 received naked microbubbles and ultrasonic cavitation (MB+cavitation). Group 4 received Endostar loaded microbubbles and ultrasonic cavitation (Endostar-MB+cavitation). Ultrasonic cavitation was performed using a high-power custom built sonicator. Contrast-enhanced ultrasound imaging (CEUS) was used to measure tumor blood flow before and after ultrasonic cavitation. In vivo fluorescence imaging was performed to monitor changes in tumor volume. Immunohistochemistry was performed to assess CD31, VEGFR-2 and alpha-v beta-3 integrin expression within the tumor. Apoptosis of the tumor cells was determined by TUNEL assay, and ultrastructural changes within the tumor were examined by electron microcopy. Ultrasonic cavitation with Endostar-MB demonstrated a significantly greater inhibition of tumor blood flow on day 7 and tumor growth on day 16 compared with naked MB and control groups. The Endostar-MB treated mice showed significantly decreased expression VEGFR-2 and alpha-v beta-3 integrin, and increased apoptosis of tumor cells and degradation of the tumor ultrastructure. Our findings indicated that the anti-vascular and anti-tumor effects of ultrasonic cavitation could be potentiated by simultaneously delivering an anti-angiogenic drug in colon cancer.

  11. Antiangiogenic Effect of (±)-Haloperidol Metabolite II Valproate Ester [(±)-MRJF22] in Human Microvascular Retinal Endothelial Cells.

    PubMed

    Olivieri, Melania; Amata, Emanuele; Vinciguerra, Shila; Fiorito, Jole; Giurdanella, Giovanni; Drago, Filippo; Caporarello, Nunzia; Prezzavento, Orazio; Arena, Emanuela; Salerno, Loredana; Rescifina, Antonio; Lupo, Gabriella; Anfuso, Carmelina Daniela; Marrazzo, Agostino

    2016-11-10

    (±)-MRJF22 [(±)-2], a novel prodrug of haloperidol metabolite II (sigma-1 receptor antagonist/sigma-2 receptor agonist ligand) obtained by conjugation to valproic acid (histone deacetylase inhibitor) via an ester bond, exhibits antiangiogenic activity, being able to reduce human retinal endothelial cell (HREC) viability in a comparable manner to bevacizumab. Moreover, (±)-2 was able to significantly reduce viable cells count, endothelial cell migration, and tube formation in vascular endothelial growth factor A (VEGF-A) stimulated HREC cultures.

  12. Development of a Novel In Vitro Human Tissue-Based Angiogenesis Assay to Evaluate the Effect of Antiangiogenic Drugs

    PubMed Central

    Woltering, Eugene A.; Lewis, James M.; Maxwell, P. Johnstone; Frey, Daniel J.; Wang, Yi-Zarn; Rothermel, John; Anthony, Catherine T.; Balster, Douglas A.; O’Leary, J. Patrick; Harrison, Lynn H.

    2003-01-01

    Objective To describe a novel in vitro human tissue-based angiogenic model that can predict an individual tumor’s response to antiangiogenic drugs. Summary Background Data A number of in vitro and in vivo angiogenesis assays exist, but they do not provide potentially useful information for the treatment of an individual patient. Clonogenic assays have been used to evaluate the response of an individual’s tumor to antineoplastic agents, but these tumor fragments are cultured in an environment that does not lead to neovessel growth. The authors have previously demonstrated that human vein disks or human tumor xenograft fragments incorporated into a 0.3% fibrin-thrombin clot will develop angiogenic vessel growth from the cut edge of the vessel disk or xenograft fragment. Methods Fresh human tumor or normal tissue disks (2 × 1 mm) from fresh surgical specimens were incorporated into fibrin-thrombin clots overlain with nutrient medium containing either 20% fetal bovine serum alone or in combination with Epothilone B, a tubulin inhibitor with antiangiogenic properties. Tissue disks were visually assessed over time to determine the percentage of wells that developed an angiogenic response. Neovessel growth, density, and length were graded at intervals using a semiquantitative visual neovessel growth-rating scheme (angiogenic index, 0–16 scale) devised in the authors’ laboratory. Results Epothilone B treatment at doses of 10−6 mol/L and 10−8 mol/L decreased the number of wells that developed an invasive angiogenic response and limited the development of vessels that invaded the matrix. At these doses, Epothilone B also caused regression of vessels in wells that had been allowed to develop an angiogenic response. Treatment of tumors or normal tissues with Epothilone B at doses less than 10−8 mol/L was ineffective. Conclusions Epothilone B may be an effective antiangiogenic agent in a variety of tumor types. The authors speculate that this in vitro model might

  13. Bis(phenylimidazoselenazolyl) diselenide as an antioxidant compound: An in vitro and in vivo study.

    PubMed

    Chagas, Pietro Maria; Fulco, Bruna da Cruz Weber; Pesarico, Ana Paula; Roehrs, Juliano Alex; Nogueira, Cristina Wayne

    2015-05-25

    The organoselenium compounds have been reported for many biological properties, especially as potent antioxidants. The compound bis(phenylimidazoselenazolyl) diselenide (BPIS) is a novel diaryl diselenide derivative, which shows antinociceptive and anti-inflammatory properties in mice, but whose antioxidant activity has not been studied. The present study aimed to investigate the antioxidant and toxicological potential of BPIS in brain of rats in vitro, and the effect of BPIS against the oxidative damage induced by sodium nitroprusside (SNP) in mouse brain. BPIS, at low molecular range, reduced lipid peroxidation (LP) and protein carbonyl (PC) content in rat brain homogenates (IC50 values of 1.35 and 0.74 μM, respectively). BPIS also presented dehydroascorbate reductase-like and glutathione-S-transferase-like, as well as DPPH and NO-scavenging activities. Related to togicological assays, BPIS inhibited δ-ALA-D and Na(+), K(+)-ATPase activities in rat brain homogenates and [(3)H]glutamate uptake in synaptosomes in vitro, but these effects were observed at higher concentrations than it had antioxidant effect (IC50 values of 16.41, 26.44 and 3.29 μM, respectively). In vivo, brains of mice treated with SNP (0.335 μmol per site; i.c.v.) showed an increase in LP and PC and a reduction in non protein thiol content, however, it was not observed significant alterations in antioxidant enzyme activities. BPIS (10 mg/kg; p.o.) protected against these alterations caused by SNP. In conclusion, the results demonstrated the antioxidant action of BPIS in in vitro assays. Furthermore, BPIS protected against oxidative damage caused by SNP in mouse brain, strengthening the potential antioxidant effect of this compound.

  14. TRIFLUOROMETHYL COMPOUNDS OF GERMANIUM

    DTIC Science & Technology

    FLUORIDES, *GERMANIUM COMPOUNDS, *HALIDES, *ORGANOMETALLIC COMPOUNDS, ALKYL RADICALS, ARSENIC COMPOUNDS, CHEMICAL BONDS, CHEMICAL REACTIONS ...CHLORIDES, CHLORINE COMPOUNDS, HYDROLYSIS, IODIDES, METHYL RADICALS, POTASSIUM COMPOUNDS, PYROLYSIS, STABILITY, SYNTHESIS, TIN COMPOUNDS.

  15. Schedule-Dependent Antiangiogenic and Cytotoxic Effects of Chemotherapy on Vascular Endothelial and Retinoblastoma Cells

    PubMed Central

    Winter, Ursula; Mena, Hebe A.; Negrotto, Soledad; Arana, Eloisa; Pascual-Pasto, Guillem; Laurent, Viviana; Suñol, Mariona; Chantada, Guillermo L.; Carcaboso, Angel M.; Schaiquevich, Paula

    2016-01-01

    Current treatment of retinoblastoma involves using the maximum dose of chemotherapy that induces tumor control and is tolerated by patients. The impact of dose and schedule on the cytotoxicity of chemotherapy has not been studied. Our aim was to gain insight into the cytotoxic and antiangiogenic effect of the treatment scheme of chemotherapy used in retinoblastoma by means of different in vitro models and to evaluate potential effects on multi-drug resistance proteins. Two commercial and two patient-derived retinoblastoma cell types and two human vascular endothelial cell types were exposed to increasing concentrations of melphalan or topotecan in a conventional (single exposure) or metronomic (7-day continuous exposure) treatment scheme. The concentration of chemotherapy causing a 50% decrease in cell proliferation (IC50) was determined by MTT and induction of apoptosis was evaluated by flow cytometry. Expression of ABCB1, ABCG2 and ABCC1 after conventional or metronomic treatments was assessed by RT-qPCR. We also evaluated the in vivo response to conventional (0.6 mg/kg once a week for 2 weeks) and metronomic (5 days a week for 2 weeks) topotecan in a retinoblastoma xenograft model. Melphalan and topotecan were cytotoxic to both retinoblastoma and endothelial cells after conventional and metronomic treatments. A significant decrease in the IC50 (median, 13-fold; range: 3–23) was observed following metronomic chemotherapy treatment in retinoblastoma and endothelial cell types compared to conventional treatment (p<0.05). Metronomic topotecan or melphalan significantly inhibited in vitro tube formation in HUVEC and EPC compared to vehicle-treated cells (p<0.05). Both treatment schemes induced apoptosis and/or necrosis in all cell models. No significant difference was observed in the expression of ABCB1, ABCC1 or ABCG2 when comparing cells treated with melphalan or topotecan between treatment schedules at the IC50 or with control cells (p>0.05). In mice, continuous

  16. Rapid, in vivo, evaluation of antiangiogenic and antineoplastic gene products by nonviral transfection of tumor cells.

    PubMed

    Weiss, Jonathan M; Shivakumar, Rama; Feller, Stephanie; Li, Lin-Hong; Hanson, Art; Fogler, William E; Fratantoni, Joseph C; Liu, Linda N

    2004-05-01

    Using a nonviral, electroporation-based gene transfection approach, we demonstrate the efficient and consistent transfection of two poorly immunogenic tumor cell lines: B16F10 melanoma and renal carcinoma (RENCA). Three genes, IL-12, angiostatin (AS), and an endostatin:angiostatin fusion protein (ES:AS) were subcloned into a DNA plasmid containing EBNA1-OriP, which was then transfected into B16F10 and RENCA cells. Significant levels of protein were secreted into the culture supernatants of transfected cells in vitro. Transfected tumor cells were injected subcutaneously into mice. All the three transgenes were capable of significantly delaying and reducing the formation of primary B16F10 and RENCA tumors, as well as B16F10 lung metastases. By day 11 post-injection, all control mice that received either mock-transfected or empty vector DNA-transfected B16F10 tumor cells had developed large primary tumors. In contrast, mice that received IL-12-transfected B16F10 cells did not develop appreciable tumors until day 17, and these were significantly smaller than controls. Similar results were observed for the RENCA model, in which only one of the IL-12 mice had developed tumors out to day 31. Expression of AS or ES:AS also significantly delayed and reduced primary tumors. Overall, ES:AS was more effective than AS alone. Furthermore, 25% of the AS mice and 33% of the ES:AS mice remained tumor-free at day 17, by which point all control mice had significant tumors. Mouse survival rates also correlated with the extent of tumor burden. Importantly, no lung metastases were detected in the lungs of mice that had received either AS or ES:AS-transfected B16F10 tumor cells and significantly fewer metastases were found in the IL-12 group. The consistency of our transfection results highlight the feasibility of directly electroporating tumor cells as a means to screen, identify, and validate in vivo potentially novel antiangiogenic and/or antineoplastic genes.

  17. Disease modifying and antiangiogenic activity of 2-Methoxyestradiol in a murine model of rheumatoid arthritis

    PubMed Central

    Plum, Stacy M; Park, Eun J; Strawn, Steve J; Moore, Elizabeth G; Sidor, Carolyn F; Fogler, William E

    2009-01-01

    Background A critical component of disease progression in rheumatoid arthritis (RA) involves neovascularization associated with pannus formation. 2-methoxyestradiol (2ME2) is a naturally occurring molecule with no known physiologic function, although at pharmacologic concentrations it has antiproliferative and antiangiogenic activities. We investigated the impact of orally administered 2ME2 on the initiation and development of proliferative synovitis using the anti-collagen monoclonal antibodies (CAIA) model. Methods Severe polyarticular arthritis was induced in Balb/c female mice by administration of 2 mg of a monoclonal antibody cocktail intravenously into the tail vein of mice. Twenty-four hours following monoclonal antibody administration, mice were injected with 25 μg of LPS (E. coli strain 0111:B4) via the intraperitoneal route. Treatment with 2ME2 (100, 75, 50, 25, 10, 1 mg/kg, p.o., daily), or vehicle control began 24 hrs following LPS challenge and continued to day 21. Hind limbs were harvested, sectioned and evaluated for DMARD activity and general histopathology by histomorphometric analysis and immunohistochemistry (vWF staining). In a separate study, different dosing regimens of 2ME2 (100 mg/kg; q.d. vs q.w. vs q.w. × 2) were evaluated. The effect of treatment with 2ME2 on gene expression of inflammatory cytokines and angiogenic growth factors in the joint space was evaluated 5 and 14 days after the induction of arthritis. Results Mice treated with 2ME2 beginning 24 hours post anti-collagen monoclonal antibody injection, showed a dose-dependent inhibition in mean arthritic scores. At study termination (day 21), blinded histomorphometric assessments of sectioned hind limbs demonstrated decreases in synovial inflammation, articular cartilage degradation, pannus formation, osteoclast activity and bone resorption. At the maximal efficacious dosing regimen (100 mg/kg/day), administration of 2ME2 resulted in total inhibition of the study parameters and

  18. Role of Angiogenesis in Endodontics: Contributions of Stem Cells and Proangiogenic and Antiangiogenic Factors to Dental Pulp Regeneration

    PubMed Central

    Saghiri, Mohammad Ali; Asatourian, Armen; Sorenson, Christine M.; Sheibani, Nader

    2016-01-01

    Introduction Dental pulp regeneration is a part of regenerative endodontics, which includes isolation, propagation, and re-transplantation of stem cells inside the prepared root canal space. The formation of new blood vessels through angiogenesis is mandatory to increase the survival rate of re-transplanted tissues. Angiogenesis is defined as the formation of new blood vessels from preexisting capillaries, which has great importance in pulp regeneration and homeostasis. Here the contribution of human dental pulp stem cells and proangiogenic and antiangiogenic factors to angiogenesis process and regeneration of dental pulp is reviewed. Methods A search was performed on the role of angiogenesis in dental pulp regeneration from January 2005 through April 2014. The recent aspects of the relationship between angiogenesis, human dental pulp stem cells, and proangiogenic and antiangiogenic factors in regeneration of dental pulp were assessed. Results Many studies have indicated an intimate relationship between angiogenesis and dental pulp regeneration. The contribution of stem cells and mechanical and chemical factors to dental pulp regeneration has been previously discussed. Conclusions Angiogenesis is an indispensable process during dental pulp regeneration. The survival of inflamed vital pulp and engineered transplanted pulp tissue are closely linked to the process of angiogenesis at sites of application. However, the detailed regulatory mechanisms involved in initiation and progression of angiogenesis in pulp tissue require investigation. PMID:25649306

  19. Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors

    PubMed Central

    Askou, Anne Louise; Aagaard, Lars; Kostic, Corinne; Arsenijevic, Yvan; Hollensen, Anne Kruse; Bek, Toke; Jensen, Thomas Gryesten; Mikkelsen, Jacob Giehm; Corydon, Thomas Juhl

    2015-01-01

    Lentivirus-based gene delivery vectors carrying multiple gene cassettes are powerful tools in gene transfer studies and gene therapy, allowing coexpression of multiple therapeutic factors and, if desired, fluorescent reporters. Current strategies to express transgenes and microRNA (miRNA) clusters from a single vector have certain limitations that affect transgene expression levels and/or vector titers. In this study, we describe a novel vector design that facilitates combined expression of therapeutic RNA- and protein-based antiangiogenic factors as well as a fluorescent reporter from back-to-back RNApolII-driven expression cassettes. This configuration allows effective production of intron-embedded miRNAs that are released upon transduction of target cells. Exploiting such multigenic lentiviral vectors, we demonstrate robust miRNA-directed downregulation of vascular endothelial growth factor (VEGF) expression, leading to reduced angiogenesis, and parallel impairment of angiogenic pathways by codelivering the gene encoding pigment epithelium-derived factor (PEDF). Notably, subretinal injections of lentiviral vectors reveal efficient retinal pigment epithelium-specific gene expression driven by the VMD2 promoter, verifying that multigenic lentiviral vectors can be produced with high titers sufficient for in vivo applications. Altogether, our results suggest the potential applicability of combined miRNA- and protein-encoding lentiviral vectors in antiangiogenic gene therapy, including new combination therapies for amelioration of age-related macular degeneration. PMID:26052532

  20. Blocking the FGF/FGFR system as a "two-compartment" antiangiogenic/antitumor approach in cancer therapy.

    PubMed

    Giacomini, Arianna; Chiodelli, Paola; Matarazzo, Sara; Rusnati, Marco; Presta, Marco; Ronca, Roberto

    2016-05-01

    Fibroblast growth factors (FGFs) are a family of pleiotropic factors produced by stromal and parenchymal tumor cells. Even though FGFs have been firstly characterized as angiogenic factors, they exert autocrine and paracrine functions not only on endothelial cells but also on tumor cells and other stromal components. Thus, the FGF/FGF receptor (FGFR) pathway may represent a key player in tumor growth by regulating the complex cross-talk between stromal and tumor compartments. The ligand dependent or independent activation of the FGF/FGFR system by gene upregulation, oncogenic mutation or amplification occurs in a variety of human tumors and is implicated in various key steps of tumor growth and progression. In addition, FGF/FGFR activation has been described as a mechanism of tumor escape in response to antiangiogenic/anti-VEGF therapies. Experimental and clinical evidences provide a compelling biologic rationale for the development of anti-FGF/FGFR targeting agents in cancer therapy. However, the development of drugs specifically targeting the FGF/FGFR pathway proved to be difficult, also due to the high redundancy and pleiotropic effects of FGF and FGFR family members. On the other hand, the possibility to develop "two-compartment" targeting agents endowed with both antiangiogenic and antitumor activities remains promising. Here we will review the preclinical and clinical approaches and potential therapeutics currently available to block the FGF/FGFR system in human cancer.

  1. Butyrate-induced proapoptotic and antiangiogenic pathways in EAT cells require activation of CAD and downregulation of VEGF

    SciTech Connect

    Belakavadi, Madesh . E-mail: belakama@umdnj.edu; Prabhakar, B.T.; Salimath, Bharathi P.

    2005-10-07

    Butyrate, a short-chain fatty acid produced in the colon, induces cell cycle arrest, differentiation, and apoptosis in transformed cell lines. In this report, we study the effects of butyrate (BuA) on the growth of Ehrlich ascites tumor (EAT) cells in vivo. BuA, when injected intraperitoneally (i.p) into mice, inhibited proliferation of EAT cells. Further, induction of apoptosis in EAT cells was monitored by nuclear condensation, annexin-V staining, DNA fragmentation, and translocation of caspase-activated DNase into nucleus upon BuA-treatment. Ac-DEVD-CHO, a caspase-3 inhibitor, completely inhibited BuA-induced apoptosis, indicating that activation of caspase-3 mediates the apoptotic pathway in EAT cells. The proapoptotic effect of BuA also reflects on the antiangiogenic pathway in EAT cells. The antiangiogenic effect of BuA in vivo was demonstrated by the downregulation of the secretion of VEGF in EAT cells. CD31 immunohistochemical staining of peritoneum sections clearly indicated a potential angioinhibitory effect of BuA in EAT cells. These results suggest that BuA, besides regulating other fundamental cellular processes, is able to modulate the expression/secretion of the key angiogenic growth factor VEGF in EAT cells.

  2. Mechanisms of the antiangiogenic activity by the hop flavonoid xanthohumol: NF-kappaB and Akt as targets.

    PubMed

    Albini, Adriana; Dell'Eva, Raffaella; Vené, Roberta; Ferrari, Nicoletta; Buhler, Donald R; Noonan, Douglas M; Fassina, Gianfranco

    2006-03-01

    Xanthohumol (XN), the principal flavonoid of the hop plant (Humulus lupulus L.) and a constituent of beer, has been suggested to have potential cancer chemopreventive activities. We have observed that most cancer chemopreventive agents show antiangiogenic properties in vitro and in vivo, a concept we termed "angioprevention." Here we show for the first time that XN can inhibit growth of a vascular tumor in vivo. Histopathology and in vivo angiogenesis assays indicated that tumor angiogenesis inhibition was involved. Further, we show the mechanisms for its inhibition of angiogenesis in vivo and related endothelial cell activities in vitro. XN repressed both the NF-kappaB and Akt pathways in endothelial cells, indicating that components of these pathways are major targets in the molecular mechanism of XN. Moreover, using in vitro analyses, we show that XN interferes with several points in the angiogenic process, including inhibition of endothelial cell invasion and migration, growth, and formation of a network of tubular-like structures. Our results suggest that XN can be added to the expanding list of antiangiogenic chemopreventive drugs whose potential in cancer prevention and therapy should be evaluated.

  3. Natural honey: a new and potent anti-angiogenic agent in the air-pouch model of inflammation.

    PubMed

    Eteraf-Oskouei, T; Najafi, M; Gharehbagheri, A

    2014-10-01

    Despite reports indicating anti-inflammatory effects of honey, the anti-angiogenic effect of honey and its impact on inflammatory mediators in the air pouch model of inflammation have not yet been studied. The aims of present study were to investigate the effects of honey on angiogenesis, inflammatory cytokine vascular endothelial growth factor (VEGF) level as an important marker of angiogenesis and prostaglandin E2 (PGE2) in the rat air pouch model of inflammation. Male Wistar rats were anesthetized, and then 20 ml and 10 ml of sterile air were injected subcutaneously in the back on days 0 and 3, respectively. On day 6, inflammation was induced by injection of 1 ml of carrageenan 1% into pouches. After 72 h, the rats were sacrificed; pouch fluid was collected in order to determine PGE2 concentration and VEGF level. The Pouches were dissected out and weighed. Angiogenesis of granulomatous tissue was assayed using a hemoglobin kit. Honey was able to reduce granulation tissue weight and angiogenesis as well as showing potent inhibitory activities against PGE2 and VEGF in air pouch model of inflammation. The decrease in angiogenesis correlates with the inhibition of PGE2 and VEGF. Honey is potentially useful in the treatment of granulomatous inflammatory conditions. It seems that the anti-angiogenic activities of honey are mediated through modulation of PGE2 and VEGF production.

  4. Expression of Total Vascular Endothelial Growth Factor and the Anti-angiogenic VEGF165b Isoform in the Vitreous of Patients with Retinopathy of Prematurity

    PubMed Central

    Zhao, Min; Xie, Wan-Kun; Bai, Yu-Jing; Huang, Lyu-Zhen; Wang, Bin; Liang, Jian-Hong; Yin, Hong; Li, Xiao-Xin; Shi, Xuan

    2015-01-01

    Background: This study was to examine the expression of total vascular endothelial growth factor (VEGF) and the anti-angiogenic VEGF165b isoform in the vitreous body of retinopathy of prematurity (ROP) patients, and to further study the role of the VEGF splicing in the development of ROP. Methods: This was a prospective clinical laboratory investigation study. All patients enrolled received standard ophthalmic examination with stage 4 ROP that required vitrectomy to collect the vitreous samples. The control samples were from congenital cataract patients. The expression of total VEGF and the anti-angiogenic VEGF165b were measured by enzyme-linked immunosorbent assay. Results were analyzed statistically using nonparametric tests. Results: The total VEGF level was markedly elevated in ROP samples while VEGF165b was markedly decreased compared to control group. The relative protein expression level of VEGF165b isoform was significantly decreased in ROP patients which were correlated with the ischemia-induced neovascularization. Conclusions: There was a switch of VEGF splicing from anti-angiogenic to pro-angiogenic family in ROP patients. A specific inhibitor that more selectively targets VEGF165and controls the VEGF splicing between pro- and anti-angiogenic families might be a more effective therapy for ROP. PMID:26365970

  5. Polychlorinated biphenyls target Notch/Dll and VEGF R2 in the mouse placenta and human trophoblast cell lines for their anti-angiogenic effects

    PubMed Central

    Kalkunte, Satyan; Huang, Zheping; Lippe, Eliana; Kumar, Sunil; Robertson, Larry W.; Sharma, Surendra

    2017-01-01

    The intrauterine environment is particularly vulnerable to environmental exposures. We previously established a mouse model that provided evidence for pregnancy complications and placental anti-angiogenesis in response to Aroclor 1254 (A-1254), a mixture of polychlorinated biphenyls (PCBs). Importantly, these effects were observed in IL-10−/−, but not wild type, mice, suggesting that IL-10 deficiency predisposes to pregnancy disruptive effects of environmental toxicants. However, the mechanisms by which PCBs cause anti-angiogenic effects are unclear. Here, we evaluated PCB-mediated anti-angiogenic effects by diverse but complementary approaches, including HUVEC-mediated trophoblast invasion in nude mice, in vitro three-dimensional capillary tube formation involving HUVEC and/or HTR8 trophoblasts, and aortic ring endothelial cell outgrowth/sprouting. Taken together, our data suggest that PCBs act as potent anti-angiogenic agents. Importantly, we show that treatment of pregnant IL-10−/− mice with A-1254 resulted in placental activation of the Notch/Delta-like ligand (Dll) pathway, a master regulator of cell-cell interaction and vascular patterning. Similar results were obtained with HUVEC and HTR8 trophoblasts. Rescue of A-1254-induced disruption of HUVEC-based tube formation by γ-secretase inhibitor L1790 confirmed the critical role of the Notch/Dll pathway. Our data suggest that PCBs impart pregnancy disruptive functions by activating the Notch/Dll pathway and by inducing anti-angiogenic effects at the maternal-fetal interface. PMID:28071720

  6. Molecularly Characterized Solvent Extracts and Saponins from Polygonum hydropiper L. Show High Anti-Angiogenic, Anti-Tumor, Brine Shrimp, and Fibroblast NIH/3T3 Cell Line Cytotoxicity

    PubMed Central

    Ayaz, Muhammad; Junaid, Muhammad; Ullah, Farhat; Sadiq, Abdul; Subhan, Fazal; Khan, Mir Azam; Ahmad, Waqar; Ali, Gowhar; Imran, Muhammad; Ahmad, Sajjad

    2016-01-01

    Polygonum hydropiper is used as anti-cancer and anti-rheumatic agent in folk medicine. This study was designed to investigate the anti-angiogenic, anti-tumor, and cytotoxic potentials of different solvent extracts and isolated saponins. Samples were analyzed using GC, Gas Chromatography–Mass Spectrometry (GC–MS) to identify major and bioactive compounds. Quantitation of antiangiogenesis for the plant's samples including methanolic extract (Ph.Cr), its subsequent fractions; n-hexane (Ph.Hex), chloroform (Ph.Chf), ethyl acetate (Ph.EtAc), n-Butanol (Ph.Bt), aqueous (Ph.Aq), saponins (Ph.Sp) were performed using the chick embryo chorioallantoic membrane (CAM) assay. Potato disc anti-tumor assay was performed on Agrobacterium tumefaciens containing tumor inducing plasmid. Cytotoxicity was performed against Artemia salina and mouse embryonic fibroblast NIH/3T3 cell line following contact toxicity and MTT cells viability assays, respectively. The GC–MS analysis of Ph.Cr, Ph.Hex, Ph.Chf, Ph.Bt, and Ph.EtAc identified 126, 124, 153, 131, and 164 compounds, respectively. In anti-angiogenic assay, Ph.Chf, Ph.Sp, Ph.EtAc, and Ph.Cr exhibited highest activity with IC50 of 28.65, 19.21, 88.75, and 461.53 μg/ml, respectively. In anti-tumor assay, Ph.Sp, Ph.Chf, Ph.EtAc, and Ph.Cr were most potent with IC50 of 18.39, 73.81, 217.19, and 342.53 μg/ml, respectively. In MTT cells viability assay, Ph.Chf, Ph.EtAc, Ph.Sp were most active causing 79.00, 72.50, and 71.50% cytotoxicity, respectively, at 1000 μg/ml with the LD50 of 140, 160, and 175 μg/ml, respectively. In overall study, Ph.Chf and Ph.Sp have shown overwhelming results which signifies their potentials as sources of therapeutic agents against cancer. PMID:27065865

  7. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models.

    PubMed

    Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Bilecz, Agnes; Daley, Frances; Kostaras, Eleftherios; Nathan, Mark R; Wan, Elaine; Frentzas, Sophia; Schweiger, Thomas; Hegedus, Balazs; Hoetzenecker, Konrad; Renyi-Vamos, Ferenc; Kuczynski, Elizabeth A; Vasudev, Naveen S; Larkin, James; Gore, Martin; Dvorak, Harold F; Paku, Sandor; Kerbel, Robert S; Dome, Balazs; Reynolds, Andrew R

    2017-02-01

    Anti-angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti-angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre-existing vessels from surrounding tissue (vessel co-option). As anti-angiogenic therapies were designed to target only new blood vessel growth, vessel co-option has been proposed as a mechanism that could drive resistance to anti-angiogenic therapy. However, vessel co-option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti-angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co-option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co-opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co-opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co-option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co-option mediates resistance to the anti-angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co-option in lung metastases occurs through at least three distinct mechanisms, that vessel co-option occurs frequently in lung metastases, and that vessel

  8. Deciphering Combinations of PI3K/AKT/mTOR Pathway Drugs Augmenting Anti-Angiogenic Efficacy In Vivo

    PubMed Central

    Sasore, Temitope; Kennedy, Breandán

    2014-01-01

    Ocular neovascularization is a common pathology associated with human eye diseases e.g. age-related macular degeneration and proliferative diabetic retinopathy. Blindness represents one of the most feared disabilities and remains a major burden to health-care systems. Current approaches to treat ocular neovascularisation include laser photocoagulation, photodynamic therapy and anti-VEGF therapies: Ranibizumab (Lucentis) and Aflibercept (Eylea). However, high clinical costs, frequent intraocular injections, and increased risk of infections are challenges related with these standards of care. Thus, there is a clinical need to develop more effective drugs that overcome these challenges. Here, we focus on an alternative approach by quantifying the in vivo anti-angiogenic efficacy of combinations of phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. The PI3K/AKT/mTOR pathway is a complex signalling pathway involved in crucial cellular functions such as cell proliferation, migration and angiogenesis. RT-PCR confirms the expression of PI3K target genes (pik3ca, pik3r1, mtor and akt1) in zebrafish trunks from 6 hours post fertilisation (hpf) and in eyes from 2 days post fertilisation (dpf). Using both the zebrafish intersegmental vessel and hyaloid vessel assays to measure the in vivo anti-angiogenic efficacy of PI3K/Akt/mTOR pathway inhibitors, we identified 5 µM combinations of i) NVP-BEZ235 (dual PI3K-mTOR inhibitor) + PI-103 (dual PI3K-mTOR inhibitor); or ii) LY-294002 (pan-PI3K inhibitor) + NVP-BEZ235; or iii) NVP-BEZ235 + rapamycin (mTOR inhibitor); or iv) LY-294002 + rapamycin as the most anti-angiogenic. Treatment of developing larvae from 2–5 dpf with 5 µM NVP-BEZ235 plus PI-103 resulted in an essentially intact ocular morphology and visual behaviour, whereas other combinations severely disrupted the developing retinal morphology and visual function. In human ARPE19 retinal pigment epithelium cells, however, no significant difference in cell number was

  9. A Decade of Experience in Developing Preclinical Models of Advanced- or Early-Stage Spontaneous Metastasis to Study Antiangiogenic Drugs, Metronomic Chemotherapy, and the Tumor Microenvironment.

    PubMed

    Kerbel, Robert S

    2015-01-01

    The clinical circumstance of treating spontaneous metastatic disease, after resection of primary tumors, whether advanced/overt or microscopic in nature, is seldom modeled in mice and may be a major factor in explaining the frequent discordance between preclinical and clinical therapeutic outcomes where the trend is "overprediction" of positive results in preclinical mouse model studies. To evaluate this hypothesis, a research program was initiated a decade ago to develop multiple models of metastasis in mice, using variants of human tumor cell lines selected in vivo for enhanced spontaneous metastatic aggressiveness after surgical resection of established orthotopic primary tumors. These models have included breast, renal, and colorectal carcinomas; ovarian cancer (but without prior surgery); and malignant melanoma. They have been used primarily for experimental therapeutic investigations involving various antiangiogenic drugs alone or with chemotherapy, especially "metronomic" low-dose chemotherapy. The various translational studies undertaken have revealed a number of clinically relevant findings. These include the following: (i) the potential of metronomic chemotherapy, especially when combined with a vascular endothelial growth factor pathway targeting drug to successfully treat advanced metastatic disease; (ii) the development of relapsed spontaneous brain metastases in mice with melanoma or breast cancer whose systemic metastatic disease is successfully controlled for a period with a given therapy; (iii) foreshadowing the failure of adjuvant antiangiogenic drug-based phase III trials; (iv) recapitulating the failure of oral antiangiogenic tyrosine kinase inhibitors plus standard chemotherapy in contrast to the modest successes of antiangiogenic antibodies plus chemotherapy in metastatic breast cancer; and (v) revealing "vessel co-option" and absence of angiogenesis as a determinant of intrinsic resistance or minimal responsiveness to antiangiogenic therapy

  10. Effect of selenium-containing compounds on hepatic chemoprotective enzymes in mice.

    PubMed

    El-Sayed, Wael M; Aboul-Fadl, Tarek; Lamb, John G; Roberts, Jeanette C; Franklin, Michael R

    2006-03-15

    Selenite and organoselenium compounds have been examined at supranutritional levels for their ability to influence the activity and mRNA levels of chemoprotective enzymes in the livers of selenium-sufficient mice and the changes compared to those elicited by oltipraz. Compounds investigated included novel selenocysteine prodrugs that have previously been evaluated for their ability to reduce the tumorigenicity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in mice. Following seven daily doses (i.g.), all compounds except 2-methylselenazolidine-4(R)-carboxylic acid (MSCA) increased thioredoxin reductase activity (43-92%) but only for 2-oxoselenazolidine-4(R)-carboxylic acid (OSCA) was there an accompanying increase in mRNA. No compound enhanced glutathione peroxidase activity, although sodium selenite significantly elevated the mRNA of this enzyme. Oltipraz was an efficacious inducer of both thioredoxin reductase and glutathione peroxidase mRNAs. Sodium selenite, selenazolidine-4(R)-carboxylic acid (SCA), and OSCA elevated NAD(P)H-quinone oxidoreductase mRNA but only for OSCA was the elevation in mRNA accompanied by an increase in enzyme activity. L-Selenocystine significantly increased this activity without increasing mRNA levels. Sodium selenite, L-selenocystine, L-selenomethionine, and Se-methyl-L-selenocysteine all enhanced glutathione S-transferase activity. The increased activity with sodium selenite was accompanied by increases in mRNAs of Gst alpha, Gst mu and Gst pi classes, while for L-selenocystine and Se-methyl-L-selenocysteine, only an elevation in the mRNA for the Gst alpha class was observed. Gst alpha and Gst mu class mRNAs were elevated by OSCA without a significant elevation in enzyme activity. SCA and MSCA both elevated a Gst pi mRNA and MSCA elevated Gst mu in addition. By comparison, oltipraz only significantly elevated the mRNA of Gst mu, adding to the conclusion that across the entire study, no selenium compound appears to be acting

  11. 3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

    SciTech Connect

    Lagerloef, Jakob H.; Kindblom, Jon; Bernhardt, Peter

    2011-08-15

    Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2

  12. Endothelial progenitor cells support tumour growth and metastatisation: implications for the resistance to anti-angiogenic therapy.

    PubMed

    Moccia, Francesco; Zuccolo, Estella; Poletto, Valentina; Cinelli, Mariapia; Bonetti, Elisa; Guerra, Germano; Rosti, Vittorio

    2015-09-01

    Endothelial progenitor cells (EPCs) have recently been shown to promote the angiogenic switch in solid neoplasms, thereby promoting tumour growth and metastatisation. The genetic suppression of EPC mobilization from bone marrow prevents tumour development and colonization of remote organs. Therefore, it has been assumed that anti-angiogenic treatments, which target vascular endothelial growth factor (VEGF) signalling in both normal endothelial cells and EPCs, could interfere with EPC activation in cancer patients. Our recent data, however, show that VEGF fails to stimulate tumour endothelial colony-forming cells (ECFCs), i.e. the only EPC subtype truly belonging to the endothelial lineage. The present article will survey current evidence about EPC involvement in the angiogenic switch: we will focus on the controversy about EPC definition and on the debate around their actual incorporation into tumour neovessels. We will then discuss how ECFC insensitivity to VEGF stimulation in cancer patients could underpin their well-known resistance to anti-VEGF therapies.

  13. Polybenzimidazole compounds

    DOEpatents

    Klaehn, John R [Idaho Falls, ID; Peterson, Eric S [Idaho Falls, ID; Orme, Christopher J [Shelley, ID; Jones, Michael G [Chubbuck, ID; Wertsching, Alan K [Idaho Falls, ID; Luther, Thomas A [Idaho Falls, ID; Trowbridge, Tammy L [Idaho Falls, ID

    2011-11-22

    A PBI compound includes imidazole nitrogens at least a portion of which are substituted with a moiety containing a carbonyl group, the substituted imidazole nitrogens being bonded to carbon of the carbonyl group. At least 85% of the nitrogens may be substituted. The carbonyl-containing moiety may include RCO--, where R is alkoxy or haloalkyl. The PBI compound may exhibit a first temperature marking an onset of weight loss corresponding to reversion of the substituted PBI that is less than a second temperature marking an onset of decomposition of an otherwise identical PBI compound without the substituted moiety. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may use more than 5 equivalents in relation to the imidazole nitrogens to be substituted.

  14. Polybenzimidazole compounds

    DOEpatents

    Klaehn, John R.; Peterson, Eric S.; Wertsching, Alan K.; Orme, Christopher J.; Luther, Thomas A.; Jones, Michael G.

    2010-08-10

    A PBI compound that includes imidazole nitrogens, at least a portion of which are substituted with an organic-inorganic hybrid moiety. At least 85% of the imidazole nitrogens may be substituted. The organic-inorganic hybrid moiety may be an organosilane moiety, for example, (R)Me.sub.2SiCH.sub.2--, where R is selected from among methyl, phenyl, vinyl, and allyl. The PBI compound may exhibit similar thermal properties in comparison to the unsubstituted PBI. The PBI compound may exhibit a solubility in an organic solvent greater than the solubility of the unsubstituted PBI. The PBI compound may be included in separatory media. A substituted PBI synthesis method may include providing a parent PBI in a less than 5 wt % solvent solution. Substituting may occur at about room temperature and/or at about atmospheric pressure. Substituting may use at least five equivalents in relation to the imidazole nitrogens to be substituted or, preferably, about fifteen equivalents.

  15. Association of Maternal Antiangiogenic Profile at Birth With Early Postnatal Loss of Microvascular Density in Offspring of Hypertensive Pregnancies

    PubMed Central

    Yu, Grace Z.; Aye, Christina Y.L.; Lewandowski, Adam J.; Davis, Esther F.; Khoo, Cheen P.; Newton, Laura; Yang, Cheng T.; Al Haj Zen, Ayman; Simpson, Lisa J.; O’Brien, Kathryn; Cook, David A.; Granne, Ingrid; Kyriakou, Theodosios; Channon, Keith M.; Watt, Suzanne M.

    2016-01-01

    Offspring of hypertensive pregnancies are more likely to have microvascular rarefaction and increased blood pressure in later life. We tested the hypothesis that maternal angiogenic profile during a hypertensive pregnancy is associated with fetal vasculogenic capacity and abnormal postnatal microvascular remodeling. Infants (n=255) born after either hypertensive or normotensive pregnancies were recruited for quantification of postnatal dermal microvascular structure at birth and 3 months of age. Vasculogenic cell potential was assessed in umbilical vein endothelial cells from 55 offspring based on in vitro microvessel tube formation and proliferation assays. Maternal angiogenic profile (soluble fms-like tyrosine kinase-1, soluble endoglin, vascular endothelial growth factor, and placental growth factor) was measured from postpartum plasma samples to characterize severity of pregnancy disorder. At birth, offspring born after hypertensive pregnancy had similar microvessel density to those born after a normotensive pregnancy, but during the first 3 postnatal months, they had an almost 2-fold greater reduction in total vessel density (−17.7±16.4% versus −9.9±18.7%; P=0.002). This postnatal loss varied according to the vasculogenic capacity of the endothelial cells of the infant at birth (r=0.49; P=0.02). The degree of reduction in both in vitro and postnatal in vivo vascular development was proportional to levels of antiangiogenic factors in the maternal circulation. In conclusion, our data indicate that offspring born to hypertensive pregnancies have reduced vasculogenic capacity at birth that predicts microvessel density loss over the first 3 postnatal months. Degree of postnatal microvessel reduction is proportional to levels of antiangiogenic factors in the maternal circulation at birth. PMID:27456522

  16. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors

    PubMed Central

    Nowak, Dawid G.; Woolard, Jeanette; Amin, Elianna Mohamed; Konopatskaya, Olga; Saleem, Moin A.; Churchill, Amanda J.; Ladomery, Michael R.; Harper, Steven J.; Bates, David O.

    2008-01-01

    Summary Vascular endothelial growth factor A (VEGFA; hereafter referred to as VEGF) is a key regulator of physiological and pathological angiogenesis. Two families of VEGF isoforms are generated by alternate splice-site selection in the terminal exon. Proximal splice-site selection (PSS) in exon 8 results in pro-angiogenic VEGFxxx isoforms (xxx is the number of amino acids), whereas distal splice-site selection (DSS) results in anti-angiogenic VEGFxxxb isoforms. To investigate control of PSS and DSS, we investigated the regulation of isoform expression by extracellular growth factor administration and intracellular splicing factors. In primary epithelial cells VEGFxxxb formed the majority of VEGF isoforms (74%). IGF1, and TNFα treatment favoured PSS (increasing VEGFxxx) whereas TGFβ1 favoured DSS, increasing VEGFxxxb levels. TGFβ1 induced DSS selection was prevented by inhibition of p38 MAPK and the Clk/sty (CDC-like kinase, CLK1) splicing factor kinase family, but not ERK1/2. Clk phosphorylates SR protein splicing factors ASF/SF2, SRp40 and SRp55. To determine whether SR splicing factors alter VEGF splicing, they were overexpressed in epithelial cells, and VEGF isoform production assessed. ASF/SF2, and SRp40 both favoured PSS, whereas SRp55 upregulated VEGFxxxb (DSS) isoforms relative to VEGFxxx. SRp55 knockdown reduced expression of VEGF165b. Moreover, SRp55 bound to a 35 nucleotide region of the 3′UTR immediately downstream of the stop codon in exon 8b. These results identify regulation of splicing by growth and splice factors as a key event in determining the relative pro- versus anti-angiogenic expression of VEGF isoforms, and suggest that p38 MAPK-Clk/sty kinases are responsible for the TGFβ1-induced DSS selection, and identify SRp55 as a key regulatory splice factor. PMID:18843117

  17. Anti-angiogenic activity of gecko aqueous extracts and its macromolecular components in CAM and HUVE-12 cells.

    PubMed

    Tang, Zhen; Huang, Shu-Qiong; Liu, Jian-Ting; Jiang, Gui-Xiang; Wang, Chun-Mei

    2015-01-01

    Gecko is a kind of traditional Chinese medicine with remarkable antineoplastic activity. However, undefined mechanisms and ambiguity regarding active ingredients limit new drug development from gecko. This study was conducted to assess anti-angiogenic properties of the aqueous extracts of fresh gecko (AG) or macromolecular components separated from AG (M-AG). An enzyme-linked immunosorbent assay (ELISA) approach was applied to detect the vascular endothelial growth factor (VEGF) secretion of the tumor cells treated with AG or M-AG. The effect of AG or M-AG on vascular endothelial cell proliferation and migratory ability was analyzed by tetrazolium dye colorimetric method, transwell and wound-healing assays. Chick embryo chorioallantoic membrane (CAM) assays were used to ensure the anti-angiogenic activity of M-AG in vivo. The results showed that AG or M-AG inhibited the VEGF secretion of tumor cells, the relative inhibition rates of AG and M-AG being 27.2% and 53.2% respectively at a concentration of 20 μL/mL. AG and M-AG inhibited the vascular endothelial (VE) cell proliferation with IC50 values of 11.5 ± 0.5 μL/mL and 12.9 ± 0.4 μL/mL respectively. The VE cell migration potential was inhibited significantly (p<0.01) by the AG (≥ 24 μL/mL) or M-AG (≥ 12 μL/ mL) treatment. In vivo, neovascularization of CAM treated with M-AG was inhibited significantly (p<0.05) at a concentration of 0.4 μL/mL. This study provided evidence that anti-angiogenesis is one of the anti-tumor mechanisms of AG and M-AG, with the latter as a promising active component.

  18. Curcumin-Combretastatin Nanocells as Breast Cancer Cytotoxic and Antiangiogenic Agent

    DTIC Science & Technology

    2008-09-01

    walled carbon nanotubes (SWCNT) and the colloidal nanogels, and loaded them with curcumin. We have demonstrated that while the nanocarriers...receptors. 15. SUBJECT TERMS Nanotechnology-based cancer therapeutics, natural anticancer compounds, curcumin, single-walled carbon nanotubes ...carbon nanotubes (SWCNT) and polymeric nanogels, were selected for loading with curcumin. SWCNT have been shown to shuttle various cargoes across

  19. Suppression of angiogenic activity of sera from diabetic patients with non-proliferative retinopathy by compounds of herbal origin and sulindac sulfone.

    PubMed

    Skopinski, Piotr; Szaflik, Jerzy; Duda-Król, Barbara; Nartowska, Jadwiga; Sommer, Ewa; Chorostowska-Wynimko, Joanna; Demkow, Urszula; Skopinska-Rózewska, Ewa

    2004-10-01

    Angiogenesis, the process of new blood vessel formation, is the key event in the mechanism of several pathological processes including diabetic retinopathy. The physiological control of angiogenesis depends on the balance between stimulatory and inhibitory factors. Therefore, a number of anti-angiogenic approaches has been developed, many of them based on the inhibition of the functional activity of pro-angiogenic factors. The aim of the present study was to compare the anti-angiogenic effectiveness of sulindac sulfone and some herbal compounds in the serum-induced angiogenesis test performed in Balb/c mice. Pooled sera from 35 patients with diabetes type 2 and retinopathy were used as pro-angiogenic stimuli. The strongest inhibitory effect was observed for the sulindac sulfone and ursolic acid in the highest concentration of 200 micro g/ml, as well as for the low-dosage concomitant treatment with 2 micro g/ml of epigallocatechin gallate (EGCG, green tea flavanol), ursolic acid (plant-derived triterpenoid), sulindac sulfone and convalamaroside (steroidal saponin). Combination treatment was significantly more effective than monotherapy with medium (20 micro g/ml) or lowest doses of tested compounds. The present study is the first to demonstrate the potent anti-angiogenic effect of the combination therapy comprising of plant-derived extracts and sulindac sulfone, as tested in the in vivo angiogenesis experimental model with sera of non-proliferative diabetic retinopathy patients used as the pro-angiogenic stimuli. We think that it might be the first step toward application of some of these compounds, in the future, in preventive anti-angiogenic therapy of these patients, as well, as in the treatment of later, proliferative stage of this disease.

  20. Multipurpose Compound

    NASA Technical Reports Server (NTRS)

    1983-01-01

    Specially formulated derivatives of an unusual basic compound known as Alcide may be the answer to effective treatment and prevention of the disease bovine mastitis, a bacterial inflammation of a cow's mammary gland that results in loss of milk production and in extreme cases, death. Manufactured by Alcide Corporation the Alcide compound has killed all tested bacteria, virus and fungi, shortly after contact, with minimal toxic effects on humans or animals. Alcide Corporation credits the existence of the mastitis treatment/prevention products to assistance provided the company by NERAC, Inc.

  1. Perfluorinated Compounds

    EPA Science Inventory

    Perfluorinated compounds such as the perfluoroalkyl acids (PFAAs) and their derivatives are important man-made chemicals that have wide consumer and industrial applications. They are relatively contemporary chemicals, being in use only since the 1950s, and until recently, have be...

  2. Biotransfomation of cyperenoic acid by Cunninghamella elegans AS 3.2028 and the potent anti-angiogenic activities of its metabolites.

    PubMed

    Chen, Yu; Tian, Jin-Long; Wu, Jing-Shuai; Sun, Tie-Min; Zhou, Li-Na; Song, Shao-Jiang; You, Song

    2017-02-16

    Cyperenoic acid (1) is one of the major sesquiterpenes isolated from Croton crassifolius, which exhibited potent anti-angiogenic activity. Traditional structural modification of 1 is difficult to perform by chemical technology due to the remarkable stability of the patchoulane skeleton. In order to overcome chemical synthesis difficulties and obtain structurally diverse derivations, microbial transformation of 1 by using Cunninghamella elegans AS 3.2028 was studied for the first time. Five new hydroxylated products 2-6 were obtained. Furthermore, cytotoxicity and anti-angiogenic activities of all the biotransformation products were evaluated by MTT assay and ELISA in HepG2 and MCF-7 cells. These results indicated that hydroxylated modification products 2-4 significantly inhibited VEGF release, which suggest the potential use of hydroxylated modification products for cancer therapy.

  3. Mechanistic Insights into the Anti-angiogenic Activity of Trypanosoma cruzi Protein 21 and its Potential Impact on the Onset of Chagasic Cardiomyopathy.

    PubMed

    Teixeira, Samuel Cota; Lopes, Daiana Silva; Gimenes, Sarah Natalie Cirilo; Teixeira, Thaise Lara; da Silva, Marcelo Santos; Brígido, Rebecca Tavares E Silva; da Luz, Felipe Andrés Cordero; da Silva, Aline Alves; Silva, Makswell Almeida; Florentino, Pilar Veras; Tavares, Paula Cristina Brígido; Dos Santos, Marlus Alves; Ávila, Veridiana de Melo Rodrigues; Silva, Marcelo José Barbosa; Elias, Maria Carolina; Mortara, Renato Arruda; da Silva, Claudio Vieira

    2017-03-21

    Chronic chagasic cardiomyopathy (CCC) is arguably the most important form of the Chagas Disease, caused by the intracellular protozoan Trypanosoma cruzi; it is estimated that 10-30% of chronic patients develop this clinical manifestation. The most common and severe form of CCC can be related to ventricular abnormalities, such as heart failure, arrhythmias, heart blocks, thromboembolic events and sudden death. Therefore, in this study, we proposed to evaluate the anti-angiogenic activity of a recombinant protein from T. cruzi named P21 (rP21) and the potential impact of the native protein on CCC. Our data suggest that the anti-angiogenic activity of rP21 depends on the protein's direct interaction with the CXCR4 receptor. This capacity is likely related to the modulation of the expression of actin and angiogenesis-associated genes. Thus, our results indicate that T. cruzi P21 is an attractive target for the development of innovative therapeutic agents against CCC.

  4. Antiangiogenic gene therapy of experimental pancreatic tumor by sFlt-1 plasmid DNA carried by RGD-modified crosslinked polyplex micelles.

    PubMed

    Vachutinsky, Yelena; Oba, Makoto; Miyata, Kanjiro; Hiki, Shigehiro; Kano, Mitsunobu R; Nishiyama, Nobuhiro; Koyama, Hiroyuki; Miyazono, Kohei; Kataoka, Kazunori

    2011-01-05

    Disulfide crosslinked polyplex micelles with RGD peptides were formed through ion complexation of thiolated c(RGDfK)-poly(ethylene glycol)-block-poly(L-lysine) (c(RGDfK)-PEG-P(Lys-SH)) and plasmid DNA encoding sFlt-1 and tested for their therapeutic effect in BxPC3 pancreatic adenocarcinoma tumor bearing mice. These micelles, systemically injected, demonstrated significant inhibition of tumor growth up to day 18, as a result of the antiangiogenic effect that was confirmed by vascular density measurements. Significant therapeutic activity of the 15% crosslinked micelle (c(RGDfK)-PEG-P(Lys-SH15)) was achieved by combined effect of increased tumor accumulation, interaction with endothelial cells and enhanced intracellular uptake through receptor-mediated endocytosis. These results suggest that RGD targeted crosslinked polyplex micelles can be effective plasmid DNA carriers for antiangiogenic gene therapy.

  5. Involvement of NO/cGMP signaling in the apoptotic and anti-angiogenic effects of beta-lapachone on endothelial cells in vitro.

    PubMed

    Kung, Hsiu-Ni; Chien, Chung-Liang; Chau, Gar-Yang; Don, Ming-Jaw; Lu, Kuo-Shyan; Chau, Yat-Pang

    2007-05-01

    Neovascularization is an essential process in tumor development, it is conceivable that anti-angiogenic treatment may block tumor growth. In angiogenesis, nitric oxide (NO) is an important factor which mediates vascular endothelial cell growth and migration. beta-Lapachone (3,4-dihydro-2,2-dimethyl-2H-naphtho-[1,2-b]pyran-5,6-dione), a natural product extracted from the lapacho tree (Tabebuia avellanedae), has been demonstrated to possess anti-cancer and anti-viral effects. Whether beta-lapachone can induce endothelial cell death or has an anti-angiogenic effect is still an enigma. We investigated the in vitro effect of beta-lapachone on endothelial cells, including human vascular endothelial cell line, EAhy926, and human umbilical vascular endothelial cells (HUVEC). Our results revealed that (1) the intracellular cGMP levels and the mitochondria membrane potential (MMP) decreased, and calpain and caspases were activated, during beta-lapachone-induced endothelial cell death; (2) co-treatment with calpain inhibitors (ALLM or ALLN) or the intracellular calcium chelator, BAPTA, but not the general caspase inhibitor, zVAD-fmk, provided significant protection against apoptosis by preventing the beta-lapachone-induced MMP decrease and cytoplasmic calcium increase; (3) addition of NO downregulated the beta-lapachone-induced cGMP depletion and protected the cells from apoptosis by blocking the MMP decrease and the calcium increase; and (4) exogenous NO protects endothelial cells against the cell death induced by beta-lapachone, but not the anti-angiogenic effect. From all the data above, we demonstrated that NO can attenuate the apoptotic effect of beta-lapachone on human endothelial cells and suggest that beta-lapachone may have potential as an anti-angiogenic drug.

  6. Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.

    PubMed

    Palmer, Kirsten R; Kaitu'u-Lino, Tu'uhevaha J; Hastie, Roxanne; Hannan, Natalie J; Ye, Louie; Binder, Natalie; Cannon, Ping; Tuohey, Laura; Johns, Terrance G; Shub, Alexis; Tong, Stephen

    2015-12-01

    In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a.

  7. Sp1 inhibition-mediated upregulation of VEGF 165 b induced by rh-endostatin enhances antiangiogenic and anticancer effect of rh-endostatin in A549.

    PubMed

    Li, Zhen-yu; Zhu, Fang; Hu, Jian-li; Peng, Gang; Chen, Jing; Zhang, Sheng; Chen, Xu; Zhang, Rui-guang; Chen, Ling-juan; Liu, Pian; Luo, Ming; Sun, Zhi-hua; Ren, Jing-hua; Huang, Li-li; Wu, Gang

    2011-08-01

    Recombinant human endostatin (rh-endostatin), a potential antiangiogenic agent, is used in non-small cell lung carcinoma treatment and represses vascular endothelial cell growth factor (VEGF) levels in tumor cell. However, precise affection of rh-endostatin on the proangiogenic VEGF isoforms (VEGF(165)) or antiangiogenic VEGF isoforms (VEGF(165)b) is not clear. We therefore tested the hypothesis that rh-endostatin could alter expression of these isoforms to regulate tumor growth. A549 cells were exposed to rh-endostatin, and the expression of VEGF(165) and VEGF(165)b was detected. The role of SP1 as a regulator of isoform expression was investigated. We then examined the anticancer and antiangiogenic efficacy of rh-endostatin in combination with exogenous VEGF(165)b against A549 cells, EA.HY 926 cells and xenograft model of human lung cancer. rh-Endostatin reduced VEGF(165) and induced VEGF(165)b as well as inhibited SP1 in A549 cells. SP1 inhibitor (betulinic acid) also developed those changes. VEGF(165)b-rh-endostatin combination was highly synergistic and inhibited growth, survival, and migration of A549 cells, VEGF-mediated VEGFR2 phosphorylation in EA.HY 926 cells, and tumor growth in xenograft model of human lung cancer. rh-Endostatin downregulates proangiogenic vascular endothelial growth factor A (VEGFA) isoform and upregulates antiangiogenic VEGFA isoform, possibly through inhibition of SP1. Furthermore, VEGF(165)b sensitizes A549 to rh-endostatin treatment and enhances the anticancer effect of rh-endostatin.

  8. Acidic pH reduces VEGF-mediated endothelial cell responses by downregulation of VEGFR-2; relevance for anti-angiogenic therapies

    PubMed Central

    Faes, Seraina; Uldry, Emilie; Planche, Anne; Santoro, Tania; Pythoud, Catherine; Demartines, Nicolas; Dormond, Olivier

    2016-01-01

    Anti-angiogenic treatments targeting the vascular endothelial growth factor or its receptors have shown clinical benefits. However, impact on long-term survival remains limited. Solid tumors display an acidic microenvironment that profoundly influences their biology. Consequences of acidity on endothelial cells and anti-angiogenic therapies remain poorly characterized and hence are the focus of this study. We found that exposing endothelial cells to acidic extracellular pH resulted in reduced cell proliferation and migration. Also, whereas VEGF increased endothelial cell proliferation and survival at pH 7.4, it had no effect at pH 6.4. Furthermore, in acidic conditions, stimulation of endothelial cells with VEGF did not result in activation of downstream signaling pathways such as AKT. At a molecular level, acidity significantly decreased the expression of VEGFR-2 by endothelial cells. Consequently, anti-angiogenic therapies that target VEGFR-2 such as sunitinib and sorafenib failed to block endothelial cell proliferation in acidic conditions. In vivo, neutralizing tumor acidity with sodium bicarbonate increased the percentage of endothelial cells expressing VEGFR-2 in tumor xenografts. Furthermore, combining sodium bicarbonate with sunitinib provided stronger anti-cancer activity than either treatment alone. Histological analysis showed that sunitinib had a stronger anti-angiogenic effect when combined with sodium bicarbonate. Overall, our results show that endothelial cells prosper independently of VEGF in acidic conditions partly as a consequence of decreased VEGFR-2 expression. They further suggest that strategies aiming to raise intratumoral pH can improve the efficacy of anti-VEGF treatments. PMID:27852069

  9. The effects of anti-angiogenic therapy on the formation of radiation-induced microbleeds in normal brain tissue of patients with glioma†

    PubMed Central

    Lupo, Janine M.; Molinaro, Annette M.; Essock-Burns, Emma; Butowski, Nicholas; Chang, Susan M.; Cha, Soonmee; Nelson, Sarah J.

    2016-01-01

    Background Radiotherapy (RT) is an integral component in managing patients with glioma, but the damage it may cause to healthy brain tissue and quality of life is of concern. Susceptibility-weighted imaging (SWI) is highly sensitive to the detection of microbleeds that occur years after RT. This study's goals were to characterize the evolution of radiation-induced microbleeds in normal-appearing brain and determine whether the administration of an anti-angiogenic agent altered this process. Methods Serial high-resolution SWI was acquired on 17 patients with high-grade glioma between 8 months and 4.5 years posttreatment with RT and adjuvant chemotherapy. Nine of these patients were also treated with the anti-angiogenic agent enzastaurin. Microbleeds were identified as discrete foci of susceptibility not corresponding to vessels, tumor, or postoperative infarct, and counted in normal-appearing brain. Analysis of covariance was performed to compare slopes of regression of individual patients' microbleed counts over time, Wilcoxon rank-sum tests examined significant differences in rates of microbleed formation between groups, and linear and quadratic mixed-effects models were employed. Results The number of microbleeds increased with time for all patients, with initial onset occurring at 8–22 months. No microbleeds disappeared once formed. The average rate of microbleed formation significantly increased after 2 years post-RT (P < .001). Patients receiving anti-angiogenic therapy exhibited fewer microbleeds overall (P < .05) and a significant reduction in initial rate of microbleed appearance (P = .01). Conclusions We have demonstrated a dramatic increase in microbleed formation after 2 years post-RT that was decelerated by the concomitant administration of anti-angiogenic therapy, which may aid in determining brain regions susceptible to RT. PMID:26206774

  10. Anti-angiogenic effect of Nelumbo nucifera leaf extracts in human umbilical vein endothelial cells with antioxidant potential.

    PubMed

    Lee, Jong Suk; Shukla, Shruti; Kim, Jung-Ae; Kim, Myunghee

    2015-01-01

    Nelumbo nucifera Gaertn (Nymphaeaceae) has long been used as a traditional herb in Chinese, Japanese, Indian, and Korean medicinal practices since prehistoric times and flourishes today as the primary form of medicine. This study reports for the first time the potent ability of N. nucifera leaf extracts to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo, as well as their antioxidant efficacy in various scavenging models and an analysis of their chemical composition. In vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs, in human umbilical vein endothelial cells (HUVECs) by using cell viability, cell proliferation and tube formation assays, and by determining intracellular reactive oxygen species (ROS) in vitro. The antioxidant efficacy of N. nucifera leaf extracts was determined in various scavenging models, including total phenolic and flavonoid content. The chemical composition of N. nucifera leaf extracts was determined by GC-MS analysis, which revealed the presence of different phytochemicals. The IC50 values for the DPPH radical scavenging activities of water and methanol extracts were found to be 1699.47 and 514.36 μg ml(-1), and their total phenolic and flavonoid contents were 85.01 ± 2.32 and 147.63 ± 2.23 mg GAE g dry mass(-1) and 35.38 ± 1.32 and 41.86 ± 1.07 mg QA g dry mass(-1), respectively. N. nucifera leaf extracts (10-100 μg ml(-1)) exhibited significant dose-dependent inhibition of VEGF-induced angiogenesis, as well as VEGF-induced proliferation and tube formation in HUVECs. In this study, N. nucifera leaf extracts displayed potent antioxidant and inhibitory effects on VEGF-induced angiogenesis. N. nucifera exerted an inhibitory effect on VEGF-induced proliferation and tube formation, as well as CAM angiogenesis in vivo. Moreover, N. nucifera leaf extracts significantly blocked VEGF-induced ROS production in HUVECs, confirming

  11. Anti-Angiogenic Effect of Nelumbo nucifera Leaf Extracts in Human Umbilical Vein Endothelial Cells with Antioxidant Potential

    PubMed Central

    Kim, Jung-Ae; Kim, Myunghee

    2015-01-01

    Nelumbo nucifera Gaertn (Nymphaeaceae) has long been used as a traditional herb in Chinese, Japanese, Indian, and Korean medicinal practices since prehistoric times and flourishes today as the primary form of medicine. This study reports for the first time the potent ability of N. nucifera leaf extracts to inhibit vascular endothelial growth factor (VEGF)-induced angiogenesis in vitro and in vivo, as well as their antioxidant efficacy in various scavenging models and an analysis of their chemical composition. In vivo anti-angiogenic activity was evaluated in a chick chorioallantoic membrane (CAM) model using fertilized chicken eggs, in human umbilical vein endothelial cells (HUVECs) by using cell viability, cell proliferation and tube formation assays, and by determining intracellular reactive oxygen species (ROS) in vitro. The antioxidant efficacy of N. nucifera leaf extracts was determined in various scavenging models, including total phenolic and flavonoid content. The chemical composition of N. nucifera leaf extracts was determined by GC-MS analysis, which revealed the presence of different phytochemicals. The IC50 values for the DPPH radical scavenging activities of water and methanol extracts were found to be 1699.47 and 514.36 μg ml−1, and their total phenolic and flavonoid contents were 85.01 ± 2.32 and 147.63 ± 2.23 mg GAE g dry mass−1 and 35.38 ± 1.32 and 41.86 ± 1.07 mg QA g dry mass−1, respectively. N. nucifera leaf extracts (10–100 μg ml−1) exhibited significant dose-dependent inhibition of VEGF-induced angiogenesis, as well as VEGF-induced proliferation and tube formation in HUVECs. In this study, N. nucifera leaf extracts displayed potent antioxidant and inhibitory effects on VEGF-induced angiogenesis. N. nucifera exerted an inhibitory effect on VEGF-induced proliferation and tube formation, as well as CAM angiogenesis in vivo. Moreover, N. nucifera leaf extracts significantly blocked VEGF-induced ROS production in HUVECs, confirming

  12. Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo

    PubMed Central

    Benedetto, Mélanie Di; Starzec, Anna; Colombo, Bruno M; Briane, Dominique; Perret, Gérard Y; Kraemer, Michel; Crépin, Michel

    2002-01-01

    1 Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA-MB-231, MDA-MB-435 and MCF-7. In vitro, NaPaC inhibited MCF-7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 μM vs 73 μM and 10 mM). IC50s were 6 and 28 μM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G0/G1 phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000-fold lower than NaPa. In vivo, CMDB (150 mg kg−1) and NaPa (40 mg kg−1) inhibited the MCF-7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg−1) decreased tumour growth by 66% without toxicity. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti-angiogenic actions make it a good candidate for a new anti-cancer drug. PMID

  13. Aponecrotic, antiangiogenic and antiproliferative effects of a novel dextran derivative on breast cancer growth in vitro and in vivo.

    PubMed

    Di Benedetto, Mélanie; Starzec, Anna; Colombo, Bruno M; Briane, Dominique; Perret, Gérard Y; Kraemer, Michel; Crépin, Michel

    2002-04-01

    1. Since the sodium phenylacetate (NaPa) was reported to enhance the inhibitory effect of carboxymethyl benzylamide dextran (CMDB) on the breast cancer growth, we performed the esterification of CMDB with NaPa to obtain a new drug carrying the characteristics of these two components. A new molecule, phenylacetate carboxymethyl benzylamide dextran, was named NaPaC. 2. We investigated in vitro and in vivo the effects of NaPaC on MCF-7ras cell growth as well as its apoptotic and antiangiogenic effects in comparison to NaPa and CMDB. In addition, we assessed in vitro the antiproliferative effects of these drugs on other breast cancer cells, including MDA-MB-231, MDA-MB-435 and MCF-7. 3. In vitro, NaPaC inhibited MCF-7ras cell proliferation by 40% at concentration lower than that of CMDB and NaPa (12 microM vs 73 microM and 10 mM). IC(50)s were 6 and 28 microM for NaPaC and CMDB, respectively. The similar results were obtained for three other breast cancer cell lines. NaPaC reduced the DNA replication and induced cell recruitment in G(0)/G(1) phase more efficiently than its components. Moreover, it induced a cell death at concentration 1000-fold lower than NaPa. 4. In vivo, CMDB (150 mg kg(-1)) and NaPa (40 mg kg(-1)) inhibited the MCF-7ras tumour growth by 37 and 57%, respectively, whereas NaPaC (15 mg kg(-1)) decreased tumour growth by 66% without toxicity. 5. NaPa or CMDB reduced the microvessel number in tumour by 50% after 7 weeks of treatment. NaPaC had the same effect after only 2 weeks. After 7 weeks, it generated a large necrosis area without detectable microvessels. In vitro, NaPaC inhibited human endothelial cell proliferation more efficiently than CMDB or NaPa. NaPaC interacts with vascular endothelial growth factor as observed by affinity electrophoresis. 6. NaPaC acts like NaPa and CMDB but in more potent manner than components used separately. Its antiproliferative, aponecrotic and anti-angiogenic actions make it a good candidate for a new anti

  14. Corosolic Acid Exhibits Anti-angiogenic and Anti-lymphangiogenic Effects on In Vitro Endothelial Cells and on an In Vivo CT-26 Colon Carcinoma Animal Model.

    PubMed

    Yoo, Ki Hyun; Park, Jong-Hwa; Lee, Dae Young; Hwang-Bo, Jeon; Baek, Nam In; Chung, In Sik

    2015-05-01

    We describe the anti-angiogenic and anti-lymphangiogenic effects of corosolic acid, a pentacyclic triterpenoid isolated from Cornus kousa Burg. A mouse colon carcinoma CT-26 animal model was employed to determine the in vivo anti-angiogenic and anti-lymphangiogenic effects of corosolic acid. Corosolic acid induced apoptosis in CT-26 cells, mediated by the activation of caspase-3. In addition, it reduced the final tumor volume and the blood and lymphatic vessel densities of tumors, indicating that it suppresses in vivo angiogenesis and lymphangiogenesis. Corosolic acid inhibited the proliferation and tube formation of human umbilical vein endothelial cells and human dermal lymphatic microvascular endothelial cells. In addition, corosolic acid decreased the proliferation and migration of human umbilical vein endothelial cells stimulated by angiopoietin-1. Pretreatment with corosolic acid decreased the phosphorylation of focal adhesion kinase (FAK) and ERK1/2, suggesting that corosolic acid contains anti-angiogenic activity that can suppress FAK signaling induced by angiopoietin-1.

  15. A novel delivery vector for targeted delivery of the antiangiogenic drug paclitaxel to angiogenic blood vessels: TLTYTWS-conjugated PEG-PLA nanoparticles

    NASA Astrophysics Data System (ADS)

    Tan, Fei; Mo, Xiao-hui; Zhao, Jian; Liang, Hui; Chen, Zhong-jian; Wang, Xiu-li

    2017-02-01

    Antiangiogenesis has been widely accepted as an attractive strategy to combat tumor growth, invasion, and metastasis. An actively targeting nanoparticle-based drug delivery system (nano-DDS) would provide an alternative method to achieve antiangiogenic antitumor therapy. In the present study, our group fabricated novel nano-DDS, TLTYTWS (TS) peptide-modified poly(ethylene glycol)-poly(lactic acid) (PEG-PLA) nanoparticles (TS-NPs) encapsulating a drug with antiangiogenic potential, paclitaxel (Ptx) (TS-Ptx-NPs). The nanoparticles were uniformly spherical and had a unimodal particle size distribution and slightly negative zeta potential. TS-NPs accumulated significantly in human umbilical vein endothelial cells (HUVECs) via energy-dependent and caveolae- and lipid raft-mediated endocytosis and improved the antiproliferative, antimigratory, and antitube-forming abilities of paclitaxel in vitro. Following intravenous administration, TS-Ptx-NPs presented favorable pharmacokinetic profiles. Melanoma distribution assays confirmed that TS-NPs achieved higher accumulation and penetration at melanoma sites. These results collectively indicated that TLTYTWS-decorated nanoparticles can be considered to be a promising nano-DDS for chemotherapies targeting tumor angiogenesis and have great potential to improve the efficacy of antiangiogenic therapy in melanoma tumor-bearing nude mice.

  16. MiRNA-21 mediates the antiangiogenic activity of metformin through targeting PTEN and SMAD7 expression and PI3K/AKT pathway

    PubMed Central

    Luo, Mao; Tan, Xiaoyong; Mu, Lin; Luo, Yulin; Li, Rong; Deng, Xin; Chen, Ni; Ren, Meiping; Li, Yongjie; Wang, Liqun; Wu, Jianbo; Wan, Qin

    2017-01-01

    Metformin, an anti-diabetic drug commonly used for type 2 diabetes therapy, is associated with anti-angiogenic effects in conditions beyond diabetes. miR-21 has been reported to be involved in the process of angiogenesis. However, the precise regulatory mechanisms by which the metformin-induced endothelial suppression and its effects on miR-21-dependent pathways are still unclear. Bioinformatic analysis and identification of miR-21 and its targets and their effects on metformin-induced antiangiogenic activity were assessed using luciferase assays, quantitative real-time PCR, western blots, scratch assays, CCK-8 assays and tubule formation assays. In this study, miR-21 was strikingly downregulated by metformin in a time- and dose-dependent manner. miR-21 directly targeted the 3′-UTR of PTEN and SMAD7, and negatively regulated their expression. Overexpression of miR-21 abrogated the metformin-mediated inhibition of endothelial cells proliferation, migration, tubule formation and the TGF-β-induced AKT, SMAD- and ERK-dependent phosphorylations, and conversely, down-regulation of miR-21 aggravated metformin’s action and revealed significant promotion effects. Our study broadens our understanding of the regulatory mechanism of miR-21 mediating metformin-induced anti-angiogenic effects, providing important implications regarding the design of novel miRNA-based therapeutic strategies against angiogenesis. PMID:28230206

  17. Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells

    SciTech Connect

    Ling, Yun; Yang, Yong . E-mail: anticancer_drug@yahoo.com.cn; Lu, Na; You, Qi-dong; Wang, Sen; Gao, Ying; Chen, Yan; Guo, Qing-Long . E-mail: valianty@hotmail.com

    2007-09-14

    Endostar, a novel recombinant human endostatin expressed and purified in Escherichia coli with an additional nine-amino acid sequence and forming another his-tag structure, was approved by the SFDA in 2005 for the treatment of non-small-cell lung cancer. But its mechanism of action has not been illustrated before. In this study, we examined the antiangiogenic activities of endostar in vitro and in vivo. The results showed that endostar suppressed the VEGF-stimulated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Endostar blocked microvessel sprouting from rat aortic rings in vitro. Moreover, it could inhibit the formation of new capillaries from pre-existing vessels in the chicken chorioallantoic membrane (CAM) assay and affect the growth of vessels in tumor. We further found the antiangiogenic effects of endostar were correlated with the VEGF-triggered signaling. Endostar suppressed the VEGF-induced tyrosine phosphorylation of KDR/Flk-1(VEGFR-2) as well as the overall VEGFR-2 expression and the activation of ERK, p38 MAPK, and AKT in HUVECs. Collectively, these data indicated the relationship between endostar and VEGF signal pathways and provided a molecular basis for the antiangiogenic effects of endostar.

  18. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2003-01-01

    Seawater and natural brines accounted for about 60 percent of U.S. magnesium compounds production during 2002. Dead-burned and caustic-calcined magnesias were recovered from seawater by Premier Chemicals in Florida. They were also recovered from well brines in Michigan by Dow Chemical, Martin Marietta Magnesia Specialties and Rohm & Haas. And they were recovered from magnesite in Nevada by Premier Chemicals.

  19. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2006-01-01

    In 2005, seawater and natural brines accounted for 51% of US magnesium compounds production. World magnesia production was estimated to be 14.5 Mt. Most of the production came from China, North Korea, Russia and Turkey. Although no specific production figures are available, Japan and the United States are estimated to account for almost one-half of the world's capacity from seawater and brines.

  20. Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer.

    PubMed

    Wang, Huaijun; Lutz, Amelie M; Hristov, Dimitre; Tian, Lu; Willmann, Jürgen K

    2017-02-01

    Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)-targeted microbubbles and (b) 3D dynamic contrast material-enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted microbubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P

  1. Identification of novel targets for antiangiogenic therapy by comparing the gene expressions of tumor and normal endothelial cells

    PubMed Central

    Otsubo, Tsuguteru; Hida, Yasuhiro; Ohga, Noritaka; Sato, Hideshi; Kai, Toshihiro; Matsuki, Yasushi; Takasu, Hideo; Akiyama, Kosuke; Maishi, Nako; Kawamoto, Taisuke; Shinohara, Nobuo; Nonomura, Katsuya; Hida, Kyoko

    2014-01-01

    Targeting tumor angiogenesis is an established strategy for cancer therapy. Because angiogenesis is not limited to pathological conditions such as cancer, molecular markers that can distinguish between physiological and pathological angiogenesis are required to develop more effective and safer approaches for cancer treatment. To identify such molecules, we determined the gene expression profiles of murine tumor endothelial cells (mTEC) and murine normal endothelial cells using DNA microarray analysis followed by quantitative reverse transcription–polymerase chain reaction analysis. We identified 131 genes that were differentially upregulated in mTEC. Functional analysis using siRNA-mediated gene silencing revealed five novel tumor endothelial cell markers that were involved in the proliferation or migration of mTEC. The expression of DEF6 and TMEM176B was upregulated in tumor vessels of human renal cell carcinoma specimens, suggesting that they are potential targets for antiangiogenic intervention for renal cell carcinoma. Comparative gene expression analysis revealed molecular differences between tumor endothelial cells and normal endothelial cells and identified novel tumor endothelial cell markers that may be exploited to target tumor angiogenesis for cancer treatment. PMID:24602018

  2. Synthesis, characterization, cytotoxicity and antiangiogenic activity of copper(II) complexes with 1-adamantoyl hydrazone bearing pyridine rings.

    PubMed

    Rodić, Marko V; Leovac, Vukadin M; Jovanović, Ljiljana S; Spasojević, Vojislav; Joksović, Milan D; Stanojković, Tatjana; Matić, Ivana Z; Vojinović-Ješić, Ljiljana S; Marković, Violeta

    2016-06-10

    Three novel copper complexes with tridentate N2O ligand di(2-pyridil) ketone 1-adamantoyl hydrazone (Addpy) of the formula [Cu(II)2Cu(I)2(Addpy)2Br2(μ-Br4)] (1), catena-poly[CuCl(μ-Addpy)(μ-Cl)CuCl2]n (2) and [Cu(Addpy)(NCS)2] (3) were synthesized. Complexes are characterized by X-ray crystallography, spectral (UV-Vis, FTIR), electrochemical (CV) analyses, and magnetochemical measurements. Investigation of anticancer potential of Cu(II) complexes, mode of cell death, apoptosis, and inhibition of angiogenesis were performed. All tested malignant cell lines (HeLa, LS174, A549, K562, and MDA-MB-231) showed high sensitivity to the examined Cu(II) complexes. It has been shown that the complexes induce apoptosis in the caspase 3-dependent manner, whereas the anti-angiogenic effects of 1, 2, and 3 have been confirmed in EA.hy926 cells using a tube formation assay.

  3. Growth hormone improves growth retardation induced by rapamycin without blocking its antiproliferative and antiangiogenic effects on rat growth plate.

    PubMed

    Álvarez-García, Óscar; García-López, Enrique; Loredo, Vanessa; Gil-Peña, Helena; Mejía-Gaviria, Natalia; Rodríguez-Suárez, Julián; Ordóñez, Flor Á; Santos, Fernando

    2012-01-01

    Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis.

  4. Anti-angiogenic potential of trypsin inhibitor purified from Cucumis melo seeds: Homology modeling and molecular docking perspective.

    PubMed

    Rasouli, Hassan; Parvaneh, Sharham; Mahnam, Azadeh; Rastegari-Pouyani, Mohsen; Hoseinkhani, Zohreh; Mansouri, Kamran

    2017-03-01

    Melons have a good source of protease inhibitors. Its fruit and seeds have been used as a traditional medicine. However, its effects on angiogenesis and mechanism of its action remain elusive. Herein trypsin inhibitor from aqueous extract of C. melo seeds (TICMS) was purified. Its effects on different steps of angiogenesis were evaluated. Also, we examined its effects on migration and angiogenesis of endothelial cells. Three dimensional model of TICMS protein was accurately built in which TICMS docked to αVβ3 integrin and VEGFR1. Electrophoresis analysis of the purified protein revealed a single band with a molecular mass of about 3kDa. Treatment with TICMS at six doses resulted in a significant decrease of endothelial cell proliferation with an IC50 value of about 20μg/ml. Tubulogenesis assay revealed that a dose dependent anti-angiogenic activity of TICMS (5-40μg/ml). Also, TICMS had inhibitory effects on VEGF, MMP-2 and MMP-9 secretion. Our docking result speculated that TICMS could bind to the cleft between the αVβ3 integrin and it able to decrease the activity of this receptor. The TICMS was also able to interact with VEGFR1 receptor, but with low probability. Based on our study, TICMS could be used as a specific angiogenesis inhibitor.

  5. Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin.

    PubMed

    Cheng, Wenming; Dahmani, Fatima Zohra; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2017-02-17

    Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

  6. Identification of two novel Chlorotoxin derivatives CA4 and CTX-23 with chemotherapeutic and anti-angiogenic potential

    PubMed Central

    Xu, Tengfei; Fan, Zheng; Li, Wenxin; Dietel, Barbara; Wu, Yingliang; Beckmann, Matthias W.; Wrosch, Jana K.; Buchfelder, Michael; Eyupoglu, Ilker Y.; Cao, Zhijian; Savaskan, Nicolai E.

    2016-01-01

    Brain tumors are fast proliferating and destructive within the brain microenvironment. Effective chemotherapeutic strategies are currently lacking which combat this deadly disease curatively. The glioma-specific chloride ion channel represents a specific target for therapy. Chlorotoxin (CTX), a peptide derived from scorpion venom, has been shown to be specific and efficacious in blocking glioma Cl− channel activity. Here, we report on two new derivatives (termed CA4 and CTX-23) designed and generated on the basis of the peptide sequence alignments of CTX and BmKCT. The novel peptides CA4 and CTX-23 are both effective in reducing glioma cell proliferation. In addition, CTX, CA4 and CTX-23 impact on cell migration and spheroid migration. These effects are accompanied by diminished cell extensions and increased nuclear sizes. Furthermore, we found that CA4 and CTX-23 are selective with low toxicity against primary neurons and astrocytes. In the ex vivo VOGiM, which maintain the entire brain tumor microenvironment, both CTX and CA4 display anti-tumor activity and reduce tumor volume. Hence, CTX and CA4 reveal anti-angiogenic properties with endothelial and angiogenic hotspots disrupting activities. These data report on the identification of two novel CTX derivatives with multiple anti-glioma properties including anti-angiogenesis. PMID:26831010

  7. Anti-angiogenic activity and antitumor efficacy of amphiphilic twin drug from ursolic acid and low molecular weight heparin

    NASA Astrophysics Data System (ADS)

    Cheng, Wenming; Zohra Dahmani, Fatima; Zhang, Juan; Xiong, Hui; Wu, Yuanyuan; Yin, Lifang; Zhou, Jianping; Yao, Jing

    2017-02-01

    Heparin, a potential blood anti-coagulant, is also known for its binding ability to several angiogenic factors through electrostatic interactions due to its polyanionic character. However, the clinical application of heparin for cancer treatment is limited by several drawbacks, such as unsatisfactory therapeutic effects and severe anticoagulant activity that could induce hemorrhaging. Herein, low molecular weight heparin (LMWH) was conjugated to ursolic acid (UA), which is also an angiogenesis inhibitor, by binding the amine group of aminoethyl-UA (UA-NH2) with the carboxylic groups of LMWH. The resulting LMWH-UA conjugate as an amphiphilic twin drug showed reduced anticoagulant activity and could also self-assemble into nanomicelles with a mean particle size ranging from 200-250 nm. An in vitro endothelial tubular formation assay and an in vivo Matrigel plug assay were performed to verify the anti-angiogenic potential of LMWH-UA. Meanwhile, the in vivo antitumor effect of LMWH-UA was also evaluated using a B16F10 mouse melanoma model. LMWH-UA nanomicelles were shown to inhibit angiogenesis both in vitro and in vivo. In addition, the i.v. administration of LMWH-UA to the B16F10 tumor-bearing mice resulted in a significant inhibition of tumor growth as compared to the free drug solutions. These findings demonstrate the therapeutic potential of LMWH-UA as a new therapeutic remedy for cancer therapy.

  8. Orthotopic animal model of pseudomyxoma peritonei: An in vivo model to test anti-angiogenic drug effects.

    PubMed

    Dohan, Anthony; Lousquy, Ruben; Eveno, Clarisse; Goere, Diane; Broqueres-You, Dong; Kaci, Rachid; Lehmann-Che, Jacqueline; Launay, Jean-Marie; Soyer, Philippe; Bonnin, Philippe; Pocard, Marc

    2014-07-01

    Pseudomyxoma peritonei (PMP) is an uncommon peritoneal mucinous carcinomatosis confined to the peritoneal cavity. The rarity of PMP in humans makes evaluation of the disease biological features and new therapeutic strategies difficult. Accordingly, there is a need for animal models of PMP. Human PMP tissue was i.p. grafted and grown into nude mice, then constituted into reliable and reproducible orthotopic models. Histological and immunostaining analysis was performed. Bevacizumab was injected twice a week either during tumor growth or after cytoreductive surgery. In vivo imaging of tumor angiogenesis was performed using barium sulfate or isolectin microangiography and Doppler ultrasonography of the superior mesenteric artery. Tumor angiogenesis was confirmed by the presence of tortuous vascular networks with high levels of expression of CD31, vascular endothelial cadherin, and desmin. Doppler ultrasonography of the superior mesenteric artery revealed a twofold increase in blood flow velocity compared with tumor-free mice (P < 0.001). Bevacizumab administration was correlated with the normalization of tumor vascularity when injected during tumor growth and with the stabilization of the histological and hemodynamic findings when injected after cytoreductive surgery. Our PMP models mimic human PMP. Our results confirmed the presence of tumor angiogenesis related to PMP growth. Our murine model allows researchers to actually bench test and evaluate, in preclinical studies, the efficacy of new therapeutic strategies and anti-angiogenic therapies.

  9. Growth Hormone Improves Growth Retardation Induced by Rapamycin without Blocking Its Antiproliferative and Antiangiogenic Effects on Rat Growth Plate

    PubMed Central

    Álvarez-García, Óscar; García-López, Enrique; Loredo, Vanessa; Gil-Peña, Helena; Mejía-Gaviria, Natalia; Rodríguez-Suárez, Julián; Ordóñez, Flor Á.; Santos, Fernando

    2012-01-01

    Rapamycin, an immunosuppressant agent used in renal transplantation with antitumoral properties, has been reported to impair longitudinal growth in young individuals. As growth hormone (GH) can be used to treat growth retardation in transplanted children, we aimed this study to find out the effect of GH therapy in a model of young rat with growth retardation induced by rapamycin administration. Three groups of 4-week-old rats treated with vehicle (C), daily injections of rapamycin alone (RAPA) or in combination with GH (RGH) at pharmacological doses for 1 week were compared. GH treatment caused a 20% increase in both growth velocity and body length in RGH animals when compared with RAPA group. GH treatment did not increase circulating levels of insulin-like growth factor I, a systemic mediator of GH actions. Instead, GH promoted the maturation and hypertrophy of growth plate chondrocytes, an effect likely related to AKT and ERK1/2 mediated inactivation of GSK3β, increase of glycogen deposits and stabilization of β-catenin. Interestingly, GH did not interfere with the antiproliferative and antiangiogenic activities of rapamycin in the growth plate and did not cause changes in chondrocyte autophagy markers. In summary, these findings indicate that GH administration improves longitudinal growth in rapamycin-treated rats by specifically acting on the process of growth plate chondrocyte hypertrophy but not by counteracting the effects of rapamycin on proliferation and angiogenesis. PMID:22493717

  10. The noni anthraquinone damnacanthal is a multi-kinase inhibitor with potent anti-angiogenic effects.

    PubMed

    García-Vilas, Javier A; Pino-Ángeles, Almudena; Martínez-Poveda, Beatriz; Quesada, Ana R; Medina, Miguel Ángel

    2017-01-28

    The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis. A number of in vitro assays contribute to determine the specific effects of damnacanthal on each of the steps of the angiogenic process, including inhibition of tubulogenesis, endothelial cell proliferation, survival, migration and production of extracellular matrix remodeling enzyme. Taken altogether, these results suggest that damancanthal could have potential interest for the treatment of cancer and other angiogenesis-dependent diseases.

  11. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2002-01-01

    Seawater and natural brines accounted for about 60% of US magnesium compounds production in 2001. Dead-burned and caustic-calcined magnesias were recovered from seawater in Florida by Premier Chemicals. They were also recovered from Michigan well brines by Dow Chemical, Martin Marietta Magnesia Specialties and Rohm & Haas. And Premier Chemicals recovered dead-burned and caustic-calcined magnesias from magnesite in Nevada. Reilly Industries and Great Salt Lake Minerals recovered magnesium chloride brines from the Great Salt Lake in Utah.

  12. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2011-01-01

    Seawater and natural brines accounted for about 54 percent of U.S. magnesium compounds production in 2010. Dead-burned magnesia was produced by Martin Marietta Magnesia Specialties from well brines in Michigan. Caustic-calcined magnesia was recovered from seawater by Premier Magnesia in Florida, from well brines in Michigan by Martin Marietta and from magnesite in Nevada by Premier Magnesia. Intrepid Potash-Wendover and Great Salt Lake Minerals Corp. recovered magnesium chloride brines from the Great Salt Lake in Utah. Magnesium hydroxide was produced from seawater by SPI Pharma in Delaware and Premier Magnesia in Florida, and by Martin Marietta from its operation mentioned above.

  13. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2010-01-01

    Seawater and natural brines accounted for about 40 percent of U.S. magnesium compounds production in 2009. Dead-burned magnesia was produced by Martin Marietta Magnesia Specialties from well brines in Michigan. Caustic-calcined magnesia was recovered from seawater by Premier Chemicals in Florida, from well brines in Michigan by Martin Marietta and from magnesite in Nevada by Premier Chemicals. Intrepid Potash-Wendover, and Great Salt Lake Minerals Corp. recovered magnesium chloride brines from the Great Salt Lake in Utah. Magnesium hydroxide was produced from seawater by SPI Pharma in Delaware and Premier Chemicals in Florida, and by Martin Marietta from its operation mentioned above.

  14. Beer and beer compounds: physiological effects on skin health.

    PubMed

    Chen, W; Becker, T; Qian, F; Ring, J

    2014-02-01

    Beer is one of the earliest human inventions and globally the most consumed alcoholic beverage in terms of volume. In addition to water, the 'German Beer Purity Law', based on the Bavarian Beer Purity Law from 1516, allows only barley, hops, yeasts and water for beer brewing. The extracts of these ingredients, especially the hops, contain an abundance of polyphenols such as kaempferol, quercetin, tyrosol, ferulic acid, xanthohumol/isoxanthohumol/8-prenylnaringenin, α-bitter acids like humulone and β-bitter acids like lupulone. 8-prenylnaringenin is the most potent phytoestrogen known to date. These compounds have been shown to possess various anti-bacterial, anti-inflammatory, anti-oxidative, anti-angiogenic, anti-melanogenic, anti-osteoporotic and anti-carcinogenic effects. Epidemiological studies on the association between beer drinking and skin disease are limited while direct evidence of beer compounds in clinical application is lacking. Potential uses of these substances in dermatology may include treatment of atopic eczema, contact dermatitis, pigmentary disorders, skin infections, skin ageing, skin cancers and photoprotections, which require an optimization of the biostability and topical delivery of these compounds. Further studies are needed to determine the bioavailability of these compounds and their possible beneficial health effects when taken by moderate beer consumption.

  15. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2007-01-01

    Seawater and natural brines accounted for about 52 percent of U.S. magnesium compounds production in 2006. Dead-burned magnesia was produced by Martin Marietta Magnesia Specialties from well brines in Michigan. Caustic-calcined magnesia was recovered from sea-water by Premier Chemicals in Florida; from well brines in Michigan by Martin Marietta and Rohm and Haas; and from magnesite in Nevada by Premier Chemicals. Intrepid Potash-Wendover and Great Salt Lake Minerals recovered magnesium chloride brines from the Great Salt Lake in Utah. Magnesium hydroxide was produced from brucite by Applied Chemical Magnesias in Texas, from seawater by SPI Pharma in Delaware and Premier Chemicals in Florida, and by Martin Marietta and Rohm and Haas from their operations mentioned above. About 59 percent of the magnesium compounds consumed in the United States was used for refractories that are used mainly to line steelmaking furnaces. The remaining 41 percent was consumed in agricultural, chemical, construction, environmental and industrial applications.

  16. Intermetallic Compounds

    NASA Astrophysics Data System (ADS)

    Takagiwa, Y.; Matsuura, Y.; Kimura, K.

    2014-06-01

    We have focused on the binary narrow-bandgap intermetallic compounds FeGa3 and RuGa3 as thermoelectric materials. Their crystal structure is FeGa3-type (tetragonal, P42/ mnm) with 16 atoms per unit cell. Despite their simple crystal structure, their room temperature thermal conductivity is in the range 4-5-W-m-1-K-1. Both compounds have narrow-bandgaps of approximately 0.3-eV near the Fermi level. Because their Seebeck coefficients are quite large negative values in the range 350-<-| S 373K|-<-550- μV-K-1 for undoped samples, it should be possible to obtain highly efficient thermoelectric materials both by adjusting the carrier concentration and by reducing the thermal conductivity. Here, we report the effects of doping on the thermoelectric properties of FeGa3 and RuGa3 as n and p-type materials. The dimensionless figure of merit, ZT, was significantly improved by substitution of Sn for Ga in FeGa3 (electron-doping) and by substitution of Zn for Ga in RuGa3 (hole-doping), mainly as a result of optimization of the electronic part, S 2 σ.

  17. Magnesium compounds

    USGS Publications Warehouse

    Kramer, D.A.

    2012-01-01

    Seawater and natural brines accounted for about 57 percent of magnesium compounds produced in the United States in 2011. Dead-burned magnesia was produced by Martin Marietta Magnesia Specialties LLC from well brines in Michigan. Caustic-calcined magnesia was recovered from seawater by Premier Magnesia LLC in Florida, from well brines in Michigan by Martin Marietta and from magnesite in Nevada by Premier Magnesia. Intrepid Potash Wendover LLC and Great Salt Lake Minerals Corp. recovered magnesium chloride brines from the Great Salt Lake in Utah. Magnesium hydroxide was produced from seawater by SPI Pharma Inc. in Delaware and Premier Magnesia in Florida, and by Martin Marietta from its brine operation in Michigan.

  18. Bismaleimide compounds

    DOEpatents

    Adams, Johnnie E.; Jamieson, Donald R.

    1986-01-14

    Bismaleimides of the formula ##STR1## wherein R.sub.1 and R.sub.2 each independently is H, C.sub.1-4 -alkyl, C.sub.1-4 -alkoxy, C1 or Br, or R.sub.1 and R.sub.2 together form a fused 6-membered hydrocarbon aromatic ring, with the proviso that R.sub.1 and R.sub.2 are not t-butyl or t-butoxy; X is O, S or Se; n is 1-3; and the alkylene bridging group, optionally, is substituted by 1-3 methyl groups or by fluorine, form polybismaleimide resins which have valuable physical properties. Uniquely, these compounds permit extended cure times, i.e., they remain fluid for a time sufficient to permit the formation of a homogeneous melt prior to curing.

  19. Bismaleimide compounds

    DOEpatents

    Adams, J.E.; Jamieson, D.R.

    1986-01-14

    Bismaleimides of the formula shown in the diagram wherein R[sub 1] and R[sub 2] each independently is H, C[sub 1-4]-alkyl, C[sub 1-4]-alkoxy, Cl or Br, or R[sub 1] and R[sub 2] together form a fused 6-membered hydrocarbon aromatic ring, with the proviso that R[sub 1] and R[sub 2] are not t-butyl or t-butoxy; X is O, S or Se; n is 1--3; and the alkylene bridging group, optionally, is substituted by 1--3 methyl groups or by fluorine, form polybismaleimide resins which have valuable physical properties. Uniquely, these compounds permit extended cure times, i.e., they remain fluid for a time sufficient to permit the formation of a homogeneous melt prior to curing.

  20. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

    PubMed

    Trapani, Laura; Segatto, Marco; Pallottini, Valentina

    2013-12-27

    Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of

  1. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people?

    PubMed Central

    Trapani, Laura; Segatto, Marco; Pallottini, Valentina

    2013-01-01

    Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of

  2. Antiangiogenic Therapy in Advanced Non-small-cell Lung Cancer: A Meta-analysis of Phase III Randomized Trials.

    PubMed

    Raphael, Jacques; Chan, Kelvin; Karim, Safiya; Kerbel, Robert; Lam, Henry; Santos, Keemo Delos; Saluja, Ronak; Verma, Sunil

    2017-01-12

    We conducted a meta-analysis to evaluate the efficacy of adding any antiangiogenic therapy (AT) to the standard of care in advanced non-small-cell lung cancer (NSCLC). The electronic databases Ovid PubMed, Cochrane Central Register of Controlled Trials, and Embase were searched to identify eligible trials. We included all phase III randomized trials with any line and type of treatment, histology. and AT dose. Pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and pooled odds ratio (OR) for overall response rates (RR) were calculated. We divided the population into 2 subgroups based on the bevacizumab dose. Data of 19,098 patients from 25 phase III trials were analyzed. Compared with the standard of care, the addition of AT did not prolong OS (HR 0.98; 95% confidence interval [CI], 0.96-1.00; P = .1 and HR 0.97; 95% CI, 0.94-1.00; P = .06 for groups 1 and 2, respectively). However, there was a significant improvement in PFS with the addition of AT (HR 0.85; 95% CI, 0.79-0.91; P < .00001 and HR 0.81; 95% CI, 0.75-0.88; P < .00001 for groups 1 and 2, respectively) and overall RR (OR 1.61; 95% CI, 1.30-2.01; P < .0001 and OR 1.72; 95% CI, 1.39-2.14; P < .00001 for groups 1 and 2, respectively). This is the first meta-analysis including only all phase III trials with AT in NSCLC showing no significant effect on OS and an improvement in PFS and RR only. The role of AT in advanced NSCLC is still questionable; strong validated biomarkers are eagerly needed to predict which subgroup might benefit the most from such therapy.

  3. Targeted tumor therapy with a fusion protein of an antiangiogenic human recombinant scFv and yeast cytosine deaminase.

    PubMed

    Schellmann, Nicole; Panjideh, Hossein; Fasold, Patricia; Bachran, Diana; Bachran, Christopher; Deckert, Peter M; Fuchs, Hendrik

    2012-09-01

    In adults, endothelial cell division occurs only in wound healing, during menstruation, or in diseases such as wet age-related macular degeneration or development of benign or malignant tissues. Angiogenesis is one of the major requirements to supply the fast developing tumor tissue with oxygen and nutrients, and enables it to spread into other tissues far from its origin. We selected the extradomain B (ED-B), a splice variant of fibronectin, which is exclusively expressed in ovaries, uterus, during wound healing, and in tumor tissues, as a target for the development of an innovative antiangiogenic, prodrug-based targeted tumor therapy approach. We designed a fusion protein termed L19CDy-His, consisting of the antibody single chain fragment L19 for targeting ED-B and yeast cytosine deaminase for the conversion of 5-fluorocytosine into cytotoxic 5-fluorouracil. We purified high amounts of the fusion protein from Pichia pastoris that is stable, enzymatically active, and retains 75% of its activity after incubation with human plasma for up to 72 hours. The binding of L19CDy-His to ED-B was confirmed by an enzyme-linked immunosorbent assay and quantified by surface plasmon resonance spectroscopy determining a KD value of 81±7 nM. L19CDy-His successfully decreased cell survival of the murine ED-B-expressing teratocarcinoma cell line F9 upon addition of the prodrug 5-fluorocytosine. Our data demonstrate the suitability of targeting ED-B by L19CDy-His for effective prodrug-based tumor therapy.

  4. Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24-25 June 2014, Milan.

    PubMed

    Bouche, Gauthier; André, Nicolas; Banavali, Shripad; Berthold, Frank; Berruti, Alfredo; Bocci, Guido; Brandi, Giovanni; Cavallaro, Ugo; Cinieri, Saviero; Colleoni, Marco; Curigliano, Giuseppe; Di Desidero, Teresa; Eniu, Alexandru; Fazio, Nicola; Kerbel, Robert; Hutchinson, Lisa; Ledzewicz, Urszula; Munzone, Elisabetta; Pasquier, Eddy; Graciela Scharovsky, O; Shaked, Yuval; Stěrba, Jaroslav; Villalba, Martin; Bertolini, Francesco

    2014-01-01

    The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative

  5. Lessons from the Fourth Metronomic and Anti-angiogenic Therapy Meeting, 24–25 June 2014, Milan

    PubMed Central

    Bouche, Gauthier; André, Nicolas; Banavali, Shripad; Berthold, Frank; Berruti, Alfredo; Bocci, Guido; Brandi, Giovanni; Cavallaro, Ugo; Cinieri, Saviero; Colleoni, Marco; Curigliano, Giuseppe; Desidero, Teresa Di; Eniu, Alexandru; Fazio, Nicola; Kerbel, Robert; Hutchinson, Lisa; Ledzewicz, Urszula; Munzone, Elisabetta; Pasquier, Eddy; Graciela Scharovsky, O; Shaked, Yuval; Štěrba, Jaroslav; Villalba, Martin; Bertolini, Francesco

    2014-01-01

    The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24–25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative

  6. Effect of antiangiogenic therapy on luciferase activity in a cytomegalovirus- or HSP70-promoter-transfected M21 tumor model

    NASA Astrophysics Data System (ADS)

    Hundt, Walter; Schink, Christian; Steinbach, Silke; O'Connell-Rodwell, Caitlin E.; Kiessling, Andreas; Librizzi, Damiano; Burbelko, Mykhaylo; Guccione, Samira

    2012-06-01

    We investigated the effect of targeted gene therapy on heat shock protein 70 expression (Hsp70) and protein production (HSP70) in a melanoma tumor model (M21; M21-L). M21 and M21-L cells transfected with a plasmid containing the Hsp70 (Hspa1b) or the cytomegalovirus (CMV) promoter and the luciferase reporter gene were injected into mice; the resulting tumors grew to a size of 650 mm3. Mice (five per group) were intravenously treated with an Arg-Gly-Asp peptide-nanoparticle/Raf-1 kinase inhibitor protein complex [RGD-NP/RAF(-)] or with a nanoparticle control. Bioluminescence imaging (IVIS®, Xenogen, USA) was performed at 12, 24, 48, and 72 h after the treatment cycle. Western blot analysis of HSP70 protein was performed to monitor protein expression. The size of the treated M21 tumors remained fairly constant (647.8+/-103.4 mm2 at the beginning versus 704.8+/-94.4 mm3 at the end of the experiment). The size of the M21-L tumors increased, similar to the untreated control tumors. Bioluminescent imaging demonstrated that when transcription was controlled by the CMV promoter, luciferase activity decreased to 17.9%+/-4.3% of baseline values in the treated M21 tumors. When transcription was controlled by the Hsp70 promoter, the highest luciferase activity (4.5+/-0.7-fold increase over base-line values) was seen 24 h after injection in the M21 tumors; however, no luciferase activity was seen in the M21-L tumors. In accordance with bioluminescent imaging, western blot analysis showed a peak in HSP70 production at 24 h after the injection of the RGD-NP/RAF(-) complex in the M21 tumors; however, no HSP70 protein induction was seen in the M21-L tumors. Thus, targeted antiangiogenic therapy can induce Hsp70 expression and HSP70 protein in melanoma tumors.

  7. Mechanisms of resistance to chemotherapeutic and anti-angiogenic drugs as novel targets for pancreatic cancer therapy

    PubMed Central

    Tamburrino, Anna; Piro, Geny; Carbone, Carmine; Tortora, Giampaolo; Melisi, Davide

    2013-01-01

    Pancreatic cancer remains one of the most lethal and poorly understood human malignancies and will continue to be a major unsolved health problem in the 21st century. Despite efforts over the past three decades to improve diagnosis and treatment, the prognosis for patients with pancreatic cancer is extremely poor with or without treatment, and incidence rates are virtually identical to mortality rates. Although advances have been made through the identification of relevant molecular pathways in pancreatic cancer, there is still a critical, unmet need for the translation of these findings into effective therapeutic strategies that could reduce the intrinsic drug resistance of this disease and for the integration of these molecularly targeted agents into established combination chemotherapy and radiotherapy regimens in order to improve patients’ survival. Tumors are heterogeneous cellular entities whose growth and progression depend on reciprocal interactions between genetically altered neoplastic cells and a non-neoplastic microenvironment. To date, most of the mechanisms of resistance studied have been related to tumor cell-autonomous signaling pathways. However, recent data suggest a putative important role of tumor microenvironment in the development and maintenance of resistance to classic chemotherapeutic and targeted therapies. This present review is meant to describe and discuss some of the most important advances in the comprehension of the tumor cell-autonomous and tumor microenvironment-related molecular mechanisms responsible for the resistance of pancreatic cancer to the proapoptotic activity of the classic chemotherapeutic agents and to the most novel anti-angiogenic drugs. We present some of the emerging therapeutic targets for the modulation of this resistant phenotype. PMID:23641216

  8. Nanoceria: a rare-earth nanoparticle as a novel anti-angiogenic therapeutic agent in ovarian cancer.

    PubMed

    Giri, Shailendra; Karakoti, Ajay; Graham, Rondell P; Maguire, Jacie L; Reilly, Christopher M; Seal, Sudipta; Rattan, Ramandeep; Shridhar, Viji

    2013-01-01

    Ovarian cancer (OvCa) is the fifth most common cause of death from all cancers among women in United Sates and the leading cause of death from gynecological malignancies. While most OvCa patients initially respond to surgical debulking and chemotherapy, 75% of patients later succumb to the disease. Thus, there is an urgent need to test novel therapeutic agents to counteract the high mortality rate associated with OvCa. In this context, we have developed and engineered Nanoceria (NCe), nanoparticles of cerium oxide, possessing anti-oxidant properties, to be used as a therapeutic agent in OvCa. We show for the first time that NCe significantly inhibited production of reactive oxygen species (ROS) in A2780 cells, attenuated growth factor (SDF1, HB-EGF, VEGF(165) and HGF) mediated cell migration and invasion of SKOV3 cells, without affecting the cell proliferation. NCe treatment also inhibited VEGF(165) induced proliferation, capillary tube formation, activation of VEGFR2 and MMP2 in human umbilical vascular endothelial cells (HUVEC). NCe (0.1 mg/kg body weigh) treatment of A2780 ovarian cancer cells injected intra-peritoneally in nude mice showed significant reduction (p<0.002) in tumor growth accompanied by decreased tumor cell proliferation as evident from reduced tumor size and Ki67 staining. Accumulation of NCe was found in tumors isolated from treated group using transmission electron microscopy (TEM) and inductively coupled plasma mass spectroscopy (ICP-MS). Reduction of the tumor mass was accompanied by attenuation of angiogenesis, as observed by reduced CD31 staining and specific apoptosis of vascular endothelial cells. Collectively, these results indicate that cerium oxide based NCe is a novel nanoparticle that can potentially be used as an anti-angiogenic therapeutic agent in ovarian cancer.

  9. Novel PI3K/AKT targeting anti-angiogenic activities of 4-vinylphenol, a new therapeutic potential of a well-known styrene metabolite

    PubMed Central

    Yue, Grace Gar-Lee; Lee, Julia Kin-Ming; Kwok, Hin-Fai; Cheng, Ling; Wong, Eric Chun-Wai; Jiang, Lei; Yu, Hua; Leung, Hoi-Wing; Wong, Yuk-Lau; Leung, Ping-Chung; Fung, Kwok-Pui; Lau, Clara Bik-San

    2015-01-01

    The pneumo- and hepato-toxicity of 4-vinylphenol (4VP), a styrene metabolite, has been previously reported. Nevertheless, the present study reported the novel anti-angiogenic activities of 4VP which was firstly isolated from the aqueous extract of a Chinese medicinal herb Hedyotis diffusa. Our results showed that 4VP at non-toxic dose effectively suppressed migration, tube formation, adhesion to extracellular matrix proteins, as well as protein and mRNA expressions of metalloproteinase-2 of human endothelial cells (HUVEC and HMEC-1). Investigation of the signal transduction revealed that 4VP down-regulated PI3K/AKT and p38 MAPK. Besides, 4VP interfered with the phosphorylation of ERK1/2, the translocation and expression of NFkappaB. In zebrafish embryo model, the new blood vessel growth was significantly blocked by 4VP (6.25–12.5 μg/mL medium). The VEGF-induced blood vessel formation in Matrigel plugs in C57BL/6 mice was suppressed by 4VP (20–100 μg/mL matrigel). In addition, the blood vessel number and tumor size were reduced by intraperitoneal 4VP (0.2–2 mg/kg) in 4T1 breast tumor-bearing BALB/c mice, with doxorubicin as positive control. Together, the in vitro and in vivo anti-angiogenic activities of 4VP were demonstrated for the first time. These findings suggest that 4VP has great potential to be further developed as an anti-angiogenic agent. PMID:26053458

  10. An immature B cell population from peripheral blood serves as surrogate marker for monitoring tumor angiogenesis and anti-angiogenic therapy in mouse models.

    PubMed

    Fagiani, Ernesta; Bill, Ruben; Pisarsky, Laura; Ivanek, Robert; Rüegg, Curzio; Christofori, Gerhard

    2015-07-01

    Tumor growth depends on the formation of new blood vessels (tumor angiogenesis) either from preexisting vessels or by the recruitment of bone marrow-derived cells. Despite encouraging results obtained with preclinical cancer models, the therapeutic targeting of tumor angiogenesis has thus far failed to deliver an enduring clinical response in cancer patients. One major obstacle for improving anti-angiogenic therapy is the lack of validated biomarkers, which allow patient stratification for suitable treatment and a rapid assessment of therapy response. Toward these goals, we have employed several mouse models of tumor angiogenesis to identify cell populations circulating in their blood that correlated with the extent of tumor angiogenesis and therapy response. Flow cytometry analyses of different combinations of cell surface markers that define subsets of bone marrow-derived cells were performed on peripheral blood mononuclear cells from tumor-bearing and healthy mice. We identified one cell population, CD45(dim)VEGFR1(-)CD31(low), that was increased in levels during active tumor angiogenesis in a variety of transgenic and syngeneic transplantation mouse models of cancer. Treatment with various anti-angiogenic drugs did not affect CD45(dim)VEGFR1(-)CD31(low) cells in healthy mice, whereas in tumor-bearing mice, a consistent reduction in their levels was observed. Gene expression profiling of CD45(dim)VEGFR1(-)CD31(low) cells characterized these cells as an immature B cell population. These immature B cells were then directly validated as surrogate marker for tumor angiogenesis and of pharmacologic responses to anti-angiogenic therapies in various mouse models of cancer.

  11. Alpha-v Integrin Targeted PET Imaging of Breast Cancer Angiogenesis and Low-Dose Metronomic Anti-Angiogenic Chemotherapy Efficacy

    DTIC Science & Technology

    2008-08-01

    Med Mol Imaging (2008) 35:1489–1498 18F-FPPRGD2 and 18F-FDG PET of Response to Abraxane Therapy Xilin Sun1,2, Yongjun Yan1, Shuanglong Liu3, Qizhen...Belotti D, Vergani V, Drudis T, et al. The microtubule-affecting drug paclitaxel has antiangiogenic activity. Clin Cancer Res. 1996;2:1843–1849. 11. Wang J...227–234. 19. Liu Z, Li ZB, Cao Q, Liu S, Wang F, Chen X. Small-animal PET of tumors with 64Cu-labeled RGD-bombesin heterodimer. J Nucl Med. 2009;50:1168

  12. The Efficacy of Combining Antiangiogenic Agents with Chemotherapy for Patients with Advanced Non-Small Cell Lung Cancer Who Failed First-Line Chemotherapy: A Systematic Review and Meta-Analysis

    PubMed Central

    Yang, Bijun; Zhang, Yaxiong; Kang, Shiyang; Zhou, Ting; Hong, Shaodong; Qin, Tao; Hu, Zhihuang; Fang, Wenfeng; Huang, Yan; Zhang, Li

    2015-01-01

    Background The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. Methods We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second-line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. Results Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). Conclusions This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy. PMID:26034985

  13. Next generation metronomic chemotherapy—report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6–8 May 2016, Mumbai

    PubMed Central

    Pantziarka, Pan; Hutchinson, Lisa; André, Nicolas; Benzekry, Sébastien; Bertolini, Francesco; Bhattacharjee, Atanu; Chiplunkar, Shubhada; Duda, Dan G.; Gota, Vikram; Gupta, Sudeep; Joshi, Amit; Kannan, Sadhana; Kerbel, Robert; Kieran, Mark; Palazzo, Antonella; Parikh, Aparna; Pasquier, Eddy; Patil, Vijay; Prabhash, Kumar; Shaked, Yuval; Sholler, Giselle Saulnier; Sterba, Jaroslav; Waxman, David J.; Banavali, Shripad

    2016-01-01

    The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th – 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies. PMID:27994645

  14. Mechanistic Insights into the Anti-angiogenic Activity of Trypanosoma cruzi Protein 21 and its Potential Impact on the Onset of Chagasic Cardiomyopathy

    PubMed Central

    Teixeira, Samuel Cota; Lopes, Daiana Silva; Gimenes, Sarah Natalie Cirilo; Teixeira, Thaise Lara; da Silva, Marcelo Santos; Brígido, Rebecca Tavares e Silva; da Luz, Felipe Andrés Cordero; da Silva, Aline Alves; Silva, Makswell Almeida; Florentino, Pilar Veras; Tavares, Paula Cristina Brígido; dos Santos, Marlus Alves; Ávila, Veridiana de Melo Rodrigues; Silva, Marcelo José Barbosa; Elias, Maria Carolina; Mortara, Renato Arruda; da Silva, Claudio Vieira

    2017-01-01

    Chronic chagasic cardiomyopathy (CCC) is arguably the most important form of the Chagas Disease, caused by the intracellular protozoan Trypanosoma cruzi; it is estimated that 10–30% of chronic patients develop this clinical manifestation. The most common and severe form of CCC can be related to ventricular abnormalities, such as heart failure, arrhythmias, heart blocks, thromboembolic events and sudden death. Therefore, in this study, we proposed to evaluate the anti-angiogenic activity of a recombinant protein from T. cruzi named P21 (rP21) and the potential impact of the native protein on CCC. Our data suggest that the anti-angiogenic activity of rP21 depends on the protein’s direct interaction with the CXCR4 receptor. This capacity is likely related to the modulation of the expression of actin and angiogenesis-associated genes. Thus, our results indicate that T. cruzi P21 is an attractive target for the development of innovative therapeutic agents against CCC. PMID:28322302

  15. The antiangiogenic effects of a vascular endothelial growth factor decoy receptor can be monitored in vivo using contrast-enhanced ultrasound imaging.

    PubMed

    Forsberg, Flemming; Ro, Raymond J; Marshall, Andrew; Liu, Ji-Bin; Chiou, See-Ying; Merton, Daniel A; Machado, Priscilla; Dicker, Adam P; Nazarian, Levon N

    2014-01-01

    The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response. We investigated whether the effects of a vascular endothelial growth factor decoy receptor (VEGF Trap, Regeneron Pharmaceuticals, Tarrytown, NY) could be monitored in vivo using contrast-enhanced ultrasonography (CEUS). Twenty nude mice (in two groups) were implanted with a human melanoma cell line (DB-1). The active group received VEGF Trap (4 × 25 mg/kg over 2 weeks), whereas the control group received an inactive protein. An ultrasound contrast agent was injected followed by power Doppler imaging (PDI) and pulse inversion harmonic imaging (PIHI; regular and intermittent). Specimens were sectioned in the same planes as the images and stained for endothelial cells (CD31), cyclooxygenase-2 (COX-2), VEGF, and hypoxia (Glut1). Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis. Mean tumor volume was smaller in the active group than in the control group (656 ± 225 vs 1,160 ± 605 mm3). Overall, PDI and VEGF correlated (r  =  .34; p =  .037). Vascularity decreased from control to treated mice with intermittent PIHI, as did the expression of CD31 and COX-2 (p ≤ .02), whereas VEGF increased (p  =  .05). CEUS appears to allow in vivo monitoring of the antiangiogenic effects of VEGF Trap in the DB-1 human melanoma xenograft model.

  16. Bone marrow-derived mesenchymal stem cells become antiangiogenic when chondrogenically or osteogenically differentiated: implications for bone and cartilage tissue engineering.

    PubMed

    Bara, Jennifer J; McCarthy, Helen E; Humphrey, Emma; Johnson, William E B; Roberts, Sally

    2014-01-01

    Osteochondral tissue repair requires formation of vascularized bone and avascular cartilage. Mesenchymal stem cells stimulate angiogenesis both in vitro and in vivo but it is not known if these proangiogenic properties change as a result of chondrogenic or osteogenic differentiation. We investigated the angiogenic/antiangiogenic properties of equine bone marrow-derived mesenchymal stem cells (eBMSCs) before and after differentiation in vitro. Conditioned media from chondrogenic and osteogenic cell pellets and undifferentiated cells was applied to endothelial tube formation assays using Matrigel™. Additionally, the cell secretome was analysed using LC-MS/MS mass spectrometry and screened for angiogenesis and neurogenesis-related factors using protein arrays. Endothelial tube-like formation was supported by conditioned media from undifferentiated eBMSCs. Conversely, chondrogenic and osteogenic conditioned media was antiangiogenic as shown by significantly decreased length of endothelial tube-like structures and degree of branching compared to controls. Undifferentiated cells produced higher levels of angiogenesis-related proteins compared to chondrogenic and osteogenic pellets. In summary, eBMSCs produce an array of angiogenesis-related proteins and support angiogenesis in vitro via a paracrine mechanism. However, when these cells are differentiated chondrogenically or osteogenically, they produce a soluble factor(s) that inhibits angiogenesis. With respect to osteochondral tissue engineering, this may be beneficial for avascular articular cartilage formation but unfavourable for bone formation where a vascularized tissue is desired.

  17. BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation.

    PubMed

    Thirusangu, Prabhu; Vigneshwaran, V; Prashanth, T; Vijay Avin, B R; Malojirao, Vikas H; Rakesh, H; Khanum, Shaukath Ara; Mahmood, Riaz; Prabhakar, B T

    2017-02-01

    Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.

  18. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy12

    PubMed Central

    Baker, Gregory J.; Yadav, Viveka Nand; Motsch, Sebastien; Koschmann, Carl; Calinescu, Anda-Alexandra; Mineharu, Yohei; Camelo-Piragua, Sandra Ines; Orringer, Daniel; Bannykh, Serguei; Nichols, Wesley S.; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2014-01-01

    As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. PMID:25117977

  19. Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum Linnaeus on human umbilical vein endothelial cells.

    PubMed

    Wu, Wen-Bin; Hung, Dian-Kun; Chang, Fung-Wei; Ong, Eng-Thaim; Chen, Bing-Huei

    2012-10-01

    Anti-inflammatory and anti-angiogenic effects of flavonoids isolated from Lycium barbarum fruits, a traditional Chinese medicine, on human umbilical vein endothelial cells (HUVECs) were investigated. Initially, flavonoids were extracted with 80% ethanol and separated using a Cosmosil 140 C18-OPN column, with the acidic fraction eluted with deionized water being composed of chlorogenic acid, caffeoyl quinic acid, caffeic acid and p-coumaric acid and the neutral fraction eluted with methanol composed of quercetin-diglycoside, rutin and kaempferol-O-rutinoside. Flavonoid extract was effective in inhibiting expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1) induced by TNF-α in HUVECs. The RT-PCR analysis indicated that ICAM-1 mRNA induced by TNF-α was inhibited by flavonoid extract. The flavonoid extract attenuated TNF-α-induced IκB phosphorylation as well as NF-κB, p65 and p50 translocation from cytosol to nucleus, through inhibition on TNF-α- and H(2)O(2)-induced intracellular reactive oxygen species (ROS) production. For the anti-angiogenic study, the flavonoid extract inhibited vascular endothelial growth factor (VEGF)-induced cell proliferation and migration in HUVECs, as well as angiogenesis. However, the flavonoid extract did not inhibit VEGF signaling. Surprisingly, HUVECs adhesion to the extracellular matrix was compromised and adhesion-induced signaling was retarded by the flavonoid extract.

  20. Improved efficacy of a novel anti-angiogenic drug combination (TL-118) against colorectal-cancer liver metastases; MRI monitoring in mice

    PubMed Central

    Edrei, Y; Gross, E; Corchia, N; Abramovitch, R

    2012-01-01

    Background: The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficiency of available treatments have raised the need for alternative curative strategies. We aimed to assess the therapeutic potential of TL-118, a new anti-angiogenic drug combination, for CRLM treatment, in a mouse model. Methods: The therapeutic potential of TL-118 was evaluated and compared with B20-4.1.1 (B20; anti-VEGF antibody) and rapamycin in CRLM-bearing mice. Tumour progression and the vascular changes were monitored by MRI. Additionally, mice survival, cell proliferation, apoptosis and vessel density were evaluated. Results: This study demonstrated an unequivocal advantage to TL-118 therapy by significantly prolonging survival (threefold) and reducing metastasis perfusion and vessel density (ninefold). The underlying mechanism for TL-118-treatment success was associated with hepatic perfusion attenuation resulting from reduced nitric-oxide (NO) serum levels as elucidated by using hemodynamic response imaging (HRI, a functional MRI combined with hypercapnia and hyperoxia). Further, systemic hepatic perfusion reduction during the initial treatment phase by adding NO inhibitor has proven to be essential for reaching maximal therapeutic effects for both TL-118 and B20. Conclusion: TL-118 harbours a potential clinical benefit to CLRM patients. Moreover, the reduction of hepatic perfusion at early stages of anti-angiogenic therapies by adding NO inhibitor is crucial for achieving maximal anti-tumour effects. PMID:22805330

  1. Magnetic resonance imaging defines cervicovaginal anatomy, cancer, and VEGF trap antiangiogenic efficacy in estrogen-treated K14-HPV16 transgenic mice.

    PubMed

    Garbow, Joel R; Santeford, Andrea C; Anderson, Jeff R; Engelbach, John A; Arbeit, Jeffrey M

    2009-10-15

    Noninvasive detection of dysplasia provides a potential platform for monitoring the efficacy of chemopreventive therapy of premalignancy, imaging the tissue compartments comprising dysplasia: epithelium, microvasculature, and stromal inflammatory cells. Here, using respiratory-gated magnetic resonance imaging (MRI), the anatomy of premalignant and malignant stages of cervical carcinogenesis in estrogen-treated K14-HPV16 transgenic mice was noninvasively defined. Dynamic contrast enhanced (DCE)-MRI was used to quantify leakage across premalignant dysplastic microvasculature. Vascular permeability as measured by DCE-MRI, K(trans), was similar in transgenic (0.053 +/- 0.020 min(-1); n = 32 mice) and nontransgenic (0.056 +/- 0.029 min(-1); n = 17 mice) animals despite a 2-fold increase in microvascular area in the former compared with the latter. DCE-MRI did detect a significant decrease in vascular permeability accompanying diminution of dysplastic microvasculature by the antiangiogenic agent, vascular endothelial growth factor Trap (K(trans) = 0.052 +/- 0.013 min(-1) pretreatment; n = 6 mice versus K(trans) = 0.019 +/- 0.008 min(-1) post-treatment; n = 5 mice). Thus, we determined that the threshold of microvessel leakage associated with cervical dysplasia was <17 kDa and highlighted the potential of DCE-MRI to noninvasively monitor the efficacy of antiangiogenic drugs or chemoprevention regimens targeting the vasculature in premalignant cervical dysplasia.

  2. Next generation metronomic chemotherapy-report from the Fifth Biennial International Metronomic and Anti-angiogenic Therapy Meeting, 6-8 May 2016, Mumbai.

    PubMed

    Pantziarka, Pan; Hutchinson, Lisa; André, Nicolas; Benzekry, Sébastien; Bertolini, Francesco; Bhattacharjee, Atanu; Chiplunkar, Shubhada; Duda, Dan G; Gota, Vikram; Gupta, Sudeep; Joshi, Amit; Kannan, Sadhana; Kerbel, Robert; Kieran, Mark; Palazzo, Antonella; Parikh, Aparna; Pasquier, Eddy; Patil, Vijay; Prabhash, Kumar; Shaked, Yuval; Sholler, Giselle Saulnier; Sterba, Jaroslav; Waxman, David J; Banavali, Shripad

    2016-01-01

    The 5(th) Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6(th) - 8(th) May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and predictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

  3. Anti-angiogenic and anti-multiple myeloma effects of oprozomib (OPZ) alone and in combination with pomalidomide (Pom) and/or dexamethasone (Dex).

    PubMed

    Sanchez, Eric; Li, Mingjie; Wang, Cathy S; Tang, George; Gillespie, Abigail; Chen, Haiming; Berenson, James R

    2017-03-06

    Oprozomib (OPZ or ONYX 0912) is an irreversible, orally administered proteasome inhibitor (PI) and an analog of carfilzomib. We set out to determine the anti-angiogenic effect of OPZ using the choriollantoic membrane/feather bud (CAM/FB) model and its anti-MM effects using MM xenograft models (LAGκ-1A, LAGλ-1). OPZ significantly reduced blood vessel formation, endothelial gene and protein expression using the CAM/FB assay. In vivo, we determined the anti-MM effects of OPZ, dexamethasone (Dex) and pomalidomide (Pom) and showed that the combinations of two drugs (OPZ+Dex or OPZ+Pom) showed marked anti-MM effects when compared to monotherapy. Pom+Dex and the triplicate combination (OPZ+Pom+Dex) showed more anti-MM effects when compared to the doublets of either OPZ+Dex or OPZ+Pom; continued treatment with all three drugs (OPZ+Pom+Dex) was superior when compared to Pom+Dex, in both MM xenograft models tested. These studies show that OPZ has anti-angiogenic effects, and that the combination of OPZ, Dex and Pom produces greater anti-MM effects in vivo when compared to any of the doublet combinations. These studies provide further support for clinical trials evaluating OPZ in combination with Pom and Dex.

  4. Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial.

    PubMed

    Schmitz-Winnenthal, Friedrich H; Hohmann, Nicolas; Niethammer, Andreas G; Friedrich, Tobias; Lubenau, Heinz; Springer, Marco; Breiner, Klaus M; Mikus, Gerd; Weitz, Jürgen; Ulrich, Alexis; Buechler, Markus W; Pianka, Frank; Klaiber, Ulla; Diener, Markus; Leowardi, Christine; Schimmack, Simon; Sisic, Leila; Keller, Anne-Valerie; Koc, Ruhan; Springfeld, Christoph; Knebel, Philipp; Schmidt, Thomas; Ge, Yingzi; Bucur, Mariana; Stamova, Slava; Podola, Lilli; Haefeli, Walter E; Grenacher, Lars; Beckhove, Philipp

    2015-04-01

    VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points - pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells.

  5. Anti-angiogenic activity of VXM01, an oral T-cell vaccine against VEGF receptor 2, in patients with advanced pancreatic cancer: A randomized, placebo-controlled, phase 1 trial

    PubMed Central

    Schmitz-Winnenthal, Friedrich H; Hohmann, Nicolas; Niethammer, Andreas G; Friedrich, Tobias; Lubenau, Heinz; Springer, Marco; Breiner, Klaus M; Mikus, Gerd; Weitz, Jürgen; Ulrich, Alexis; Buechler, Markus W; Pianka, Frank; Klaiber, Ulla; Diener, Markus; Leowardi, Christine; Schimmack, Simon; Sisic, Leila; Keller, Anne-Valerie; Koc, Ruhan; Springfeld, Christoph; Knebel, Philipp; Schmidt, Thomas; Ge, Yingzi; Bucur, Mariana; Stamova, Slava; Podola, Lilli; Haefeli, Walter E; Grenacher, Lars; Beckhove, Philipp

    2015-01-01

    VEGFR-2 is expressed on tumor vasculature and a target for anti-angiogenic intervention. VXM01 is a first in kind orally applied tumor vaccine based on live, attenuated Salmonella bacteria carrying an expression plasmid, encoding VEGFR-2. We here studied the safety, tolerability, T effector (Teff), T regulatory (Treg) and humoral responses to VEGFR2 and anti-angiogenic effects in advanced pancreatic cancer patients in a randomized, dose escalation phase I clinical trial. Results of the first 3 mo observation period are reported. Locally advanced or metastatic, pancreatic cancer patients were enrolled. In five escalating dose groups, 30 patients received VXM01 and 15 placebo on days 1, 3, 5, and 7. Treatment was well tolerated at all dose levels. No dose-limiting toxicities were observed. Salmonella excretion and salmonella-specific humoral immune responses occurred in the two highest dose groups. VEGFR2 specific Teff, but not Treg responses were overall increased in vaccinated patients. We furthermore observed a significant reduction of tumor perfusion after 38 d in vaccinated patients together with increased levels of serum biomarkers indicative of anti-angiogenic activity, VEGF-A, and collagen IV. Vaccine specific Teff responses significantly correlated with reductions of tumor perfusion and high levels of preexisting VEGFR2-specific Teff while those showing no antiangiogenic activity had low levels of preexisting VEGFR2 specific Teff, showed a transient early increase of VEGFR2-specific Treg and reduced levels of VEGFR2-specific Teff at later time points – pointing to the possibility that early anti-angiogenic activity might be based at least in part on specific reactivation of preexisting memory T cells. PMID:26137397

  6. The use of angiogenic and antiangiogenic factors in the differential diagnosis of pre-eclampsia, antiphospholipid syndrome nephropathy and lupus nephritis.

    PubMed

    de Jesus, G R; de Jesus, N R; Levy, R A; Klumb, E M

    2014-10-01

    Pre-eclampsia (PE) is a major cause of maternal mortality and morbidity, perinatal deaths, preterm birth and intrauterine growth restriction. Differential diagnosis with antiphospholipid syndrome (APS) nephropathy and systemic lupus erythematosus (SLE) nephritis during pregnancy is difficult, if not sometimes impossible, as all three diseases may present hypertension and proteinuria. Improvement in diagnosis of PE has also offered new paths for differential diagnosis with other conditions and the analysis of angiogenic (vascular endothelial growth factor, placental growth factor) and antiangiogenic factors (serum soluble fms-like tyrosine kinase 1, soluble endoglin) is promising for differentiation between PE, APS nephropathy and SLE nephritis. This article reviews published studies about those factors in non-pregnant and pregnant patients with APS and SLE, comparing with patterns described in PE.

  7. Tomato cystine-knot miniproteins possessing anti-angiogenic activity exhibit in vitro gastrointestinal stability, intestinal absorption and resistance to food industrial processing.

    PubMed

    Treggiari, Davide; Zoccatelli, Gianni; Chignola, Roberto; Molesini, Barbara; Minuz, Pietro; Pandolfini, Tiziana

    2017-04-15

    The cystine-knot miniproteins present in tomato fruit (TCMPs) have been shown to exert anti-angiogenic effects by inhibiting endothelial cell migration and to display resistance to gastrointestinal proteolytic attack. To better define the pharmacological potential of TCMPs, their oral bioavailability and their resistance to industrial processing must be assessed. To explore the intestinal transport of TCMPs we used the differentiated Caco-2 cells model. After 24h incubation, 37.73±9.34% of TCMPs crossed the epithelium, without altering the integrity of the cell layer. To assess the effects of the industrial processing on the biochemical features and the biological activity of TCMPs, we developed a method for purifying the proteins from tomato paste. The tomato-paste purified TCMPs retained the resistance to gastrointestinal digestion and the inhibitory activity towards endothelial cell migration. Our previous and present results collectively demonstrate that TCMPs possess interesting features for drug development.

  8. Noninvasive monitoring of early antiangiogenic therapy response in human nasopharyngeal carcinoma xenograft model using MRI with RGD-conjugated ultrasmall superparamagnetic iron oxide nanoparticles

    PubMed Central

    Cui, Yanfen; Zhang, Caiyuan; Luo, Ran; Liu, Huanhuan; Zhang, Zhongyang; Xu, Tianyong; Zhang, Yong; Wang, Dengbin

    2016-01-01

    Purpose Arginine-glycine-aspartic acid (RGD)-based nanoprobes allow specific imaging of integrin αvβ3, a protein overexpressed during angiogenesis. Therefore, this study applied a novel RGD-coupled, polyacrylic acid (PAA)-coated ultrasmall superparamagnetic iron oxide (USPIO) (referred to as RGD-PAA-USPIO) in order to detect tumor angiogenesis and assess the early response to antiangiogenic treatment in human nasopharyngeal carcinoma (NPC) xenograft model by magnetic resonance imaging (MRI). Materials and methods The binding specificity of RGD-PAA-USPIO with human umbilical vein endothelial cells (HUVECs) was confirmed by Prussian blue staining and transmission electron microscopy in vitro. The tumor targeting of RGD-PAA-USPIO was evaluated in the NPC xenograft model. Later, mice bearing NPC underwent MRI at baseline and after 4 and 14 days of consecutive treatment with Endostar or phosphate-buffered saline (n=10 per group). Results The specific uptake of the RGD-PAA-USPIO nanoparticles was mainly dependent on the interaction between RGD and integrin αvβ3 of HUVECs. The tumor targeting of RGD-PAA-USPIO was observed in the NPC xenograft model. Moreover, the T2 relaxation time of mice in the Endostar-treated group decreased significantly compared with those in the control group both on days 4 and 14, consistent with the immunofluorescence results of CD31 and CD61 (P<0.05). Conclusion This study demonstrated that the magnetic resonance molecular nanoprobes, RGD-PAA-USPIOs, allow noninvasive in vivo imaging of tumor angiogenesis and assessment of the early response to antiangiogenic treatment in NPC xenograft model, favoring its potential clinical translation. PMID:27895477

  9. Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma12

    PubMed Central

    Han, Kyung Seok; Raven, Peter A.; Frees, Sebastian; Gust, Kilian; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Kollmannsberger, Cristian; Gleave, Martin E.; So, Alan I.

    2015-01-01

    Vascular endothelial growth factor (VEGF)–targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC. PMID:26678908

  10. Cellular Adaptation to VEGF-Targeted Antiangiogenic Therapy Induces Evasive Resistance by Overproduction of Alternative Endothelial Cell Growth Factors in Renal Cell Carcinoma.

    PubMed

    Han, Kyung Seok; Raven, Peter A; Frees, Sebastian; Gust, Kilian; Fazli, Ladan; Ettinger, Susan; Hong, Sung Joon; Kollmannsberger, Cristian; Gleave, Martin E; So, Alan I

    2015-11-01

    Vascular endothelial growth factor (VEGF)-targeted antiangiogenic therapy significantly inhibits the growth of clear cell renal cell carcinoma (RCC). Eventually, therapy resistance develops in even the most responsive cases, but the mechanisms of resistance remain unclear. Herein, we developed two tumor models derived from an RCC cell line by conditioning the parental cells to two different stresses caused by VEGF-targeted therapy (sunitinib exposure and hypoxia) to investigate the mechanism of resistance to such therapy in RCC. Sunitinib-conditioned Caki-1 cells in vitro did not show resistance to sunitinib compared with parental cells, but when tested in vivo, these cells appeared to be highly resistant to sunitinib treatment. Hypoxia-conditioned Caki-1 cells are more resistant to hypoxia and have increased vascularity due to the upregulation of VEGF production; however, they did not develop sunitinib resistance either in vitro or in vivo. Human endothelial cells were more proliferative and showed increased tube formation in conditioned media from sunitinib-conditioned Caki-1 cells compared with parental cells. Gene expression profiling using RNA microarrays revealed that several genes related to tissue development and remodeling, including the development and migration of endothelial cells, were upregulated in sunitinib-conditioned Caki-1 cells compared with parental and hypoxia-conditioned cells. These findings suggest that evasive resistance to VEGF-targeted therapy is acquired by activation of VEGF-independent angiogenesis pathways induced through interactions with VEGF-targeted drugs, but not by hypoxia. These results emphasize that increased inhibition of tumor angiogenesis is required to delay the development of resistance to antiangiogenic therapy and maintain the therapeutic response in RCC.

  11. Monte Carlo study of the dose enhancement effect of gold nanoparticles during X-ray therapies and evaluation of the anti-angiogenic effect on tumour capillary vessels.

    PubMed

    Amato, Ernesto; Italiano, Antonio; Leotta, Salvatore; Pergolizzi, Stefano; Torrisi, Lorenzo

    2013-01-01

    Gold nanoparticles (GNPs) are a promising radiosensitizer agent in radiotherapy. Through a simulation performed with the Geant4 Monte Carlo code, we evaluated the dose enhancement effect of GNPs during therapies with an x-ray tube operating at 150 kV (E = 55 keV and E(max) = 150 keV) and we studied the impact of GNP diffusion out of the tumour vessels, in terms of antiangiogenic and cytotoxic effects. Firstly, a single x-ray beam was assumed to irradiate a parallelepiped volume of soft tissue, in which a GNP-doped "target" volume was placed at different depths. Average dose enhancement factors (DEF) in presence of GNPs were obtained as a function of the target depth and GNP concentration, uniformly distributed; values ranging between 1.6 for 10 mg Au/g at 0 cm and 7.2 for 200 mg Au/g at 5 cm were determined. Furtherly, a second geometry was adopted, in which a blood capillary vessel (10 μm thick and 10 μm of inner radius) was placed at the centre of a cubic volume of soft tissue; doses and DEFs to the capillary endothelium as well as to the surrounding viable tumour were evaluated, for different models of GNP diffusion. Our results indicate that the radial DEF profiles around the vessel are in close relationship with the radial profiles of GNP concentration assumed, except for at sharp gradients of concentration. DEFs at the endothelium ranged from 1.6 to 6.5, for GNP concentrations in the blood of 10 and 200 mg/ml, respectively. These data can be helpful for the development of new and more specific GNP-based radiosensitizers of potential interest in radiotherapy, exploiting the combined benefit of anti-angiogenic and cytotoxic dose enhancement effects.

  12. Gene electrotransfer of plasmid antiangiogenic metargidin peptide (AMEP) in disseminated melanoma: safety and efficacy results of a phase I first-in-man study.

    PubMed

    Spanggaard, Iben; Snoj, Marko; Cavalcanti, Andrea; Bouquet, Céline; Sersa, Gregor; Robert, Caroline; Cemazar, Maja; Dam, Elisabeth; Vasseur, Bérangère; Attali, Pierre; Mir, Lluis M; Gehl, Julie

    2013-09-01

    Antiangiogenic metargidin peptide (AMEP) is a novel anticancer agent exerting antiproliferative and antiangiogenic effects by binding to αvβ3 and α5β1 integrins. Electrotransfer designates the use of electric pulses (electroporation) to transfer plasmid DNA into tissues. This first-in-man phase I study investigated safety and tolerability of intratumoral plasmid AMEP electrotransfer into cutaneous metastatic melanoma. Secondary objectives were efficacy and pharmacokinetics. Five patients with disseminated melanoma without further treatment options were treated at two dose levels (1 and 2 mg DNA). In each patient, two cutaneous lesions were identified (one treated and one control). At day 1 and day 8, plasmid AMEP was injected intratumorally followed by electrotransfer. Patients were monitored weekly until day 29, and at day 64. Local efficacy was assessed at day 29 by direct measurement, and posttreatment biopsies for AMEP mRNA levels were evaluated by reverse transcriptase quantitative polymerase chain reaction. Plasmid copy number in blood and urine was determined by quantitative polymerase chain reaction. Minimal systemic toxicity was observed, including transient fever and transitory increase in C-reactive protein. No related serious adverse events occurred. Plasmid AMEP was detected in plasma but not in urine. AMEP mRNA was found in three of five treated lesions and none of the control lesions. At day 29, all five treated lesions were stable in diameter, whereas four of five control lesions increased more than 20%. No response occurred in distant lesions. This first-in-man study on electrotransfer of plasmid AMEP into cutaneous melanoma shows that the procedure and drug are safe and that local transfection was obtained.

  13. Vicrostatin – An Anti-Invasive Multi-Integrin Targeting Chimeric Disintegrin with Tumor Anti-Angiogenic and Pro-Apoptotic Activities

    PubMed Central

    Minea, Radu O.; Helchowski, Corey M.; Zidovetzki, Samuel J.; Costa, Fritz K.; Swenson, Stephen D.; Markland, Francis S.

    2010-01-01

    Similar to other integrin-targeting strategies, disintegrins have previously shown good efficacy in animal cancer models with favorable pharmacological attributes and translational potential. Nonetheless, these polypeptides are notoriously difficult to produce recombinantly due to their particular structure requiring the correct pairing of multiple disulfide bonds for biological activity. Here, we show that a sequence-engineered disintegrin (called vicrostatin or VCN) can be reliably produced in large scale amounts directly in the oxidative cytoplasm of Origami B E. coli. Through multiple integrin ligation (i.e., αvβ3, αvβ5, and α5β1), VCN targets both endothelial and cancer cells significantly inhibiting their motility through a reconstituted basement membrane. Interestingly, in a manner distinct from other integrin ligands but reminiscent of some ECM-derived endogenous anti-angiogenic fragments previously described in the literature, VCN profoundly disrupts the actin cytoskeleton of endothelial cells (EC) inducing a rapid disassembly of stress fibers and actin reorganization, ultimately interfering with EC's ability to invade and form tubes (tubulogenesis). Moreover, here we show for the first time that the addition of a disintegrin to tubulogenic EC sandwiched in vitro between two Matrigel layers negatively impacts their survival despite the presence of abundant haptotactic cues. A liposomal formulation of VCN (LVCN) was further evaluated in vivo in two animal cancer models with different growth characteristics. Our data demonstrate that LVCN is well tolerated while exerting a significant delay in tumor growth and an increase in the survival of treated animals. These results can be partially explained by potent tumor anti-angiogenic and pro-apoptotic effects induced by LVCN. PMID:20532165

  14. Olmesartan Potentiates the Anti-Angiogenic Effect of Sorafenib in Mice Bearing Ehrlich's Ascites Carcinoma: Role of Angiotensin (1–7)

    PubMed Central

    Abd-Alhaseeb, Mohammad M.; Zaitone, Sawsan A.; Abou-El-Ela, Soad H.; Moustafa, Yasser M.

    2014-01-01

    Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1–7) agonist or an angiotensin (1–7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1–7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1–7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer. PMID:24465768

  15. Novel pyrazole and indazole derivatives: synthesis and evaluation of their anti-proliferative and anti-angiogenic activities.

    PubMed

    Tzanetou, Evangelia; Liekens, Sandra; Kasiotis, Konstantinos M; Fokialakis, Nikolas; Haroutounian, Serkos A

    2012-10-01

    The synthesis of several new pyrazole and indazole derivatives from acetophenone and tetralone substrates is reported. The bioactivities of the new compounds were evaluated through in vitro assays for endothelial cell proliferation and tube formation. Results herein indicate that the easily prepared compounds containing the indazole structural framework exhibit potent cytostatic properties against all cell lines tested, with compounds 13 and 14 being the most active displaying IC(50) values of 1.5 ± 0.4 µM and 5.6 ± 2.5 µM, respectively, against MCF-7 cells. In addition, the indazole derivative 16 was assessed as a competent inhibitor of endothelial tube formation at 30 µM.

  16. Bioactive Compounds Isolated from Microalgae in Chronic Inflammation and Cancer

    PubMed Central

    Talero, Elena; García-Mauriño, Sofía; Ávila-Román, Javier; Rodríguez-Luna, Azahara; Alcaide, Antonio; Motilva, Virginia

    2015-01-01

    The risk of onset of cancer is influenced by poorly controlled chronic inflammatory processes. Inflammatory diseases related to cancer development include inflammatory bowel disease, which can lead to colon cancer, or actinic keratosis, associated with chronic exposure to ultraviolet light, which can progress to squamous cell carcinoma. Chronic inflammatory states expose these patients to a number of signals with tumorigenic effects, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPK) activation, pro-inflammatory cytokines and prostaglandins release and ROS production. In addition, the participation of inflammasomes, autophagy and sirtuins has been demonstrated in pathological processes such as inflammation and cancer. Chemoprevention consists in the use of drugs, vitamins, or nutritional supplements to reduce the risk of developing or having a recurrence of cancer. Numerous in vitro and animal studies have established the potential colon and skin cancer chemopreventive properties of substances from marine environment, including microalgae species and their products (carotenoids, fatty acids, glycolipids, polysaccharides and proteins). This review summarizes the main mechanisms of actions of these compounds in the chemoprevention of these cancers. These actions include suppression of cell proliferation, induction of apoptosis, stimulation of antimetastatic and antiangiogenic responses and increased antioxidant and anti-inflammatory activity. PMID:26437418

  17. Compounds affecting cholesterol absorption

    NASA Technical Reports Server (NTRS)

    Hua, Duy H. (Inventor); Koo, Sung I. (Inventor); Noh, Sang K. (Inventor)

    2004-01-01

    A class of novel compounds is described for use in affecting lymphatic absorption of cholesterol. Compounds of particular interest are defined by Formula I: ##STR1## or a pharmaceutically acceptable salt thereof.

  18. Dinitroso and polynitroso compounds

    PubMed Central

    Gowenlock, Brian G.; Richter-Addo, George B.

    2005-01-01

    The growing interest in the chemistry of C-nitroso compounds (RN=O; R = alkyl or aryl group) is due in part to the recognition of their participation in various metabolic processes of nitrogen-containing compounds. C-Nitroso compounds have a rich organic chemistry in their own right, displaying interesting intra- and intermolecular dimerization processes and addition reactions with unsaturated compounds. In addition, they have a fascinating coordination chemistry. While most of the attention has been directed towards C-nitroso compounds containing a single –NO moiety, there is an emerging area of research dealing with dinitroso and polynitroso compounds. In this critical review, we present and discuss the synthetic routes and properties of these relatively unexplored dinitroso and polynitroso compounds, and suggest areas of further development involving these compounds. (126 references.) PMID:16100619

  19. Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78 potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/eIF2α pathway

    PubMed Central

    Han, Kyung Seok; Li, Na; Raven, Pater A.; Fazli, Ladan; Frees, Sebastian; Ettinger, Susan; Park, Ki Chung; Hong, Sung Joon; Gleave, Martin E.; So, Alan I.

    2015-01-01

    Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC. PMID:26472187

  20. Adaptive immune contexture at the tumour site and downmodulation of circulating myeloid-derived suppressor cells in the response of solitary fibrous tumour patients to anti-angiogenic therapy

    PubMed Central

    Tazzari, M; Negri, T; Rini, F; Vergani, B; Huber, V; Villa, A; Dagrada, P; Colombo, C; Fiore, M; Gronchi, A; Stacchiotti, S; Casali, P G; Pilotti, S; Rivoltini, L; Castelli, C

    2014-01-01

    Background: Host immunity is emerging as a key player in the prognosis and response to treatment of cancer patients. However, the impact of the immune system and its modulation by therapies are unknown in rare soft tissue sarcomas such as solitary fibrous tumours (SFTs), whose management in the advanced forms includes anti-angiogenic therapy. Here, we studied the in situ and systemic immune status of advanced SFT patients and the effects of sunitinib malate (SM) in association with the clinical efficacy. Methods: Immune contexture of SFTs was assessed by immunohistochemistry in lesions from untreated or SM-treated patients. Frequency of circulating myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and T-cell functions was assessed ex vivo in SFT patients prior and during anti-angiogenic therapy. Patients with long-term tumour control were included to correlate immune profiles and clinical responses. Results: Anti-angiogenic naïve SFT lesions were heavily infiltrated by CD163+CD14+CD68− and CD163+CD14−CD68− myeloid cells but devoid of T cells. Conversely, post-SM tumours acquired a new subset of CD68+CD14+ myeloid cells and displayed traits of an on-going adaptive immunity, strongly enriched in activated CD8+ and CD4+ T cells. These changes at the tumour site paralleled the alleviation of systemic immunosuppression and the drop in the frequency of circulating monocytic MDSCs (mMDSCs) and granulocytic MDSCs (gMDSCs). Rebound in the number of mMDSCs, but not of gMDSCs occurred at disease progression, and a reduced percentages of mMDSCs, comparable to those found in healthy donors (HDs), endured only in the SM-responsive patients. Conclusions: The immune contexture of SFT patients is heavily involved in anti-angiogenic therapy and it could be exploited to achieve more durable disease control through immune-based combination strategies. PMID:25101565

  1. Anti-tumor innate immunity activated by intermittent metronomic cyclophosphamide treatment of 9L brain tumor xenografts is preserved by anti-angiogenic drugs that spare VEGF receptor 2

    PubMed Central

    2014-01-01

    Background Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. Methods and approach Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors. Results Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor regression by anti-angiogenic receptor tyrosine kinase inhibitors, previously observed in several brain tumor models, was recapitulated in the 9L tumor model with the VEGFR2-specific inhibitory monoclonal antibody DC101 (p < 0.01), implicating VEGFR2 signaling as an essential step in metronomic cyclophosphamide-stimulated immune cell recruitment. In contrast, sorafenib, a multi-receptor tyrosine kinase inhibitor with comparatively weak VEGF receptor phosphorylation inhibitory activity, was strongly anti-angiogenic but did not block metronomic cyclophosphamide-induced innate immunity or tumor regression (p > 0.05). Conclusions The interference by receptor tyrosine kinase inhibitors in the immunogenic actions of intermittent metronomic chemotherapy is not a consequence of anti-angiogenesis per se, as demonstrated in an implanted 9L tumor model. Furthermore, this undesirable interaction with tyrosine kinase inhibitors can be

  2. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat

    PubMed Central

    Lanza, Gregory M.; Jenkins, John; Schmieder, Anne H.; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S.; Eldridge, Lindsey; Allen, John S.; Williams, Todd; Scott, Michael J.; Razani, Babak; Wagner, Elizabeth M.

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous 19F/1H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3+ macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3+ CD45+ leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in a

  3. Acute Temporal Changes of MRI-Tracked Tumor Vascular Parameters after Combined Anti-angiogenic and Radiation Treatments in a Rat Glioma Model: Identifying Signatures of Synergism.

    PubMed

    Elmghirbi, Rasha; Nagaraja, Tavarekere N; Brown, Stephen L; Panda, Swayamprava; Aryal, Madhava P; Keenan, Kelly A; Bagher-Ebadian, Hassan; Cabral, Glauber; Ewing, James R

    2017-01-01

    In this study we used magnetic resonance imaging (MRI) biomarkers to monitor the acute temporal changes in tumor vascular physiology with the aim of identifying the vascular signatures that predict response to combined anti-angiogenic and radiation treatments. Forty-three athymic rats implanted with orthotopic U-251 glioma cells were studied for approximately 21 days after implantation. Two MRI studies were performed on each animal, pre- and post-treatment, to measure tumor vascular parameters. Two animal groups received treatment comprised of Cilengitide, an anti-angiogenic agent and radiation. The first group received a subcurative regimen of Cilengitide 1 h before irradiation, while the second group received a curative regimen of Cilengitide 8 h before irradiation. Cilengitide was given as a single dose (4 mg/kg; intraperitoneal) after the pretreatment MRI study and before receiving a 20 Gy radiation dose. After irradiation, the post-treatment MRI study was performed at selected time points: 2, 4, 8 and 12 h (n = ≥5 per time point). Significant changes in vascular parameters were observed at early time points after combined treatments in both treatment groups (1 and 8 h). The temporal changes in vascular parameters in the first group (treated 1 h before exposure) resembled a previously reported pattern associated with radiation exposure alone. Conversely, in the second group (treated 8 h before exposure), all vascular parameters showed an initial response at 2-4 h postirradiation, followed by an apparent lack of response at later time points. The signature time point to define the "synergy" of Cilengitide and radiation was 4 h postirradiation. For example, 4 h after combined treatments using a 1 h separation (which followed the subcurative regimen), tumor blood flow was significantly decreased, nearly 50% below baseline (P = 0.007), whereas 4 h after combined treatments using an 8 h separation (which followed the curative regimen), tumor blood flow was only 10

  4. The human oviduct transcriptome reveals an anti-inflammatory, anti-angiogenic, secretory and matrix-stable environment during embryo transit.

    PubMed

    Hess, A P; Talbi, S; Hamilton, A E; Baston-Buest, D M; Nyegaard, M; Irwin, J C; Barragan, F; Kruessel, J S; Germeyer, A; Giudice, L C

    2013-10-01

    The human oviduct serves as a conduit for spermatozoa in the peri-ovulatory phase and nurtures and facilitates transport of the developing embryo for nidation during the luteal phase. Interactions between the embryo and oviductal epithelial surface proteins and secreted products during embryo transit are largely undefined. This study investigated gene expression in the human oviduct in the early luteal versus follicular phases to identify candidate genes and biomolecular processes that may participate in maturation and transport of the embryo as it traverses this tissue. Oviductal RNA was hybridized to oligonucleotide arrays and resulting data were analysed by bioinformatic approaches. There were 650 genes significantly down-regulated and 683 genes significantly up-regulated (P<0.05) in the luteal versus follicular phase. Quantitative real-time PCR, immunoblot analysis and immunohistochemistry confirmed selected gene expression and cellular protein localization. Down-regulated genes involved macrophage recruitment, immunomodulation and matrix-degeneration, and up-regulated genes involved anti-inflammatory, ion transport, anti-angiogenic and early pregnancy recognition. The oviduct displayed some similarities and differences in progesterone-regulated genes compared with the human endometrium. Together, these data suggest a unique hormonally regulated environment during embryo development, maturation and transport through human oviduct and some conservation of progesterone signalling in tissues of common embryological origin. The oviduct serves as a conduit for spermatozoa in the peri-ovulatory phase and it nurtures and facilitates transport of the developing embryo during the luteal phase of the menstrual cycle, although precise interactions between the embryo and oviductal epithelium and secreted products are largely undefined. Herein, we investigated gene expression in human oviduct to identify candidate genes and processes that may participate in maturation and

  5. Anti-angiogenic Nanotherapy Inhibits Airway Remodeling and Hyper-responsiveness of Dust Mite Triggered Asthma in the Brown Norway Rat.

    PubMed

    Lanza, Gregory M; Jenkins, John; Schmieder, Anne H; Moldobaeva, Aigul; Cui, Grace; Zhang, Huiying; Yang, Xiaoxia; Zhong, Qiong; Keupp, Jochen; Sergin, Ismail; Paranandi, Krishna S; Eldridge, Lindsey; Allen, John S; Williams, Todd; Scott, Michael J; Razani, Babak; Wagner, Elizabeth M

    2017-01-01

    Although angiogenesis is a hallmark feature of asthmatic inflammatory responses, therapeutic anti-angiogenesis interventions have received little attention. Objective: Assess the effectiveness of anti-angiogenic Sn2 lipase-labile prodrugs delivered via αvβ3-micellar nanotherapy to suppress microvascular expansion, bronchial remodeling, and airway hyper-responsiveness in Brown Norway rats exposed to serial house dust mite (HDM) inhalation challenges. Results: Anti-neovascular effectiveness of αvβ3-mixed micelles incorporating docetaxel-prodrug (Dxtl-PD) or fumagillin-prodrug (Fum-PD) were shown to robustly suppress neovascular expansion (p<0.01) in the upper airways/bronchi of HDM rats using simultaneous (19)F/(1)H MR neovascular imaging, which was corroborated by adjunctive fluorescent microscopy. Micelles without a drug payload (αvβ3-No-Drug) served as a carrier-only control. Morphometric measurements of HDM rat airway size (perimeter) and vessel number at 21d revealed classic vascular expansion in control rats but less vascularity (p<0.001) after the anti-angiogenic nanotherapies. CD31 RNA expression independently corroborated the decrease in airway microvasculature. Methacholine (MCh) induced respiratory system resistance (Rrs) was high in the HDM rats receiving αvβ3-No-Drug micelles while αvβ3-Dxtl-PD or αvβ3-Fum-PD micelles markedly and equivalently attenuated airway hyper-responsiveness and improved airway compliance. Total inflammatory BAL cells among HDM challenged rats did not differ with treatment, but αvβ3(+) macrophages/monocytes were significantly reduced by both nanotherapies (p<0.001), most notably by the αvβ3-Dxtl-PD micelles. Additionally, αvβ3-Dxtl-PD decreased BAL eosinophil and αvβ3(+) CD45(+) leukocytes relative to αvβ3-No-Drug micelles, whereas αvβ3-Fum-PD micelles did not. Conclusion: These results demonstrate the potential of targeted anti-angiogenesis nanotherapy to ameliorate the inflammatory hallmarks of asthma in

  6. TU-G-BRA-07: Characterization of Tumor Proliferation During Successive Cycles of Anti-Angiogenic Therapy Using [F-18]FLT PET/CT

    SciTech Connect

    Scarpelli, M; Perlman, S; Harmon, S; Perk, T; Scully, P; Bruce, J; Liu, G; Jeraj, R

    2015-06-15

    Purpose: Studies have shown cessation of anti-angiogenic treatment during the first cycle of therapy resulted in rebound of tumor proliferation (flare). This study characterized proliferation dynamics during the first and third cycle of anti-angiogenic treatment using [F-18]FLT PET. Methods: Thirteen patients with various solid cancers were treated with Axitinib (Pfizer, Inc) at a dose of 5mg orally, twice daily, on contiguous three-week cycles with intermittent dosing (two-weeks-on/one-week-off). All patients received three FLT PET/CT scans during cycle 1 (C1): at baseline (C1D0), peak Axitinib concentration (C1D14), and the end of washout (C1D21). Ten patients received up to an additional three scans at corresponding time points during cycle 3 (C3). Lesions were identified by a nuclear medicine physician and manually contoured. Tumor burden was quantified using standard SUV metrics. Correlations between imaging metrics across C1 and C3 were calculated using the Spearman correlation. Results: At C1 peak drug concentration 11/13 patients had decreases in SUVtotal, with median decrease of 50% (change from C1D0 to C1D14). At C3 peak drug concentration 7/7 patients had decreases in SUVtotal, with median decrease of 20% (C3D0 to C3D14). Proliferative flare during C1 washout (>20% increase from C1D14 to C1D21) occurred in 9/13 patients, with median SUVtotal increase of 190%. Flare was also seen in C3 for 5/5 patients, with median SUVtotal increase of 70% (change from C3D14 to C3D21). Correlations were found between changes in imaging metrics across C1 and C3, notably the change in SUVtotal from C1D0 to C1D21 and the change in SUVtotal from C1D0 to C3D0 (ρ = 0.80). Conclusion: Measurements of SUVtotal showed that both patient response to treatment and flare were evident in both cycles of treatment. Correlation between changes in SUVtotal across C1 and C3 suggest early time points could be used to characterize patient response in later cycles. Research funded in part by

  7. A Highly Pure Sub-Fraction of Shallot Extract With Potent in vitro Anti-Angiogenic Activity.

    PubMed

    Famil Samavati, Shima; Mohammadi-Motlagh, Hamid-Reza; Mostafaie, Ali

    2014-01-01

    Our previous studies showed that various extracts of Persian shallot (Allium hirtifolium) have anti- angiogenic effects. This study has been undertaken to isolate and identify the major effective anti- angiogeneic sub-fraction of shallot. After preparation of the 50% hydroalcoholic extract of shallot bulbs, the extract was successively fractionated into n- hexane, ethyl acetate, n- butanol and aqueous fractions. Anti-angiogenesis activity of fractions was examined by in vitro angiogenesis assay. The ethyl acetate fraction which had the most anti-angiogenesis activity was further fractionated to four sub- fractions by thin layer chromatography (TLC), silica gel column chromatography and then analyzed by High Performance TLC (HPTLC) with ethyl acetate-methanol- water as the solvent system. Our results showed that one of the four sub- fractions, as the major band in HPTLC, had the most anti- angiogenic activity. Purification and characterization of the major anti- angiogenic compound/compounds of shallot's extract may constitute one means by which diets rich in shallot confer protection against cancer and finally introduce new agents with pharmacological activities in shallot as a potential candidate in cancer therapy.

  8. Intra-Animal Comparison between Three-dimensional Molecularly Targeted US and Three-dimensional Dynamic Contrast-enhanced US for Early Antiangiogenic Treatment Assessment in Colon Cancer1

    PubMed Central

    Wang, Huaijun; Lutz, Amelie M.; Hristov, Dimitre; Tian, Lu; Willmann, Jürgen K.

    2017-01-01

    Purpose To perform an intra-animal comparison between (a) three-dimensional (3D) molecularly targeted ultrasonography (US) by using clinical-grade vascular endothelial growth factor receptor 2 (VEGFR2)–targeted microbubbles and (b) 3D dynamic contrast material–enhanced (DCE) US by using nontargeted microbubbles for assessment of antiangiogenic treatment effects in a murine model of human colon cancer. Materials and Methods Twenty-three mice with human colon cancer xenografts were randomized to receive either single-dose antiangiogenic treatment (bevacizumab, n = 14) or control treatment (saline, n = 9). At baseline and 24 hours after treatment, animals were imaged with a clinical US system equipped with a clinical matrix array transducer by using the following techniques: (a) molecularly targeted US with VEGFR2-targeted microbubbles, (b) bolus DCE US with nontargeted microbubbles, and (c) destruction-replenishment DCE US with nontargeted microbubbles. VEGFR2-targeted US signal, peak enhancement, area under the time-intensity curve, time to peak, relative blood volume (rBV), relative blood flow, and blood flow velocity were quantified. VEGFR2 expression and percentage area of blood vessels were assessed ex vivo with quantitative immunofluorescence and correlated with corresponding in vivo US parameters. Statistical analysis was performed with Wilcoxon signed rank tests and rank sum tests, as well as Pearson correlation analysis. Results Molecularly targeted US signal with VEGFR2-targeted micro-bubbles, peak enhancement, and rBV significantly decreased (P ≤ .03) after a single antiangiogenic treatment compared with those in the control group; similarly, ex vivo VEGFR2 expression (P = .03) and percentage area of blood vessels (P = .03) significantly decreased after antiangiogenic treatment. Three-dimensional molecularly targeted US signal correlated well with VEGFR2 expression (r = 0.86, P = .001), and rBV (r = 0.71, P = .01) and relative blood flow (r = 0.78, P

  9. A multiscale computational model predicts distribution of anti-angiogenic isoform VEGF165b in peripheral arterial disease in human and mouse

    PubMed Central

    Chu, Liang-Hui; Ganta, Vijay Chaitanya; Choi, Min H.; Chen, George; Finley, Stacey D.; Annex, Brian H.; Popel, Aleksander S.

    2016-01-01

    Angiogenesis is the growth of new blood vessels from pre-existing microvessels. Peripheral arterial disease (PAD) is caused by atherosclerosis that results in ischemia mostly in the lower extremities. Clinical trials including VEGF-A administration for therapeutic angiogenesis have not been successful. The existence of anti-angiogenic isoform (VEGF165b) in PAD muscle tissues is a potential cause for the failure of therapeutic angiogenesis. Experimental measurements show that in PAD human muscle biopsies the VEGF165b isoform is at least as abundant if not greater than the VEGF165a isoform. We constructed three-compartment models describing VEGF isoforms and receptors, in human and mouse, to make predictions on the secretion rate of VEGF165b and the distribution of various isoforms throughout the body based on the experimental data. The computational results are consistent with the data showing that in PAD calf muscles secrete mostly VEGF165b over total VEGF. In the PAD calf compartment of human and mouse models, most VEGF165a and VEGF165b are bound to the extracellular matrix. VEGF receptors VEGFR1, VEGFR2 and Neuropilin-1 (NRP1) are mostly in ‘Free State’. This study provides a computational model of VEGF165b in PAD supported by experimental measurements of VEGF165b in human and mouse, which gives insight of VEGF165b in therapeutic angiogenesis and VEGF distribution in human and mouse PAD model. PMID:27853189

  10. ICAM-1-Targeted, Lcn2 siRNA-Encapsulating Liposomes are Potent Anti-angiogenic Agents for Triple Negative Breast Cancer

    PubMed Central

    Guo, Peng; Yang, Jiang; Jia, Di; Moses, Marsha A.; Auguste, Debra T.

    2016-01-01

    Lipocalin 2 (Lcn2) is a promising therapeutic target as well as a potential diagnostic biomarker for breast cancer. It has been previously shown to promote breast cancer progression by inducing the epithelial to mesenchymal transition in breast cancer cells as well as by enhancing angiogenesis. Lcn2 levels in urine and tissue samples of breast cancer patients has also been correlated with breast cancer status and poor patient prognosis. In this study, we have engineered a novel liposomal small interfering RNA (siRNA) delivery system to target triple negative breast cancer (TNBC) via a recently identified molecular target, intercellular adhesion molecule-1 (ICAM-1). This ICAM-1-targeted, Lcn2 siRNA- encapsulating liposome (ICAM-Lcn2-LP) binds human TNBC MDA-MB-231cells significantly stronger than non-neoplastic MCF-10A cells. Efficient Lcn2 knockdown by ICAM-Lcn2-LPs led to a significant reduction in the production of vascular endothelial growth factor (VEGF) from MDA-MB-231 cells, which, in turn, led to reduced angiogenesis both in vitro and in vivo. Angiogenesis (neovascularization) is a requirement for solid tumor growth and progression, and its inhibition is an important therapeutic strategy for human cancers. Our results indicate that a tumor-specific strategy such as the TNBC-targeted, anti-angiogenic therapeutic approach developed here, may be clinically useful in inhibiting TNBC progression. PMID:26722369

  11. Phenylboronic acid-sugar grafted polymer architecture as a dual stimuli-responsive gene carrier for targeted anti-angiogenic tumor therapy.

    PubMed

    Kim, Jinhwan; Lee, Yeong Mi; Kim, Hyunwoo; Park, Dongsik; Kim, Jihoon; Kim, Won Jong

    2016-01-01

    We present a cationic polymer architecture composed of phenylboronic acid (PBA), sugar-installed polyethylenimine (PEI), and polyethylene glycol (PEG). The chemical bonding of PBA with the diol in the sugar enabled the crosslinking of low-molecular-weight (MW) PEI to form high-MW PEI, resulting in strong interaction with anionic DNA for gene delivery. Inside the cell, the binding of PBA and sugar was disrupted by either acidic endosomal pH or intracellular ATP, so gene payloads were released effectively. This dual stimuli-responsive gene release drove the polymer to deliver DNA for high transfection efficiency with low cytotoxicity. In addition, PBA moiety with PEGylation facilitated the binding of polymer/DNA polyplexes to sialylated glycoprotein which is overexpressed on the tumor cell membrane, and thus provided high tumor targeting ability. Therapeutic application of our polymer was demonstrated as an anti-angiogenic gene delivery agent for tumor growth inhibition. Our judicious designed polymer structure based on PBA provides enormous potential as a gene delivery agent for effective gene therapy by stimuli-responsiveness and tumor targeting.

  12. Combining antiangiogenic therapy with neoadjuvant chemotherapy increases treatment efficacy in stage IIIA (N2) non-small cell lung cancer without increasing adverse effects

    PubMed Central

    Zhao, Xiaoliang; Su, Yanjun; You, Jian; Gong, Liqun; Zhang, Zhenfa; Wang, Meng; Zhao, Zhenqing; Zhang, Zhen; Li, Xiaolin; Wang, Changli

    2016-01-01

    To evaluate the safety and efficacy of combining Endostar antiangiogenic therapy with neoadjuvant chemotherapy for the treatment of stage IIIA (N2) NSCLC, we conducted a randomized, controlled, open-label clinical study of 30 NSCLC patients. Patients were randomly assigned to the test or control groups, which received either two cycles of an NP neoadjuvant chemotherapy regimen combined with Endostar or the NP regimen alone, respectively, at a 2:1 ratio. Efficacy was assessed after 3 weeks, and surgical resection occurred within 4 weeks, in the 26 patients who successfully completed treatment. While total response rates (RR) and clinical benefit rates (CBR) did not differ between the experimental groups, total tumor regression rates (TRR) were higher in the test group than in the control group. Median DFS and OS also did not differ between the test and control groups. Clinical perioperative indicators, including intraoperative blood loss, number of dissected lymph node groups, duration of postoperative indwelling catheter use, and time to postoperative discharge, were comparable in the test and control groups. Finally, hematological and non-hematological toxicities and postoperative pathological indicators, including down-staging ratio, complete resection ratio, and metastatic lymph node ratio, also did not differ between the groups. Overall, combining Endostar with NP neoadjuvant chemotherapy increased therapeutic efficacy without increasing adverse effects in stage IIIA-N2 NSCLC patients. This study is registered with ClinicalTrials.gov (number NCT02497118). PMID:27566586

  13. Rapamycin/DiR loaded lipid-polyaniline nanoparticles for dual-modal imaging guided enhanced photothermal and antiangiogenic combination therapy.

    PubMed

    Wang, Jinping; Guo, Fang; Yu, Meng; Liu, Li; Tan, Fengping; Yan, Ran; Li, Nan

    2016-09-10

    Imaging-guided photothermal therapy (PTT) has promising application for treating tumors. Nevertheless, so far imaging-guided photothermal drug-delivery systems have been developed with limited success for tumor chemo-photothermal therapy. In this study, as the proof-of-concept, a stimuli-responsive tumor-targeting rapamycin/DiR loaded lipid-polyaniline nanoparticle (RDLPNP) for dual-modal imaging-guided enhanced PTT efficacy is reported for the first time. In this system, polyaniline (PANI) with π-π electronic conjugated system and effective photothermal efficiency is chosen as the appropriate model receptor of fluorescence resonance energy transfer (FRET), and loaded cyanine probe (e.g., 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyanine iodide, DiR) acts as the donor of near-infrared fluorescence (NIRF). In addition, rapamycin (RAPA), which is used as the antiangiogenesis chemotherapeutic drug, can cutdown the tumor vessels and delay tumor growth obviously. After intravenous treatment of RDLPNPs into Hela tumor bearing mice, fluorescent (from DiR) and enhanced photoacoustic (from DLPNPs) signals were found in tumor site over time, which reached to peak at the 6h time point. After irradiating with an NIR laser, a good anti-tumor effect was observed owing to the enhanced photothermal and antiangiogenic effect of RDLPNPs. These results show that the multifunctional nanoparticle can be used as a promising imaging-guided photothermal drug delivery nanoplatform for cancer therapy.

  14. In vitro and in vivo antiangiogenic activity of a novel deca-peptide derived from human tissue-type plasminogen activator kringle 2

    SciTech Connect

    Su, Li; Xu, Xun; Zhao, Hui; Gu, Qing; Zou, Haidong

    2010-06-11

    A synthetic deca-peptide corresponding to the amino acid sequence Arg{sup 54}-Trp{sup 63} of human tissue-type plasminogen activator (t-PA) kringle 2 domain, named TKII-10, is produced and tested for its ability to inhibit endothelial cell proliferation, migration, tube formation in vitro, and angiogenesis in vivo. At the same time, another peptide TKII-10S composed of the same 10 amino acids as TKII-10, but in a different sequence, is also produced and tested. The results show that TKII-10 potently inhibits VEGF-stimulated endothelial cell migration and tube formation in a dose-dependent, as well as sequence-dependent, manner in vitro while it is inactive in inhibiting endothelial cell proliferation. Furthermore, TKII-10 potently inhibits angiogenesis in chick chorioallantoic membrane and mouse cornea. The middle four amino acids DGDA in their sequence play an important role in TKII-10 angiogenesis inhibition{sub .} These results suggest that TKII-10 is a novel angiogenesis inhibitor that may serve as a prototype for antiangiogenic drug development.

  15. A new anti-angiogenic small molecule, G0811, inhibits angiogenesis via targeting hypoxia inducible factor (HIF)-1α signal transduction

    SciTech Connect

    Kim, Ki Hyun; Jung, Hye Jin; Kwon, Ho Jeong

    2013-11-15

    Highlights: •G0811 suppresses HIF-1α expression without cell toxicity. •G0811 exhibits anti-angiogenic activity both in vitro and in vivo. •G0811 provides a new molecular scaffold for the development of therapeutics targeting angiogenesis. -- Abstract: Regulation of hypoxia inducible factor (HIF)-1α stabilization, which in turn contributes to adaptation of tumor cells to hypoxia has been highlighted as a promising therapeutic target in angiogenesis-related diseases. We have identified a new small molecule, G0811, as a potent angiogenesis inhibitor that targets HIF-1α signal transduction. G0811 suppressed HIF-1α stability in cancer cells and inhibited in vitro and in vivo angiogenesis, as validated by tube formation, chemoinvasion, and chorioallantoic membrane (CAM) assays. In addition, G0811 effectively decreased the expression of vascular endothelial growth factor (VEGF), which is one of target genes of HIF-1α. However, G0811 did not exhibit anti-proliferative activities or toxicity in human umbilical vein endothelial cells (HUVECs) at effective doses. These results demonstrate that G0811 could be a new angiogenesis inhibitor that acts by targeting HIF-1α signal transduction pathway.

  16. Combination antiangiogenic therapy in advanced breast cancer: a phase 1 trial of vandetanib, a VEGFR inhibitor, and metronomic chemotherapy, with correlative platelet proteomics.

    PubMed

    Mayer, Erica L; Isakoff, Steven J; Klement, Giannoula; Downing, Sean R; Chen, Wendy Y; Hannagan, Keri; Gelman, Rebecca; Winer, Eric P; Burstein, Harold J

    2012-11-01

    This phase 1 study evaluated the safety and tolerability of antiangiogenic therapy using vandetanib and metronomic cyclophosphamide and methotrexate in metastatic breast cancer. Eligible patients had metastatic breast cancer with 0-4 prior chemotherapy regimens. All received cyclophosphamide 50 mg daily, methotrexate 2.5 mg days 1-2 weekly, and vandetanib daily in 3 dose-escalation cohorts: 100 mg (C1), 200 mg (C2), and 300 mg (C3). The primary endpoint was safety and tolerability; secondary endpoints included response rate and evaluation of platelet-associated proteins. Twenty three patients were treated and evaluable for toxicity. Common mild toxicities included nausea, vomiting, LFTs abnormalities, fatigue, and rash. Three episodes of dose-limiting toxicity occurred in C3. In all cohorts, 1/3 of patients required vandetanib dose reduction, and 22 % ended therapy for toxicity. Of the 20 response-evaluable patients, 10 % demonstrated partial response and 15 % stable disease ≥24 weeks. Proteomic analyses demonstrated changes in platelet content of angiogenesis regulators, including vascular endothelial growth factor and platelet factor 4, with exposure to therapy. This regimen was tolerable at a maximum vandetanib dose of 200 mg; modest clinical activity was observed in this heavily pretreated population. Changes in the platelet proteome may serve as pharmacodynamic markers of angiogenesis inhibition. Metronomic chemotherapy is an attractive partner with biologics and deserves further study in metastatic breast cancer.

  17. Dual blockade of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) exhibits potent anti-angiogenic effects.

    PubMed

    Li, Dong; Xie, Kun; Zhang, Longzhen; Yao, Xuejing; Li, Hongwen; Xu, Qiaoyu; Wang, Xin; Jiang, Jing; Fang, Jianmin

    2016-07-28

    Both vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF or FGF-2) are potent pro-angiogenic factors and play a critical role in cancer development and progression. Clinical anti-VEGF therapy trials had a major challenge due to upregulated expression of other pro-angiogenic factor, like FGF-2. This study developed a novel chimeric decoy receptor VF-Trap fusion protein to simultaneously block activity of both VEGF and FGF pathways in order to achieve an additive or synergistic anti-tumor effect. Our in vitro data showed that VF-Trap potently blocked proliferation and migration of both VEGF- and FGF-2-induced vascular endothelial cells. In animal models, treatment of xenograft tumors with VF-Trap resulted in significant inhibition of tumor growth compared to blockage of the single molecule, like VEGF or FGF blocker. In addition, VF-Trap was also more potent in inhibition of ocular angiogenesis in a mouse oxygen-induced retinopathy (OIR) model. These data demonstrated the potent anti-angiogenic effects of this novel VF-Trap fusion protein on blockage of VEGF and FGF-2 activity in vitro and in animal models. Further study will assess its effects in clinic as a therapeutic agent for angiogenesis-related disorders, such as cancer and ocular vascular diseases.

  18. Anti-tumoral, anti-angiogenic and anti-metastatic efficacy of a tetravalent bispecific antibody (TAvi6) targeting VEGF-A and angiopoietin-2

    PubMed Central

    Scheuer, Werner; Thomas, Markus; Hanke, Petra; Sam, Johannes; Osl, Franz; Weininger, Diana; Baehner, Monika; Seeber, Stefan; Kettenberger, Hubert; Schanzer, Jürgen; Brinkmann, Ulrich; Weidner, K. Michael; Regula, Jörg; Klein, Christian

    2016-01-01

    ABSTRACT Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer. PMID:26864324

  19. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells.

    PubMed

    Liu, Ran-Yi; Zhou, Ling; Zhang, Yan-Ling; Huang, Bi-Jun; Ke, Miao-la; Chen, Jie-Min; Li, Li-Xia; Fu, Xiang; Wu, Jiang-Xue; Huang, Wenlin

    2013-12-13

    A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  20. XAFS Model Compound Library

    DOE Data Explorer

    Newville, Matthew

    The XAFS Model Compound Library contains XAFS data on model compounds. The term "model" compounds refers to compounds of homogeneous and well-known crystallographic or molecular structure. Each data file in this library has an associated atoms.inp file that can be converted to a feff.inp file using the program ATOMS. (See the related Searchable Atoms.inp Archive at http://cars9.uchicago.edu/~newville/adb/) This Library exists because XAFS data on model compounds is useful for several reasons, including comparing to unknown data for "fingerprinting" and testing calculations and analysis methods. The collection here is currently limited, but is growing. The focus to date has been on inorganic compounds and minerals of interest to the geochemical community. [Copied, with editing, from http://cars9.uchicago.edu/~newville/ModelLib/

  1. Preparation of uranium compounds

    DOEpatents

    Kiplinger, Jaqueline L; Montreal, Marisa J; Thomson, Robert K; Cantat, Thibault; Travia, Nicholas E

    2013-02-19

    UI.sub.3(1,4-dioxane).sub.1.5 and UI.sub.4(1,4-dioxane).sub.2, were synthesized in high yield by reacting turnings of elemental uranium with iodine dissolved in 1,4-dioxane under mild conditions. These molecular compounds of uranium are thermally stable and excellent precursor materials for synthesizing other molecular compounds of uranium including alkoxide, amide, organometallic, and halide compounds.

  2. Nitrodifluoraminoterphenyl compounds and processes

    DOEpatents

    Lerom, M.W.; Peters, H.M.

    1975-07-08

    This patent relates to the nitrodifluoraminoterphenyl compounds: 3,3''-bis (difluoramino)-2,2'' 4,4', 4'',6,6',6''-octanitro-m-terphenyl (DDONT) and 3,3''-bis(difluoramino)-2,2',2''4,4',4'',6,6',6''-nonanitro-m-terphenyl (DDNONA). Procedures are described wherein diamino precursors of the indicated compounds are prepared and the final compounds are obtained by a fluorination operation. The compounds are highly energetic and suitable for use as explosives and particularly in exploding bridge wire (EBW) detonators. (auth)

  3. The anti-angiogenic agent fumagillin covalently modifies a conserved active-site histidine in the Escherichia coli methionine aminopeptidase

    PubMed Central

    Lowther, W. Todd; McMillen, Debra A.; Orville, Allen M.; Matthews, Brian W.

    1998-01-01

    Methionine aminopeptidase (MetAP) exists in two forms (type I and type II), both of which remove the N-terminal methionine from proteins. It previously has been shown that the type II enzyme is the molecular target of fumagillin and ovalicin, two epoxide-containing natural products that inhibit angiogenesis and suppress tumor growth. By using mass spectrometry, N-terminal sequence analysis, and electronic absorption spectroscopy we show that fumagillin and ovalicin covalently modify a conserved histidine residue in the active site of the MetAP from Escherichia coli, a type I enzyme. Because all of the key active site residues are conserved, it is likely that a similar modification occurs in the type II enzymes. This modification, by occluding the active site, may prevent the action of MetAP on proteins or peptides involved in angiogenesis. In addition, the results suggest that these compounds may be effective pharmacological agents against pathogenic and resistant forms of E. coli and other microorganisms. PMID:9770455

  4. The antiangiogenic effects of polyisoprenylated cysteinyl amide inhibitors in HUVEC, chick embryo and zebrafish is dependent on the polyisoprenyl moiety

    PubMed Central

    Nkembo, Augustine T.; Ntantie, Elizabeth; Salako, Olufisayo O.; Amissah, Felix; Poku, Rosemary A.; Latinwo, Lekan M.; Lamango, Nazarius S.

    2016-01-01

    Angiogenesis is essential for solid tumor growth, therapeutic resistance and metastasis, the latest accounting for 90% of cancer deaths. Although angiogenesis is essential for the malignant transformations in solid tumors and therefore is an attractive target, few drugs are available that block tumor angiogenesis. The focus has been to block signaling by receptor tyrosine kinases (RTKs), such as for vascular endothelial growth factor (VEGF), whose activation abrogate apoptosis and promote angiogenesis. The polyisoprenylated cysteinyl amide inhibitors (PCAIs) were designed to modulate aberrant polyisoprenylated small G-proteins such as mutant Ras whose constitutive activation promotes RTKs signaling. Since polyisoprenylation is essential for protein-protein interactions and functions of G-proteins, we hypothesized that the PCAIs would disrupt the monomeric G-protein signaling thereby effectively inhibiting angiogenesis. In this study we determined the effects of PCAIs on human umbilical vein endothelial cells (HUVEC) tube formation, cell viability, cell migration and invasion as well as in vivo using the chick chorioallantoic membrane (CAM) and zebrafish models. At sub- to low micromolar concentrations, the PCAIs inhibit the native and VEGF-stimulated cell migration and invasion as well as tube formation and angiogenesis in CAM and zebrafish embryos. The concentrations that block the angiogenic processes were lower than those that induce cell death. Since angiogenesis is essential for tumor growth but otherwise limited to wound healing, feeding fat cells and uterine wall repair in adults, it is conceivable that these compounds can be developed into safer therapeutics for cancers and retinal neovascularization that leads to loss of vision. PMID:27626690

  5. Water-Exchange-Modified Kinetic Parameters from Dynamic Contrast-Enhanced MRI as Prognostic Biomarkers of Survival in Advanced Hepatocellular Carcinoma Treated with Antiangiogenic Monotherapy

    PubMed Central

    Lee, Sang Ho; Hayano, Koichi; Zhu, Andrew X.; Sahani, Dushyant V.; Yoshida, Hiroyuki

    2015-01-01

    Background To find prognostic biomarkers in pretreatment dynamic contrast-enhanced MRI (DCE-MRI) water-exchange-modified (WX) kinetic parameters for advanced hepatocellular carcinoma (HCC) treated with antiangiogenic monotherapy. Methods Twenty patients with advanced HCC underwent DCE-MRI and were subsequently treated with sunitinib. Pretreatment DCE-MRI data on advanced HCC were analyzed using five different WX kinetic models: the Tofts-Kety (WX-TK), extended TK (WX-ETK), two compartment exchange, adiabatic approximation to tissue homogeneity (WX-AATH), and distributed parameter (WX-DP) models. The total hepatic blood flow, arterial flow fraction (γ), arterial blood flow (BFA), portal blood flow, blood volume, mean transit time, permeability-surface area product, fractional interstitial volume (vI), extraction fraction, mean intracellular water molecule lifetime (τC), and fractional intracellular volume (vC) were calculated. After receiver operating characteristic analysis with leave-one-out cross-validation, individual parameters for each model were assessed in terms of 1-year-survival (1YS) discrimination using Kaplan-Meier analysis, and association with overall survival (OS) using univariate Cox regression analysis with permutation testing. Results The WX-TK-model-derived γ (P = 0.022) and vI (P = 0.010), and WX-ETK-model-derived τC (P = 0.023) and vC (P = 0.042) were statistically significant prognostic biomarkers for 1YS. Increase in the WX-DP-model-derived BFA (P = 0.025) and decrease in the WX-TK, WX-ETK, WX-AATH, and WX-DP-model-derived vC (P = 0.034, P = 0.038, P = 0.028, P = 0.041, respectively) were significantly associated with an increase in OS. Conclusions The WX-ETK-model-derived vC was an effective prognostic biomarker for advanced HCC treated with sunitinib. PMID:26366997

  6. A dual-targeting PDGFRβ/VEGF-A molecule assembled from stable antibody fragments demonstrates anti-angiogenic activity in vitro and in vivo

    PubMed Central

    Gilbertson, Debra G; Frank, Amanda; Vu, Tuyen; Ardourel, Dan; Ostrander, Craig; Stevens, Brenda; Julien, Susan; Franke, Secil; Meengs, Brent; Brody, Jennifer; Presnell, Scott; Hamacher, Nels B; Lantry, Megan; Wolf, Anitra; Bukowski, Tom; Rosler, Robert; Yen, Cindy; Anderson-Haley, Monica; Brasel, Kenneth; Pan, Qi; Franklin, Hank; Thompson, Penny; Dodds, Mike; Underwood, Sara; Peterson, Scott; Sivakumar, Pallavur V; Snavely, Mark

    2010-01-01

    Targeting angiogenesis is a promising approach to the treatment of solid tumors and age-related macular degeneration (AMD). Inhibition of vascularization has been validated by the successful marketing of monoclonal antibodies (mAbs) that target specific growth factors or their receptors, but there is considerable room for improvement in existing therapies. Combination of mAbs targeting both the VeGF and pDGF pathways has the potential to increase the efficacy of anti-angiogenic therapy without the accompanying toxicities of tyrosine kinase inhibitors and the inability to combine efficiently with traditional chemotherapeutics. However, development costs and regulatory issues have limited the use of combinatorial approaches for the generation of more efficacious treatments. The concept of mediating disease pathology by targeting two antigens with one therapeutic was proposed over two decades ago. While mAbs are particularly suitable candidates for a dual-targeting approach, engineering bispecificity into one molecule can be difficult due to issues with expression and stability, which play a significant role in manufacturability. Here, we address these issues upstream in the process of developing a bispecific antibody (bsAb). Single-chain antibody fragments (scFvs) targeting pDGFRβ and VeGF-A were selected for superior stability. the scFvs were fused to both termini of human Fc to generate a bispecific, tetravalent molecule. resulting molecule displays potent activity, binds both targets simultaneously, and is stable in serum. assembly of a bsAb using stable monomeric units allowed development of an anti-pDGFRB/VeGF-A antibody capable of attenuating angiogenesis through two distinct pathways and represents an efficient method for rapid engineering of dual-targeting molecules. PMID:20065654

  7. HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr{sup −/−} mice

    SciTech Connect

    Kim, Junghyun; Kim, Chan-Sik; Jo, Kyuhyung; Cho, Yun-Seok; Kim, Hyun-Gyu; Lee, Geun-Hyeog; Lee, Yun Mi; Sohn, Eunjin; Kim, Jin Sook

    2015-01-02

    Highlights: • HL-217 is a new synthetic topical anti-angiogenic agent. • HL-217 attenuated subretinal neovascularization in Vldlr{sup −/−} mice. • HL-217 blocked the binding of PDGF-BB to PDGFRβ. - Abstract: HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr{sup −/−}) mice. In three-week-old male Vldlr{sup −/−} mice, HL-217 (1.5 or 3 mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRβ interaction was evaluated in vitro. The neovascular area in the Vldlr{sup −/−} mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRβ interaction (IC{sub 50} = 38.9 ± 0.7 μM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB.

  8. Dynamic Contrast Enhanced MRI Assessing the Antiangiogenic Effect of Silencing HIF-1α with Targeted Multifunctional ECO/siRNA Nanoparticles.

    PubMed

    Malamas, Anthony S; Jin, Erlei; Gujrati, Maneesh; Lu, Zheng-Rong

    2016-07-05

    Stabilization of hypoxia inducible factor 1α (HIF-1α), a biomarker of hypoxia, in hypoxic tumors mediates a variety of downstream genes promoting tumor angiogenesis and cancer cell survival as well as invasion, and compromising therapeutic outcome. In this study, dynamic contrast enhanced MRI (DCE-MRI) with a biodegradable macromolecular MRI contrast agent was used to noninvasively assess the antiangiogenic effect of RGD-targeted multifunctional lipid ECO/siHIF-1α nanoparticles in a mouse HT29 colon cancer model. The RGD-targeted ECO/siHIF-1α nanoparticles resulted in over 50% reduction in tumor size after intravenous injection at a dose of 2.0 mg of siRNA/kg every 3 days for 3 weeks compared to a saline control. DCE-MRI revealed significant decline in vascularity and over a 70% reduction in the tumor blood flow, permeability-surface area product, and plasma volume fraction vascular parameters in the tumor treated with the targeted ECO/siHIF-1α nanoparticles. The treatment with targeted ECO/siRNA nanoparticles resulted in significant silencing of HIF-1α expression at the protein level, which also significantly suppressed the expression of VEGF, Glut-1, HKII, PDK-1, LDHA, and CAIX, which are all important players in tumor angiogenesis, glycolytic metabolism, and pH regulation. By possessing the ability to elicit a multifaceted effect on tumor biology, silencing HIF-1α with RGD-targeted ECO/siHIF-1α nanoparticles has great promise as a single therapy or in combination with traditional chemotherapy or radiation strategies to improve cancer treatment.

  9. Comprehensive Evaluation of the Anti-Angiogenic and Anti-Neoplastic Effects of Endostar on Liver Cancer through Optical Molecular Imaging

    PubMed Central

    Xue, Zhenwen; Chi, Chongwei; Jia, Xiaohua; Tian, Jie

    2014-01-01

    Molecular imaging enables non-invasive monitoring of tumor growth, progression, and drug treatment response, and it has become an important tool to promote biological studies in recent years. In this study, we comprehensively evaluated the in vivo anti-angiogenic and anti-neoplastic effects of Endostar on liver cancer based on the optical molecular imaging systems including micro-computer tomography (Micro-CT), bioluminescence molecular imaging (BLI) and fluorescence molecular tomography (FMT). Firefly luciferase (fLuc) and green fluorescent protein (GFP) dual labeled human hepatocellular carcinoma cells (HCC-LM3-fLuc-GFP cells) were used to establish the subcutaneous and orthotopic liver tumor model. After the tumor cells were implanted 14∼18 days, Endostar (5 mg/kg/day) was administered through an intravenous tail vein injection for continuous 14 days. The computer tomography angiography (CTA) and BLI were carried out for the subcutaneous tumor model. FMT was executed for the orthotopic tumor model. The CTA data showed that tumor vessel formation and the peritumoral vasculature of subcutaneous tumor in the Endostar treatment group was significantly inhibited compared to the control group. The BLI data exhibited the obvious tumor inhibition day 8 post-treatment. The FMT detected the tumor suppression effects of Endostar as early as day 4 post-treatment and measured the tumor location. The above data confirmed the effects of Endostar on anti-angiogenesis and tumor suppression on liver cancer. Our system combined CTA, BLI, and FMT to offer more comprehensive information about the effects of Endostar on the suppression of vessel and tumor formation. Optical molecular imaging system enabled the non-invasive and reliable assessment of anti-tumor drug efficacy on liver cancer. PMID:24416426

  10. RNAi-mediated gene knockdown and anti-angiogenic therapy of RCCs using a cyclic RGD-modified liposomal-siRNA system.

    PubMed

    Sakurai, Yu; Hatakeyama, Hiroto; Sato, Yusuke; Hyodo, Mamoru; Akita, Hidetaka; Ohga, Noritaka; Hida, Kyoko; Harashima, Hideyoshi

    2014-01-10

    Angiogenesis is one of crucial processes associated with tumor growth and development, and consequently a prime target for cancer therapy. Although tumor endothelial cells (TECs) play a key role in pathological angiogenesis, investigating phenotypical changes in neovessels when a gene expression in TEC is suppressed is a difficult task. Small interfering RNA (siRNA) represents a potential agent due to its ability to silence a gene of interest. We previously developed a system for in vivo siRNA delivery to cancer cells that involves a liposomal-delivery system, a MEND that contains a unique pH-sensitive cationic lipid, YSK05 (YSK-MEND). In the present study, we report on the development of a system that permits the delivery of siRNA to TECs by combining the YSK-MEND and a ligand that is specific to TECs. Cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) is a well-known ligand to αVβ3 integrin, which is selectively expressed at high levels in TECs. We incorporated cRGD into the YSK-MEND (RGD-MEND) to achieve an efficient gene silencing in TECs. Quantitative RT-PCR and the 5' rapid amplification of cDNA ends PCR indicated that the intravenous injection of RGD-MEND at a dose of 4.0mg/kg induced a significant RNAi-mediated gene reduction in TEC but not in endothelial cells of other organs. Finally, we evaluated the therapeutic potency of the RGD-MEND encapsulating siRNA against vascular endothelial growth factor receptor 2. A substantial delay in tumor growth was observed after three sequential RGD-MEND injections on alternate days. In conclusion, the RGD-MEND represents a new approach for the characterization of TECs and for us in anti-angiogenic therapy.

  11. Anti-angiogenic and anti-cancer evaluation of betulin nanoemulsion in chicken chorioallantoic membrane and skin carcinoma in Balb/c mice.

    PubMed

    Dehelean, Cristina A; Feflea, Stefana; Gheorgheosu, Dorina; Ganta, Srinivas; Cimpean, Anca M; Muntean, Danina; Amiji, Mansoor M

    2013-04-01

    Betulin (Bet), the main component of birch tree bark, has been recently reported to exert anticancer activity in several cell lines; however the underlying mechanisms are only partially elucidated. The aims of the present work were to assess the in vivo effects of betulin administered as nanoemulsion (NE) in two experimental models: (i) the chicken embryo chorioallantoic membrane (CAM) assay for the study of anti-angiogenic effects and (ii) the two-stage model of skin carcinoma induced in mice for the study of anti-tumor and anti-inflammatory effects, respectively. On the CAM of the chicken betulin in nanoemulsion (BetNE) shows a good penetrability at extra-embryonic tissue level, affecting both the chorioallantoic membrane as well as the yolk sac by reducing the capillary density. In the animal model, the potential impact of local application of betulin on the respiratory function of isolated liver mitochondria was further assessed. Topical application of betulin nanoemulsion for 12 weeks together with DMBA (7,12-dimethylbenz[a]anthracene) and TPA (12-O-tetradecanoylphorbol 13-acetate), as tumor initiator and promoter, enhanced the active respiration of isolated liver mitochondria. Betulin also inhibit skin tumor apparition and promotion, proved by histological results and VEGF (vascular endothelial growth factor) expression correlated to non-invasive measurements. Betulin is active in nanoemulsion formulation as a potential inhibitory on the angiogenic process in CAM assay. BetNE can develop a potent anti-inflammatory and anti-carcinogenic activity with a low toxicity at skin level. It can also influence the penetration of carcinogens and reduce damage in main organs (e.g., liver).

  12. The effect of anti-angiogenic agents on overall survival in metastatic oesophago-gastric cancer: A systematic review and meta-analysis

    PubMed Central

    Sjoquist, Katrin M.; Goldstein, David; Price, Timothy J.; Martin, Andrew J.; Bang, Yung-Jue; Kang, Yoon-Koo; Pavlakis, Nick

    2017-01-01

    Background Studies of anti-angiogenic agents (AAs), combined with chemotherapy (chemo) or as monotherapy in metastatic oesophago-gastric cancer (mOGC), have reported mixed outcomes. We undertook systematic review and meta-analysis to determine their overall benefits and harms. Methods Randomized controlled trials in mOGC were sought investigating the addition of AAs to standard therapy (best supportive care or chemo). The primary endpoint was overall survival (OS) with secondary endpoints progression-free survival (PFS), overall response rate (ORR) and toxicity. Estimates of treatment effect from individual trials were combined using standard techniques. Subgroup analyses were performed by line of therapy, region, age, performance status, histological type, number of metastatic sites, primary site, mechanism of action and HER2 status. Results Fifteen trials evaluating 3502 patients were included in quantitative analysis. The addition of AAs was associated with improved OS: HR 0·81 (95% CI 0·75–0·88, p<0·00001) and improved PFS: HR 0·68 (95% CI 0·63–0·74, p<0·00001). Subgroup analyses favoured greater benefit for OS in 2nd/3rd line settings (HR 0·74) compared to 1st-line settings (HR 0·91) (X2 = 6·00, p = 0·01). OS benefit was seen across all regions—Asia (HR 0·83) and rest of world (HR 0·75)—without significant subgroup interaction. Results from 8 trials evaluating 2602 patients were pooled for toxicity > = Grade 3: with OR 1·39 (95% CI 1·17–1·65). Conclusions The addition of AAs to standard therapy in mOGC improves OS. Improved efficacy was only observed in 2nd- or 3rd-line setting and not in 1st-line setting. Consistent OS benefit was present across all geographical regions. This benefit is at the expense of increased overall toxicity. PMID:28222158

  13. Continuous administration of bevacizumab plus capecitabine, even after acquired resistance to bevacizumab, restored anti-angiogenic and antitumor effect in a human colorectal cancer xenograft model

    PubMed Central

    Iwai, Toshiki; Sugimoto, Masamichi; Harada, Suguru; Yorozu, Keigo; Kurasawa, Mitsue; Yamamoto, Kaname

    2016-01-01

    Vascular endothelial growth factor (VEGF)-neutralizing therapy with bevacizumab has become increasingly important for treating colorectal cancer. It was demonstrated that second-line chemotherapy together with bevacizumab after disease progression (PD) on first-line therapy including bevacizumab showed clinical benefits in metastatic colorectal and breast cancers (ML18147 trial, TANIA trial). One of the rationales for these trials was that the refractoriness to first-line therapy is caused by resistance to not so much bevacizumab as to the chemotherapeutic agents. Nevertheless, resistance to bevacizumab cannot be ruled out because VEGF-independent angiogenesis has been reported to be a mechanism of resistance to anti-VEGF therapy. In this study, we used a xenograft model with the human colon cancer HT-29 cells to investigate the mechanisms underlying the effect of continued administration of bevacizumab plus capecitabine even after resistance to bevacizumab was acquired. The combination of capecitabine plus bevacizumab exhibited significantly stronger antitumor and anti-angiogenic activities than did monotherapy with either agent. Capecitabine treatment significantly increased the intratumoral VEGF level compared with the control group; however, the combination with bevacizumab neutralized the VEGF. Among angiogenic factors other than VEGF, intratumoral galectin-3, which reportedly promotes angiogenesis both dependent on, and independently of VEGF, was significantly decreased in the capecitabine group and the combination group compared with the control group. In an in vitro experiment, 5-fluorouracil (5-FU), an active metabolite of capecitabine, inhibited galectin-3 production by HT-29 cells. These results suggested that capecitabine has a dual mode of action: namely, inhibition of tumor cell growth and inhibition of galectin-3 production by tumor cells. Thus, capecitabine and bevacizumab may work in a mutually complementary manner in tumor angiogenesis inhibition

  14. An oncolytic adenovirus enhances antiangiogenic and antitumoral effects of a replication-deficient adenovirus encoding endostatin by rescuing its selective replication in nasopharyngeal carcinoma cells

    SciTech Connect

    Liu, Ran-yi; Zhou, Ling; Zhang, Yan-ling; Huang, Bi-jun; Ke, Miao-la; Chen, Jie-min; Li, Li-xia; Fu, Xiang; Wu, Jiang-xue; Huang, Wenlin

    2013-12-13

    Highlights: •H101 promotes endostatin expression by Ad-Endo via rescuing Ad-Endo replication. •H101 rescued Ad-Endo replication by supplying E1A and E1B19k proteins. •Ad-Endo enhanced the cytotoxicity of H101 in NPC cells. •Ad-Endo and oncolytic Ad H101 have synergistic antitumor effects on NPC. -- Abstract: A replication-deficient adenovirus (Ad) encoding secreted human endostatin (Ad-Endo) has been demonstrated to have promising antiangiogenic and antitumoral effects. The E1B55k-deleted Ad H101 can selectively lyse cancer cells. In this study, we explored the antitumor effects and cross-interactions of Ad-Endo and H101 on nasopharyngeal carcinoma (NPC). The results showed that H101 dramatically promoted endostatin expression by Ad-Endo via rescuing Ad-Endo replication in NPC cells, and the expressed endostatin proteins significantly inhibited the proliferation of human umbilical vein endothelial cells. E1A and E1B19k products are required for the rescuing of H101 to Ad-Endo replication in CNE-1 and CNE-2 cells, but not in C666-1 cells. On the other hand, Ad-Endo enhanced the cytotoxicity of H101 by enhancing Ad replication in NPC cells. The combination of H101 and Ad-Endo significantly inhibited CNE-2 xenografts growth through the increased endostatin expression and Ad replication. These findings indicate that the combination of Ad-Endo gene therapy and oncolytic Ad therapeutics could be promising in comprehensive treatment of NPC.

  15. Volatile Organic Compounds (VOCs)

    MedlinePlus

    ... United States Environmental Protection Agency Search Search Indoor Air Quality (IAQ) Share Facebook Twitter Google+ Pinterest Contact Us Volatile Organic Compounds' Impact on Indoor Air Quality On this page: Introduction Sources Health Effects Levels ...

  16. Heart testing compound

    DOEpatents

    Knapp, Jr., Furn F.; Goodman, Mark M.

    1985-01-01

    The compound 15-(p-[.sup.125 I]-iodophenyl)-6-tellurapentadecanoic acid is disclosed as a myocardial imaging agent having rapid and pronounced uptake, prolonged myocardial retention, and low in vivo deiodination.

  17. [Laboratory of Biopolymer Compounds].

    PubMed

    Ostapchuk, A M

    2008-01-01

    General information is presented concerning the Laboratory of Biological Polymeric Compounds at the Institute of Microbiology and Virology of the National Academy of Sciences of Ukraine; equipment, analytical and biophysical methods applied in the laboratory are listed.

  18. Heart testing compound

    DOEpatents

    Knapp, F.F. Jr.; Goodman, M.M.

    1983-06-29

    The compound 15-(p-(/sup 125/I)-iodophenyl)-6-tellurapentadecanoic acid is disclosed as a myocardial imaging agent having rapid and pronounced uptake, prolonged myocardial retention, and low in vivo deiodination.

  19. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation

    SciTech Connect

    Lamy, Sylvie Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R.

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention. - Highlights: • We investigated five compounds contained in extra virgin olive oil on angiogenesis. • Hydroxytyrosol, taxifolin and oleic acid are the best angiogenesis inhibitors. • Olive oil compounds affect endothelial cell functions essential for

  20. Chemistry of peroxide compounds

    NASA Technical Reports Server (NTRS)

    Volnov, I. I.

    1981-01-01

    The history of Soviet research from 1866 to 1967 on peroxide compounds is reviewed. This research dealt mainly with peroxide kinetics, reactivity and characteristics, peroxide production processes, and more recently with superoxides and ozonides and emphasis on the higher oxides of group 1 and 2 elements. Solid state fluidized bed synthesis and production of high purity products based on the relative solubilities of the initial, intermediate, and final compounds and elements in liquid ammonia are discussed.

  1. Compound composite odontoma

    PubMed Central

    Girish, G; Bavle, Radhika M; Singh, Manish Kumar; Prasad, Sahana N

    2016-01-01

    The term odontoma has been used as a descriptor for any tumor of odontogenic origin. It is a growth in which both epithelial and mesenchymal cells exhibits complete differentiation. Odontomas are considered as hamartomas rather than true neoplasm. They are usually discovered on routine radiographic examination. Odontomas, according to the World Health Organization, are classified into complex odontoma and compound odontomas. The present paper reports a case of compound composite odontomas. PMID:27194882

  2. Compound composite odontoma.

    PubMed

    Girish, G; Bavle, Radhika M; Singh, Manish Kumar; Prasad, Sahana N

    2016-01-01

    The term odontoma has been used as a descriptor for any tumor of odontogenic origin. It is a growth in which both epithelial and mesenchymal cells exhibits complete differentiation. Odontomas are considered as hamartomas rather than true neoplasm. They are usually discovered on routine radiographic examination. Odontomas, according to the World Health Organization, are classified into complex odontoma and compound odontomas. The present paper reports a case of compound composite odontomas.

  3. Antiangiogenic effects of indole-3-carbinol and 3,3'-diindolylmethane are associated with their differential regulation of ERK1/2 and Akt in tube-forming HUVEC.

    PubMed

    Kunimasa, Kazuhiro; Kobayashi, Tomomi; Kaji, Kazuhiko; Ohta, Toshiro

    2010-01-01

    We previously reported that indole-3-carbinol (I3C), found in cruciferous vegetables, suppresses angiogenesis in vivo and in vitro. However, the underlying molecular mechanisms still remain unclear. Antiangiogenic effects of its major metabolite, 3,3'-diindolylmethane (DIM), also have not been fully elucidated. In this study, we investigated the effects of these indoles on angiogenesis and tested a hypothesis that I3C and DIM inhibit angiogenesis and induce apoptosis by affecting angiogenic signal transduction in human umbilical vein endothelial cells (HUVEC). We found that I3C and DIM at 25 micromol/L significantly inhibited tube formation and only DIM induced a significant increase in apoptosis in tube-forming HUVEC. DIM showed a stronger antiangiogenic activity than I3C. At the molecular level, I3C and DIM markedly inactivated extracellular signal-regulated kinase 1/2 (ERK1/2) and the inhibitory effect of DIM was significantly greater than that of I3C. DIM treatment also resulted in activation of the caspase pathway and inactivation of Akt, whereas I3C did not affect them. These results indicate that I3C and DIM had a differential potential in the regulation of the 2 principal survival signals, ERK1/2 and Akt, in endothelial cells. We also demonstrated that pharmacological inhibition of ERK1/2 and/or Akt was enough to inhibit tube formation and induce caspase-dependent apoptosis in tube-forming HUVEC. We conclude that both I3C and DIM inhibit angiogenesis at least in part via inactivation of ERK1/2 and that inactivation of Akt by DIM is responsible for its stronger antiangiogenic effects than those of I3C.

  4. Phenolic Molding Compounds

    NASA Astrophysics Data System (ADS)

    Koizumi, Koji; Charles, Ted; de Keyser, Hendrik

    Phenolic Molding Compounds continue to exhibit well balanced properties such as heat resistance, chemical resistance, dimensional stability, and creep resistance. They are widely applied in electrical, appliance, small engine, commutator, and automotive applications. As the focus of the automotive industry is weight reduction for greater fuel efficiency, phenolic molding compounds become appealing alternatives to metals. Current market volumes and trends, formulation components and its impact on properties, and a review of common manufacturing methods are presented. Molding processes as well as unique advanced techniques such as high temperature molding, live sprue, and injection/compression technique provide additional benefits in improving the performance characterisitics of phenolic molding compounds. Of special interest are descriptions of some of the latest innovations in automotive components, such as the phenolic intake manifold and valve block for dual clutch transmissions. The chapter also characterizes the most recent developments in new materials, including long glass phenolic molding compounds and carbon fiber reinforced phenolic molding compounds exhibiting a 10-20-fold increase in Charpy impact strength when compared to short fiber filled materials. The role of fatigue testing and fatigue fracture behavior presents some insight into long-term reliability and durability of glass-filled phenolic molding compounds. A section on new technology outlines the important factors to consider in modeling phenolic parts by finite element analysis and flow simulation.

  5. Biodegradation of nitroaromatic compounds.

    PubMed

    Spain, J C

    1995-01-01

    Nitroaromatic compounds are released into the biosphere almost exclusively from anthropogenic sources. Some compounds are produced by incomplete combustion of fossil fuels; others are used as synthetic intermediates, dyes, pesticides, and explosives. Recent research revealed a number of microbial systems capable of transforming or biodegrading nitroaromatic compounds. Anaerobic bacteria can reduce the nitro group via nitroso and hydroxylamino intermediates to the corresponding amines. Isolates of Desulfovibrio spp. can use nitroaromatic compounds as their source of nitrogen. They can also reduce 2,4,6-trinitrotoluene to 2,4,6-triaminotoluene. Several strains of Clostridium can catalyze a similar reduction and also seem to be able to degrade the molecule to small aliphatic acids. Anaerobic systems have been demonstrated to destroy munitions and pesticides in soil. Fungi can extensively degrade or mineralize a variety of nitroaromatic compounds. For example, Phanerochaete chrysosporium mineralizes 2,4-dinitrotoluene and 2,4,6-trinitrotoluene and shows promise as the basis for bioremediation strategies. The anaerobic bacteria and the fungi mentioned above mostly transform nitroaromatic compounds via fortuitous reactions. In contrast, a number of nitroaromatic compounds can serve as growth substrates for aerobic bacteria. Removal or productive metabolism of nitro groups can be accomplished by four different strategies. (a) Some bacteria can reduce the aromatic ring of dinitro and trinitro compounds by the addition of a hydride ion to form a hydride-Meisenheimer complex, which subsequently rearomatizes with the elimination of nitrite. (b) Monooxygenase enzymes can add a single oxygen atom and eliminate the nitro group from nitrophenols. (c) Dioxygenase enzymes can insert two hydroxyl groups into the aromatic ring and precipitate the spontaneous elimination of the nitro group from a variety of nitroaromatic compounds. (d) Reduction of the nitro group to the corresponding

  6. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation.

    PubMed

    Lamy, Sylvie; Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention.

  7. Sulfur compounds in coal

    NASA Technical Reports Server (NTRS)

    Attar, A.; Corcoran, W. H.

    1977-01-01

    The literature on the chemical structure of the organic sulfur compounds (or functional groups) in coal is reviewed. Four methods were applied in the literature to study the sulfur compounds in coal: direct spectrometric and chemical analysis, depolymerization in drastic conditions, depolymerization in mild conditions, and studies on simulated coal. The data suggest that most of the organic sulfur in coal is in the form of thiophenic structures and aromatic and aliphatic sulfides. The relative abundance of the sulfur groups in bituminous coal is estimated as 50:30:20%, respectively. The ratio changes during processing and during the chemical analysis. The main effects are the transformation during processing of sulfides to the more stable thiophenic compounds and the elimination of hydrogen sulfide.

  8. Compound management beyond efficiency.

    PubMed

    Burr, Ian; Winchester, Toby; Keighley, Wilma; Sewing, Andreas

    2009-06-01

    Codeveloping alongside chemistry and in vitro screening, compound management was one of the first areas in research recognizing the need for efficient processes and workflows. Material management groups have centralized, automated, miniaturized and, importantly, found out what not to do with compounds. While driving down cost and improving quality in storage and processing, researchers still face the challenge of interfacing optimally with changing business processes, in screening groups, and with external vendors and focusing on biologicals in many companies. Here we review our strategy to provide a seamless link between compound acquisition and screening operations and the impact of material management on quality of the downstream processes. Although this is driven in part by new technologies and improved quality control within material management, redefining team structures and roles also drives job satisfaction and motivation in our teams with a subsequent positive impact on cycle times and customer feedback.

  9. Metalloid compounds as drugs

    PubMed Central

    Sekhon, B. S.

    2013-01-01

    The six elements commonly known as metalloids are boron, silicon, germanium, arsenic, antimony, and tellurium. Metalloid containing compounds have been used as antiprotozoal drugs. Boron-based drugs, the benzoxaboroles have been exploited as potential treatments for neglected tropical diseases. Arsenic has been used as a medicinal agent and arsphenamine was the main drug used to treat syphilis. Arsenic trioxide has been approved for the treatment of acute promyelocytic leukemia. Pentavalent antimonials have been the recommended drug for visceral leishmaniasis and cutaneous leishmaniasis. Tellurium (IV) compounds may have important roles in thiol redox biological activity in the human body, and ammonium trichloro (dioxoethylene-O, O’-)tellurate (AS101) may be a promising agent for the treatment of Parkinson’s disease. Organosilicon compounds have been shown to be effective in vitro multidrug-resistance reverting agents. PMID:24019824

  10. Organic compounds in meteorites

    NASA Technical Reports Server (NTRS)

    Anders, E.; Hayatsu, R.; Studier, M. H.

    1973-01-01

    The problem of whether organic compounds originated in meteorites as a primary condensate from a solar gas or whether they were introduced as a secondary product into the meteorite during its residence in a parent body is examined by initially attempting to reconstruct the physical conditions during condensation (temperature, pressure, time) from clues in the inorganic matrix of the meteorite. The condensation behavior of carbon under these conditions is then analyzed on the basis of thermodynamic calculations, and compounds synthesized in model experiments on the condensation of carbon are compared with those actually found in meteorites. Organic compounds in meteorites seem to have formed by catalytic reactions of carbon monoxide, hydrogen, and ammonia in the solar nebula at 360 to 400 K temperature and about 3 to 7.6 microtorr pressure. The onset of these reactions was triggered by the formation of suitable catalysts (magnetite, hydrated silicates) at these temperatures.

  11. Fluoroalkylation of organic compounds

    NASA Astrophysics Data System (ADS)

    Mikhaylov, D. Yu; Budnikova, Yu H.

    2013-09-01

    Data on fluoroalkylation and perfluoroalkylation methods in organic synthesis are analyzed, summarized and described systematically. The most practically important properties of compounds with fluoroalkyl substituents are illustrated. The key trends and the potential of this field of organic chemistry are considered. Electrochemical syntheses of perfluoroalkyl derivatives that are inaccessible or experimentally difficult to prepare by regular chemical techniques are presented. Particular attention is paid to processes involving organometallic compounds as well as to prospects for the development of this field of research. The bibliography includes 226 references.

  12. Microoptical compound lens

    DOEpatents

    Sweatt, William C.; Gill, David D.

    2007-10-23

    An apposition microoptical compound lens comprises a plurality of lenslets arrayed around a segment of a hollow, three-dimensional optical shell. The lenslets collect light from an object and focus the light rays onto the concentric, curved front surface of a coherent fiber bundle. The fiber bundle transports the light rays to a planar detector, forming a plurality of sub-images that can be reconstructed as a full image. The microoptical compound lens can have a small size (millimeters), wide field of view (up to 180.degree.), and adequate resolution for object recognition and tracking.

  13. Effects of cordycepin on HepG2 and EA.hy926 cells: Potential antiproliferative, antimetastatic and anti-angiogenic effects on hepatocellular carcinoma.

    PubMed

    Lu, Haisheng; Li, Xiting; Zhang, Jianying; Shi, Hui; Zhu, Xiaofeng; He, Xiaoshun

    2014-05-01

    Hepatocellular carcinoma (HCC) is a hypervascular tumor and accumulating evidence suggests that angiogenesis plays an important role in HCC development. Cordycepin, also known as 3'-deoxyadenosine, is a derivative of adenosine, and numerous cellular enzymes cannot differentiate the two. The aim of the present study was to determine whether cordycepin regulates proliferation, migration and angiogenesis in a human umbilical vein endothelial cell line (EA.hy926) and in a hepatocellular carcinoma cell line (HepG2). MTT was used to assess cell proliferation. Apoptosis was analyzed by flow cytometry (propidium iodide staining). Transwell and wound healing assays were used to analyze the migration and invasion of HepG2 and EA.hy926 cells. Angiogenesis in EA.hy926 cells was assessed using a tube formation assay. Cordycepin strongly suppressed HepG2 and EA.hy926 cell proliferation in a dose- and time-dependent manner. Cordycepin induced EA.hy926 cell apoptosis in a dose-dependent manner (2,000 μg/ml: 50.20±1.55% vs. 0 μg/ml: 2.62±0.19%; P<0.01). Cordycepin inhibited EA.hy926 cell migration (percentage of wound healing area, 2,000 μg/ml: 3.45±0.29% vs. 0 μg/ml: 85.48±0.84%; P<0.05), as well as tube formation (total length of tubular structure, 1,000 μg/ml: 107±39 μm vs. 0 μg/ml: 936±56 μm; P<0.05). Cordycepin also efficiently inhibited HepG2 cell invasion and migration. High-performance liquid chromatography analysis of the cytosol from EA.hy926 cells showed that cordycepin was stable for 3 h. In conclusion, cordycepin not only inhibited human HepG2 cell proliferation and invasion, but also induced apoptosis and inhibited migration and angiogenesis in vascular endothelial cells, suggesting that cordycepin may be used as a novel anti-angiogenic therapy in HCC.

  14. Phytochemical screening of Artemisia arborescens L. by means of advanced chromatographic techniques for identification of health-promoting compounds.

    PubMed

    Costa, Rosaria; Ragusa, Salvatore; Russo, Marina; Certo, Giovanna; Franchina, Flavio A; Zanotto, Antonio; Grasso, Elisa; Mondello, Luigi; Germanò, Maria Paola

    2016-01-05

    Artemisia arborescens, also known as tree wormwood, is a typical species of the Mediterranean flora. It has been used in folk medicine for its antispasmodic, anti-pyretic, anti-inflammatory, and abortifacient properties. In the current study, the application of multidimensional comprehensive gas chromatography (GC×GC), allowed to obtain a detailed fingerprint of the essential oil from A. arborescens aerial parts, highlighting an abundant presence of chamazulene followed by camphor, β-thujone, myrcene, and α-pinene. Moreover, flavonoids in the dichloromethane extract were analyzed by means of liquid chromatography with photodiode array and atmospheric pressure chemical ionization-mass spectrometry detections (HPLC-PDA and HPLC-APCI-MS). Six polymethoxyflavones were identified and three of them, including chrysosplenetin, eupatin, and cirsilineol, were described in this species for the first time. The anti-angiogenic activity was investigated in the dichloromethane extract by two in vivo models, chick chorioallantoic membrane (CAM) and zebrafish embryos. Results showed that this extract produced a strong reduction on vessel formation, both on zebrafish (57% of inhibition, 0.1 mg/mL) and chick chorioallantoic membrane (58% of inhibition, 0.8 mg/mL). The high separation power and sensitivity of the analytical methodology applied confirmed the safety of A. arborescens essential oil for human consumption, due to the very low level of the psychotrope α-thujone determined. Moreover, the knowledge of the flavonoidic profile holds a great significance for the use of A. arborescens as a valuable source of anti-angiogenic compounds that might contribute to the valorization of the phytotherapeutic potential of this plant.

  15. Aminopropyl thiophene compounds

    DOEpatents

    Goodman, Mark M.; Knapp, Jr., Furn F.

    1990-01-01

    Radiopharmaceuticals useful in brain imaging comprising radiohalogenated thienylethylamine derivatives. The compounds are 5-halo-thiophene-2-isopropyl amines able to cross the blood-brain barrier and be retained for a sufficient length of time to allow the evaluation of regional blood flow by radioimaging of the brain.

  16. PERSISTENT PERFLUORINATED ORGANIC COMPOUNDS

    EPA Science Inventory

    Perfluorinated compounds (PFCs) have gained notoriety in the recent past. Global distribution of PFCs in wildlife, environmental samples and humans has sparked a recent increase in new investigations concerning PFCs. Historically PFCs have been used in a wide variety of consume...

  17. Compound floating pivot micromechanisms

    DOEpatents

    Garcia, Ernest J.

    2001-04-24

    A new class of tilting micromechanical mechanisms have been developed. These new mechanisms use compound floating pivot structures to attain far greater tilt angles than are practical using other micromechanical techniques. The new mechanisms are also capable of bi-directional tilt about multiple axes.

  18. Selenium and Compounds

    Integrated Risk Information System (IRIS)

    Selenium and Compounds ; CASRN 7782 - 49 - 2 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for Noncarcin

  19. Boron and Compounds

    Integrated Risk Information System (IRIS)

    EPA 635 / 04 / 052 www.epa.gov / iris TOXICOLOGICAL REVIEW OF BORON AND COMPOUNDS ( CAS No . 7440 - 42 - 8 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) June 2004 U.S . Environmental Protection Agency Washington , DC DISCLAIMER This document has been reviewed

  20. Zinc and Compounds

    Integrated Risk Information System (IRIS)

    EPA / 635 / R - 05 / 002 TOXICOLOGICAL REVIEW OF ZINC AND COMPOUNDS ( CAS No . 7440 - 66 - 6 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) July 2005 U.S . Environmental Protection Agency Washington D.C . DISCLAIMER This document has been reviewed in accordanc

  1. 8-fluoropurine compounds

    SciTech Connect

    Barrio, Jorge R.; Satyamurthy, Nagichettiar; Namavari, Mohammad; Phelps, Michael E.

    2001-01-01

    An efficient, regiocontrolled approach to the synthesis of 8-fluoropurines by direct fluorination of purines with dilute elemental fluorine, or acetyl hypofluorite, is provided. In a preferred embodiment, a purine compound is dissolved in a polar solvent and reacted with a dilute mixture of F.sub.2 in He or other inert gas.

  2. Barium and Compounds

    Integrated Risk Information System (IRIS)

    EPA / 635 / R - 05 / 001 www.epa.gov / iris TOXICOLOGICAL REVIEW OF BARIUM AND COMPOUNDS ( CAS No . 7440 - 39 - 3 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) March 1998 Minor revisions January 1999 Reference dose revised June 2005 U.S . Environmental Protec

  3. Beryllium and compounds

    Integrated Risk Information System (IRIS)

    EPA / 635 / R - 98 / 008 TOXICOLOGICAL REVIEW OF BERYLLIUM AND COMPOUNDS ( CAS No . 7440 - 41 - 7 ) In Support of Summary Information on the Integrated Risk Information System ( IRIS ) April 1998 U.S . Environmental Protection Agency Washington , DC DISCLAIMER This document has been reviewed in acco

  4. Urinary Compounds in Autism

    ERIC Educational Resources Information Center

    Alcorn, A.; Berney, T.; Bretherton, K.; Mills, M.; Savery, D.; Shattock, P.

    2004-01-01

    Although earlier claims to identify specific compounds in the urine of people with autism had been discredited, it was subsequently suggested that there might be biochemical characteristics that were specific to early childhood, particularly in those who also did not have a severe degree of intellectual disability This study was to establish…

  5. Lead and compounds (inorganic)

    Integrated Risk Information System (IRIS)

    Lead and compounds ( inorganic ) ; CASRN 7439 - 92 - 1 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Assessments for

  6. Fun with Ionic Compounds

    ERIC Educational Resources Information Center

    Logerwell, Mollianne G.; Sterling, Donna R.

    2007-01-01

    Ionic bonding is a fundamental topic in high school chemistry, yet it continues to be a concept that students struggle to understand. Even if they understand atomic structure and ion formation, it can be difficult for students to visualize how ions fit together to form compounds. This article describes several engaging activities that help…

  7. Toxicity of dipyridyl compounds and related compounds.

    PubMed

    Li, Shenggang; Crooks, Peter A; Wei, Xiaochen; de Leon, Jose

    2004-01-01

    Five dipyridyl isomers, 2,2'-, 2,3'-, 2,4'-, 3,3'-, and 4,4'-dipyridyl, are products resulting from the pyrolytic degradation of tobacco products and degradation of the herbicide paraquat, and therefore may be present in the environment. In this article, the toxicological properties of these dipyridyl isomers in humans and animals are reviewed. Epidemiological studies suggest that cancerous skin lesions in workers involved in the manufacturing of paraquat may be associated with exposure to dipyridyl compounds. Experimental animal studies suggest that dipyridyl isomers may have several toxicological effects. Three of the dipyridyl isomers (the 2,2', 2,4', and 4,4' isomers) appear to be inducers of some metabolic enzymes. The 2,2'-dipyridyl isomer, an iron chelator, appears to influence vasospasm in primate models of stroke. The cytotoxic effects of 2,2'-dipyridyl on several leukemia cell lines have been reported, and a potent teratogenic effect of 2,2'-dipyridyl has been observed in rats. Based on the results of paraquat studies in experimental animal models, it has been proposed that paraquat may have deleterious effects on dopaminergic neurons. These findings support the epidemiological evidence that paraquat exposure may be associated with the development of Parkinson's disease. Studies designed to determine an association between paraquat exposure and Parkinson's disease are complicated by the possibility that metabolic changes may influence the neurotoxicity of paraquat and/or its metabolites. Preliminary unpublished data in mice show that 300-mg/kg doses of 2,2'-dipyridyl are neurotoxic, and 300-mg/kg doses of 2,4'- and 4,4'-dipyridyls are lethal. These results are consistent with earlier studies in Sherman rats using high 2,2'- and 4,4'-dipyridyl doses. New studies are needed to further explore the toxicological properties of dipyridyls and their potential public health impact.

  8. Organic compounds in meteorites

    NASA Technical Reports Server (NTRS)

    Lawless, J. G.

    1980-01-01

    Recent studies of carbonaceous chondrites provide evidence that certain organic compounds are indigenous and the result of an abiotic, chemical synthesis. The results of several investigators have established the presence of amino acids and precursors, mono- and dicarboxylic acids, N-heterocycles, and hydrocarbons as well as other compounds. For example, studies of the Murchison and Murray meteorites have revealed the presence of at least 40 amino acids with nearly equal abundances of D and L isomers. The population consists of both protein and nonprotein amino acids including a wide variety of linear, cyclic, and polyfunctional types. Results show a trend of decreasing concentration with increasing carbon number, with the most abundant being glycine (41 n Moles/g). These and other results to be reviewed provide persuasive support for the theory of chemical evolution and provide the only natural evidence for the protobiological subset of molecules from which life on earth may have arisen.

  9. Oral compound nevus.

    PubMed

    Cardoso, Lyzete Berriel; Consalaro, Alberto; da Silva Santos, Paulo Sérgio; da Silva Sampieri, Marcelo Bonifácio; Tinoco-Araújo, José Endrigo

    2014-02-18

    The melanocytic nevus is a benign and focal proliferation of nevus cells that can be congenital or acquired. Intraoral lesions are uncommon, and the etiology and pathogenesis are poorly understood. The occurrence rate of oral compound nevus is about 5.9% to 16.5% of all oral melanocytic nevi. A 22-year-old male patient presented with a dark brown macule on the buccal mucosa of the maxilla in the region of tooth 26. The lesion was elliptical, 0.7 x 0.5 cm, well circumscribed, asymptomatic, and the evolution time was unknown. An excisional biopsy was performed and microscopic analysis revealed nests of nevus cells in the epithelium and underlying connective tissue that were compatible with melanocytic compound nevus. Owing to the clinical similarity between oral melanocytic nevus and oral melanoma, a histopathological analysis is mandatory for definitive diagnosis.

  10. Antifungal compounds from cyanobacteria.

    PubMed

    Shishido, Tânia K; Humisto, Anu; Jokela, Jouni; Liu, Liwei; Wahlsten, Matti; Tamrakar, Anisha; Fewer, David P; Permi, Perttu; Andreote, Ana P D; Fiore, Marli F; Sivonen, Kaarina

    2015-04-13

    Cyanobacteria are photosynthetic prokaryotes found in a range of environments. They are infamous for the production of toxins, as well as bioactive compounds, which exhibit anticancer, antimicrobial and protease inhibition activities. Cyanobacteria produce a broad range of antifungals belonging to structural classes, such as peptides, polyketides and alkaloids. Here, we tested cyanobacteria from a wide variety of environments for antifungal activity. The potent antifungal macrolide scytophycin was detected in Anabaena sp. HAN21/1, Anabaena cf. cylindrica PH133, Nostoc sp. HAN11/1 and Scytonema sp. HAN3/2. To our knowledge, this is the first description of Anabaena strains that produce scytophycins. We detected antifungal glycolipopeptide hassallidin production in Anabaena spp. BIR JV1 and HAN7/1 and in Nostoc spp. 6sf Calc and CENA 219. These strains were isolated from brackish and freshwater samples collected in Brazil, the Czech Republic and Finland. In addition, three cyanobacterial strains, Fischerella sp. CENA 298, Scytonema hofmanni PCC 7110 and Nostoc sp. N107.3, produced unidentified antifungal compounds that warrant further characterization. Interestingly, all of the strains shown to produce antifungal compounds in this study belong to Nostocales or Stigonematales cyanobacterial orders.

  11. Toxicity of platinum compounds.

    PubMed

    Hartmann, Jörg Thomas; Lipp, Hans-Peter

    2003-06-01

    Since the introduction of platinum-based combination chemotherapy, particularly cisplatin, the outcome of the treatment of many solid tumours has changed. The leading platinum compounds in cancer chemotherapy are cisplatin, carboplatin and oxaliplatin. They share some structural similarities; however, there are marked differences between them in therapeutic use, pharmacokinetics and adverse effects profiles [1-4]. Compared to cisplatin, carboplatin has inferior efficacy in germ-cell tumour, head and neck cancer and bladder and oesophageal carcinoma, whereas both drugs seem to have comparable efficacy in advanced non-small cell and small cell lung cancer as well as ovarian cancer [5-7]. Oxaliplatin belongs to the group of diaminocyclohexane platinum compounds. It is the first platinum-based drug that has marked efficacy in colorectal cancer when given in combination with 5-fluorouracil and folinic acid [8,9]. Other platinum compounds such as oral JM216, ZD0473, BBR3464 and SPI-77, which is a pegylated liposomal formulation of cisplatin, are still under investigation [10-13], whereas nedaplatin has been approved in Japan for the treatment of non-small cell lung cancer and other solid tumours. This review focuses on cisplatin, carboplatin and oxaliplatin.

  12. Toxic compounds in honey.

    PubMed

    Islam, Md Nazmul; Khalil, Md Ibrahim; Islam, Md Asiful; Gan, Siew Hua

    2014-07-01

    There is a wealth of information about the nutritional and medicinal properties of honey. However, honey may contain compounds that may lead to toxicity. A compound not naturally present in honey, named 5-hydroxymethylfurfural (HMF), may be formed during the heating or preservation processes of honey. HMF has gained much interest, as it is commonly detected in honey samples, especially samples that have been stored for a long time. HMF is a compound that may be mutagenic, carcinogenic and cytotoxic. It has also been reported that honey can be contaminated with heavy metals such as lead, arsenic, mercury and cadmium. Honey produced from the nectar of Rhododendron ponticum contains alkaloids that can be poisonous to humans, while honey collected from Andromeda flowers contains grayanotoxins, which can cause paralysis of limbs in humans and eventually leads to death. In addition, Melicope ternata and Coriaria arborea from New Zealand produce toxic honey that can be fatal. There are reports that honey is not safe to be consumed when it is collected from Datura plants (from Mexico and Hungary), belladonna flowers and Hyoscamus niger plants (from Hungary), Serjania lethalis (from Brazil), Gelsemium sempervirens (from the American Southwest), Kalmia latifolia, Tripetalia paniculata and Ledum palustre. Although the symptoms of poisoning due to honey consumption may differ depending on the source of toxins, most common symptoms generally include dizziness, nausea, vomiting, convulsions, headache, palpitations or even death. It has been suggested that honey should not be considered a completely safe food.

  13. Compound chondrules fused cold

    NASA Astrophysics Data System (ADS)

    Hubbard, Alexander

    2015-07-01

    About 4-5% of chondrules are compound: two separate chondrules stuck together. This is commonly believed to be the result of the two component chondrules having collided shortly after forming, while still molten. This allows high velocity impacts to result in sticking. However, at T ∼ 1100 K, the temperature below which chondrules collide as solids (and hence usually bounce), coalescence times for droplets of appropriate composition are measured in tens of seconds. Even at 1025 K, at which temperature theory predicts that the chondrules must have collided extremely slowly to have stuck together, the coalescence time scale is still less than an hour. These coalescence time scales are too short for the collision of molten chondrules to explain the observed frequency of compound chondrules. We suggest instead a scenario where chondrules stuck together in slow collisions while fully solid; and the resulting chondrule pair was subsequently briefly heated to a temperature in the range of 900-1025 K. In that temperature window the coalescence time is finite but long, covering a span of hours to a decade. This is particularly interesting because those temperatures are precisely the critical window for thermally ionized MRI activity, so compound chondrules provide a possible probe into that vital regime.

  14. Compound cycle engine program

    NASA Technical Reports Server (NTRS)

    Bobula, G. A.; Wintucky, W. T.; Castor, J. G.

    1986-01-01

    The Compound Cycle Engine (CCE) is a highly turbocharged, power compounded power plant which combines the lightweight pressure rise capability of a gas turbine with the high efficiency of a diesel. When optimized for a rotorcraft, the CCE will reduce fuel burned for a typical 2 hr (plus 30 min reserve) mission by 30 to 40 percent when compared to a conventional advanced technology gas turbine. The CCE can provide a 50 percent increase in range-payload product on this mission. A program to establish the technology base for a Compound Cycle Engine is presented. The goal of this program is to research and develop those technologies which are barriers to demonstrating a multicylinder diesel core in the early 1990's. The major activity underway is a three-phased contract with the Garrett Turbine Engine Company to perform: (1) a light helicopter feasibility study, (2) component technology development, and (3) lubricant and material research and development. Other related activities are also presented.

  15. Medical benefits of using natural compounds and their derivatives having multiple pharmacological actions.

    PubMed

    Kimura, Ikuko

    2006-03-01

    The multiple pharmacological actions of a unique compound are a prerequisite for classifying drugs as highly efficacious, because the multiple pharmacological actions offer the possibility of treating various symptoms of chronic diseases as described below. 1) Sustained hyperglycemia induces macrovascular and microvascular complications in type 2 diabetes mellitus. Antihyperglycemic medication and the control of postprandial hyperglycemia are essentially important for normalizing plasma glucose level. Gymnemic acid IV isolated from Gymnema sylvestre (Asclepiadaceae) leaves has antisweet, antihyperglycemic, glucose uptake inhibitory, and gut glycosidase inhibitory effects. Most of these pharmacological effects may synergistically contribute to alleviating type 2 diabetes-related symptoms. 2) Diabetic skeletal and vascular smooth muscles are hypersensitive to chemical transmitters, cytokines and autacoids. The sensitivity of neuromuscular synapses is enhanced in diabetes, which seems to be closely associated with neuropathy as one of the diabetic complications. beta-Eudesmol found in Atractylodes lancea rhizome has a desensitizing channel blocking action to nicotinic acetylcholine receptors, anti-angiogenic action in vascular endothelium, and neuronal differentiation actions. These multiple pharmacological actions are favorable for treating angiogenic diseases possibly including the complications of diabetes, namely, retinopathy and nephropathy, and cancer. 3) Nipradilol is clinically utilized as a topical antiglaucoma drug. The ocular hypotensive effects of this compound are brought about by its alpha1 and beta-adrenergic receptor blocking actions, and nitric oxide (NO) releasing action. NO directly activates cyclooxygenases. All these pharmacologic effects are beneficial for treating glaucoma. The selectivity and specificity of drug action are required for treating acute diseases, infections or for acting as useful reagents. The pleiotropic actions of natural

  16. Offset Compound Gear Drive

    NASA Technical Reports Server (NTRS)

    Stevens, Mark A.; Handschuh, Robert F.; Lewicki, David G.

    2010-01-01

    The Offset Compound Gear Drive is an in-line, discrete, two-speed device utilizing a special offset compound gear that has both an internal tooth configuration on the input end and external tooth configuration on the output end, thus allowing it to mesh in series, simultaneously, with both a smaller external tooth input gear and a larger internal tooth output gear. This unique geometry and offset axis permits the compound gear to mesh with the smaller diameter input gear and the larger diameter output gear, both of which are on the same central, or primary, centerline. This configuration results in a compact in-line reduction gear set consisting of fewer gears and bearings than a conventional planetary gear train. Switching between the two output ratios is accomplished through a main control clutch and sprag. Power flow to the above is transmitted through concentric power paths. Low-speed operation is accomplished in two meshes. For the purpose of illustrating the low-speed output operation, the following example pitch diameters are given. A 5.0 pitch diameter (PD) input gear to 7.50 PD (internal tooth) intermediate gear (0.667 reduction mesh), and a 7.50 PD (external tooth) intermediate gear to a 10.00 PD output gear (0.750 reduction mesh). Note that it is not required that the intermediate gears on the offset axis be of the same diameter. For this example, the resultant low-speed ratio is 2:1 (output speed = 0.500; product of stage one 0.667 reduction and stage two 0.750 stage reduction). The design is not restricted to the example pitch diameters, or output ratio. From the output gear, power is transmitted through a hollow drive shaft, which, in turn, drives a sprag during which time the main clutch is disengaged.

  17. Neurotoxicity of organomercurial compounds.

    PubMed

    Sanfeliu, Coral; Sebastià, Jordi; Cristòfol, Rosa; Rodríguez-Farré, Eduard

    2003-01-01

    Mercury is a ubiquitous contaminant, and a range of chemical species is generated by human activity and natural environmental change. Elemental mercury and its inorganic and organic compounds have different toxic properties, but all them are considered hazardous in human exposure. In an equimolecular exposure basis, organomercurials with a short aliphatic chain are the most harmful compounds and they may cause irreversible damage to the nervous system. Methylmercury (CH(3)Hg(+)) is the most studied following the neurotoxic outbreaks identified as Minamata disease and the Iraq poisoning. The first description of the CNS pathology dates from 1954. Since then, the clinical neurology, the neuropathology and the mechanisms of neurotoxicity of organomercurials have been widely studied. The high thiol reactivity of CH(3)Hg(+), as well as all mercury compounds, has been suggested to be the basis of their harmful biological effects. However, there is clear selectivity of CH(3)Hg(+) for specific cell types and brain structures, which is not yet fully understood. The main mechanisms involved are inhibition of protein synthesis, microtubule disruption, increase of intracellular Ca(2+) with disturbance of neurotransmitter function, oxidative stress and triggering of excitotoxicity mechanisms. The effects are more damaging during CNS development, leading to alterations of the structure and functionality of the nervous system. The major source of CH(3)Hg(+) exposure is the consumption of fish and, therefore, its intake is practically unavoidable. The present concern is on the study of the effects of low level exposure to CH(3)Hg(+) on human neurodevelopment, with a view to establishing a safe daily intake. Recommendations are 0.4 micro g/kg body weight/day by the WHO and US FDA and, recently, 0.1 micro g/kg body weight/day by the US EPA. Unfortunately, these levels are easily attained with few meals of fish per week, depending on the source of the fish and its position in the

  18. Oligosilanylated Antimony Compounds

    PubMed Central

    2015-01-01

    By reactions of magnesium oligosilanides with SbCl3, a number of oligosilanylated antimony compounds were obtained. When oligosilanyl dianions were used, either the expected cyclic disilylated halostibine was obtained or alternatively the formation of a distibine was observed. Deliberate formation of the distibine from the disilylated halostibine was achieved by reductive coupling with C8K. Computational studies of Sb–Sb bond energies, barriers of pyramidal inversion at Sb, and the conformational behavior of distibines provided insight for the understanding of the spectroscopic properties. PMID:25937691

  19. Superconductivity in plutonium compounds

    NASA Astrophysics Data System (ADS)

    Sarrao, J. L.; Bauer, E. D.; Mitchell, J. N.; Tobash, P. H.; Thompson, J. D.

    2015-07-01

    Although the family of plutonium-based superconductors is relatively small, consisting of four compounds all of which crystallize in the tetragonal HoCoGa5 structure, these materials serve as an important bridge between the known Ce- and U-based heavy fermion superconductors and the high-temperature cuprate superconductors. Further, the partial localization of 5f electrons that characterizes the novel electronic properties of elemental plutonium appears to be central to the relatively high superconducting transition temperatures that are observed in PuCoGa5, PuRhGa5, PuCoIn5, and PuRhIn5.

  20. Titanium alkoxide compound

    DOEpatents

    Boyle, Timothy J.

    2007-08-14

    A titanium alkoxide composition is provided, as represented by the chemical formula (OC.sub.6H.sub.5N).sub.2Ti(OC.sub.6H.sub.5NH.sub.2).sub.2. As prepared, the compound is a crystalline substance with a hexavalent titanium atom bonded to two OC.sub.6H.sub.5NH.sub.2 groups and two OC.sub.6H.sub.5N groups with a theoretical molecular weight of 480.38, comprising 60.01% C, 5.04% H and 11.66% N.

  1. Immunomodulating compounds in Basidiomycetes

    PubMed Central

    Mizuno, Masashi; Nishitani, Yosuke

    2013-01-01

    Mushrooms are distinguished as important food containing immunomodulating and anticancer agents. These compounds belong mostly to polysaccharides especially β-d-glucans. Among them, β-1,3-glucan with side chain β-1,6-glucose residues have more important roles in immunomodulating and antitumor activities. In this review, we have introduced polysaccharide mainly from Lentinula edodes and Agaricus blazei Murill with immunomodulating and antitumor activities. In addition, the mechanism of activation of immune response and signal cascade are also reviewed. PMID:23704809

  2. Boronated porphyrin compounds

    DOEpatents

    Kahl, Stephen B.; Koo, Myoung-Seo

    1992-01-01

    A compound is described having the structure ##STR1## where R preferably is ##STR2## and most preferably R.sup.3 is a closo-carborane and R.sup.2 is --H, an alkyl or aryl having 1 to about 7 carbon atoms, This invention was made with Government support under NIH Grant No. CA-37961 awarded by the Department of Health and Human Services and under the Associated Universities Inc. Contract No. De-AC02-76CH00016 with the U.S. Department of Energy. The Government has rights in this invention.

  3. Boronated porphyrin compounds

    DOEpatents

    Kahl, S.B.; Koo, M.S.

    1992-09-22

    A compound is described having the structure ##STR1## where R preferably is ##STR2## and most preferably R.sup.3 is a closo-carborane and R.sup.2 is --H, an alkyl or aryl having 1 to about 7 carbon atoms, This invention was made with Government support under NIH Grant No. CA-37961 awarded by the Department of Health and Human Services and under the Associated Universities Inc. Contract No. De-AC02-76CH00016 with the U.S. Department of Energy. The Government has rights in this invention.

  4. Color Classification of Coordination Compounds.

    ERIC Educational Resources Information Center

    Poncini, Laurence; Wimmer, Franz L.

    1987-01-01

    Proposes that colored compounds be classified by reference to a standard color-order system incorporating a color dictionary. Argues that the colors of new compounds could be incorporated into the characterization process and into computer storage systems. (TW)

  5. Special Risks of Pharmacy Compounding

    MedlinePlus

    ... Consumer Updates RSS Feed The Special Risks of Pharmacy Compounding Get Consumer Updates by E-mail Consumer ... page: A Troubling Trend What You Can Do Pharmacy compounding is a practice in which a licensed ...

  6. FLUOROCARBON N-F COMPOUNDS

    DTIC Science & Technology

    FLUORIDES, *FLUORINATED HYDROCARBONS, ALKYL RADICALS, CARBOXYLIC ACIDS, CATALYSTS , CESIUM COMPOUNDS, CHEMICAL EQUILIBRIUM, IMIDES, IMINES, MOLECULAR...STRUCTURE, NITRILES, NUCLEAR MAGNETIC RESONANCE, PROPENES, REACTION KINETICS, SUBSTITUTION REACTIONS , SULFUR COMPOUNDS, SYNTHESIS.

  7. Design, Synthesis, in Vitro, and in Vivo Anticancer and Antiangiogenic Activity of Novel 3-Arylaminobenzofuran Derivatives Targeting the Colchicine Site on Tubulin

    PubMed Central

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Prencipe, Filippo; Lopez-Cara, Carlota; Ortega, Santiago Schiaffino; Brancale, Andrea; Hamel, Ernest; Castagliuolo, Ignazio; Mitola, Stefania; Ronca, Roberto; Bortolozzi, Roberta; Porcù, Elena; Basso, Giuseppe; Viola, Giampietro

    2015-01-01

    A new series of compounds characterized by the presence of a 2-methoxy/ethoxycarbonyl group, combined with either no substituent or a methoxy group at each of the four possible positions of the benzene portion of the 3-(3′,4′,5′-trimethoxyanilino)benzo[b]furan skeleton, were evaluated for antiproliferative activity against cancer cells in culture and, for selected, highly active compounds, inhibition of tubulin polymerization, cell cycle effects, and in vivo potency. The greatest antiproliferative activity occurred with a methoxy group introduced at the C-6 position, the least with this substituent at C-4. Thus far, the most promising compound in this series was 2-methoxycarbonyl-3-(3′,4′,5′-trimethoxyanilino)-6-methoxybenzo-[b]furan (3g), which inhibited cancer cell growth at nanomolar concentrations (IC50 values of 0.3–27 nM), bound to the colchicine site of tubulin, induced apoptosis, and showed, both in vitro and in vivo, potent vascular disrupting properties derived from the effect of this compound on vascular endothelial cells. Compound 3g had in vivo antitumor activity in a murine model comparable to the activity obtained with combretastatin A-4 phosphate. PMID:25785605

  8. High temperature superconducting compounds

    NASA Astrophysics Data System (ADS)

    Goldman, Allen M.

    1992-11-01

    The major accomplishment of this grant has been to develop techniques for the in situ preparation of high-Tc superconducting films involving the use of ozone-assisted molecular beam epitaxy. The techniques are generalizable to the growth of trilayer and multilayer structures. Films of both the DyBa2Cu3O(7-x) and YBa2Cu3O(7-x) compounds as well as the La(2-x)Sr(x)CuO4 compound have been grown on the usual substrates, SrTiO3, YSZ, MgO, and LaAlO3, as well as on Si substrates without any buffer layer. A bolometer has been fabricated on a thermally isolated SiN substrate coated with YSZ, an effort carried out in collaboration with Honeywell Inc. The deposition process facilitates the fabrication of very thin and transparent films creating new opportunities for the study of superconductor-insulator transitions and the investigation of photo-doping with carriers of high temperature superconductors. In addition to a thin film technology, a patterning technology has been developed. Trilayer structures have been developed for FET devices and tunneling junctions. Other work includes the measurement of the magnetic properties of bulk single crystal high temperature superconductors, and in collaboration with Argonne National Laboratory, measurement of electric transport properties of T1-based high-Tc films.

  9. Altered Matrix Metalloproteinase-2 and -9 Expression/Activity Links Placental Ischemia and Anti-angiogenic sFlt-1 to Uteroplacental and Vascular Remodeling and Collagen Deposition in Hypertensive Pregnancy

    PubMed Central

    Li, Wei; Mata, Karina M.; Mazzuca, Marc Q.; Khalil, Raouf A.

    2014-01-01

    Preeclampsia is a complication of pregnancy manifested as maternal hypertension and often fetal growth restriction. Placental ischemia could be an initiating event, but the linking mechanisms leading to hypertension and growth restriction are unclear. We have shown an upregulation of matrix metalloproteinases (MMPs) during normal pregnancy (Norm-Preg). To test the role of MMPs in hypertensive-pregnancy (HTN-Preg), maternal and fetal parameters, MMPs expression, activity and distribution, and collagen and elastin content were measured in uterus, placenta and aorta of Norm-Preg rats and in rat model of reduced uteroplacental perfusion pressure (RUPP). Maternal blood pressure was higher, and uterine, placental and aortic weight, and the litter size and pup weight were less in RUPP than Norm-Preg rats. Western blots and gelatin zymography revealed decreases in amount and gelatinase activity of MMP-2 and MMP-9 in uterus, placenta and aorta of RUPP compared with Norm-Preg rats. Immunohistochemistry confirmed reduced MMPs in uterus, placenta and aortic media of RUPP rats. Collagen, but not elastin, was more abundant in uterus, placenta and aorta of RUPP than Norm-Preg rats. The anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) decreased MMPs in uterus, placenta and aorta of Norm-Preg rats, and vascular endothelial growth factor (VEGF) reversed the decreases in MMPs in tissues of RUPP rats. Thus placental ischemia and anti-angiogenic sFlt-1 decrease uterine, placental and vascular MMP-2 and MMP-9, leading to increased uteroplacental and vascular collagen, and growth-restrictive remodeling in HTN-Preg. Angiogenic factors and MMP activators may reverse the decrease in MMPs and enhance growth-permissive remodeling in preeclampsia. PMID:24704473

  10. Intracranial compound odontome.

    PubMed

    de Faria, Paulo Rogério; Cardoso, Sérgio Vitorino; Rocha, Ademir; Gomes, Débora Cristiane; de Castro, Samuel Caputo; Loyola, Adriano Mota

    2009-10-01

    An exceedingly rare case of an extragnathic odontome is described arising within the brain. A 10-year-old boy complained of progressive frontal headache for 5 years. Axial computerized tomography the head revealed a solid, calcified lesion with well-defined borders localized in the sellar and suprasellar region composed of multiple calcified structures resembling teeth. The diagnosis was compound odontome. Physical examination and blood analysis revealed hypopituitarism. The patient was submitted for radical tumour resection. He developed persistent diabetes insipidus, hypothyroidism and adrenal insufficiency for which appropriate replacement therapy has been necessary. This case demonstrates that an odontogenic lesion may arise in brain tissues due to the embryological relationship between primordial stomodeum and Rathke's pouch. Its development could be associated with endocrine disturbances.

  11. Design and Development of Peptides from the Anti-Angiogenic Pigment Epithelial-Derived Factor for the Therapy of Prostate Cancer

    DTIC Science & Technology

    2006-12-01

    to perform, but also re- quire substantial amounts of test compound and most rely on selective morphometric analysis (eg, vessel counts, vascular...Several geometric configurations (discoid, spheroid, and so forth) were tested before selecting a cylindrical shape generated by a section of silicone

  12. Vimocin and vidapin, cyclic KTS peptides, are dual antagonists of α1β1/α2β1 integrins with antiangiogenic activity.

    PubMed

    Momic, Tatjana; Katzehendler, Jehoshua; Benny, Ofra; Lahiani, Adi; Cohen, Gadi; Noy, Efrat; Senderowitz, Hanoch; Eble, Johannes A; Marcinkiewicz, Cezary; Lazarovici, Philip

    2014-09-01

    Obtustatin and viperistatin, members of the disintegrin protein family, served as lead compounds for the synthesis of linear and cyclic peptides containing the KTS binding motif. The most active linear peptide, a viperistatin analog, indicated the importance of Cys(19) and Cys(29), as well as the presence of Arg at position 24 for their biologic activity, and was used as the basic sequence for the synthesis of cyclic peptides. Vimocin (compound 6) and vidapin (compound 10) showed a high potency (IC50 = 0.17 nM) and intermediate efficacy (20 and 40%) in inhibition of adhesion of α1/α2 integrin overexpressor cells to respective collagens. Vimocin was more active in inhibition of the wound healing (53%) and corneal micropocket (17%) vascularization, whereas vidapin was more potent in inhibition of migration in the Matrigel tube formation assay (90%). Both compounds similarly inhibited proliferation (50-90%) of endothelial cells, and angiogenesis induced by vascular endothelial growth factor (80%) and glioma (55%) in the chorioallantoic membrane assay. These peptides were not toxic to endothelial cell cultures and caused no acute toxicity upon intravenous injection in mice, and were stable for 10-30 hours in human serum. The in vitro and in vivo potency of the peptides are consistent with conformational ensembles and "bioactive" space shared by obtustatin and viperistatin. These findings suggest that vimocin and vidapin can serve as dual α1β1/α2β1 integrin antagonists in antiangiogenesis and cancer therapy.

  13. Oil-in-water biocompatible microemulsion as a carrier for the antitumor drug compound methyl dihydrojasmonate

    PubMed Central

    da Silva, Gisela Bevilacqua Rolfsen Ferreira; Scarpa, Maria Virginia; Carlos, Iracilda Zepone; Quilles, Marcela Bassi; Lia, Raphael Carlos Comeli; do Egito, Eryvaldo Socrates Tabosa; de Oliveira, Anselmo Gomes

    2015-01-01

    Methyl dihydrojasmonate (MJ) has been studied because of its application as an antitumor drug compound. However, as MJ is a poorly water-soluble compound, a suitable oil-in-water microemulsion (ME) has been studied in order to provide its solubilization in an aqueous media and to allow its administration by the parenteral route. The ME used in this work was characterized on the pseudo-ternary phase diagram by dynamic light scattering and rheological measurements. Regardless of the drug presence, the droplet size was directly dependent on the oil/surfactant (O/S) ratio. Furthermore, the drug incorporation into the ME significantly increased the ME diameter, mainly at low O/S ratios. The rheological evaluation of the systems showed that in the absence of drug a Newtonian behavior was observed. On the other hand, in the presence of MJ the ME systems revealed pseudoplastic behavior, independently of the O/S ratio. The in vivo studies demonstrated that not only was the effect on the tumor inhibition inversely dependent on the MJ-loaded ME administered dose, but also it was slightly higher than the doxorubicin alone, which was used as the positive control. Additionally, a small antiangiogenic effect for MJ-loaded ME was found at doses in which it possesses antitumor activity. MJ revealed to be nontoxic at doses higher than 350 mg/kg, which was higher than the dose that provides tumor-inhibition effect in this study. Because the MJ-loaded ME was shown to have anticancer activity comparable to doxorubicin, the ME described here may be considered a suitable vehicle for parenteral administration of MJ. PMID:25609963

  14. Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds.

    PubMed Central

    Shibata, S

    2001-01-01

    More than 25 dammarane-type tetracyclic triterpenoid saponins have been isolated from ginseng, the root and rhizome of Panax ginseng C.A. Meyer (Araliaceae). The genuine sapogenins of those saponins, 20(S)-protopanaxa-diol and -triol, were identified as 20(S) 12beta-hydroxy-and 20(S) 6alpha,12beta-dihydroxy-dammarenediol-II, respectively. There are two types of preparations from ginseng: white ginseng prepared by drying after peelling off and red ginseng prepared by steaming and drying. Some partly deglycosylated saponins such as ginsenoside Rh-1, Rh-2, and Rg-3 are obtained from red ginseng as artifacts produced during steaming. Several workers studied the metabolic transformation by human intestinal bacteria after oral administration of ginsenoside Rb-1 and Rb-2 and found that the stepwise deglyco-sylation yielded compound K and finally 20(S)-protopanaxadiol. Ginsenoside Rg-1 was converted into 20(S)-protopanaxatriol via ginsenoside Rh-1. Yun et al. in Korea conducted the epidemiological case-control studies of ginseng and suggested its cancer preventing activities. Kitagawa et al. demonstrated in vitro that ginsenosides, especially 20(R)-ginsenoside Rg-3, specifically inhibited cancer cell invasion and metastasis. Azuma et al. found that ginsenoside Rb-2 inhibited tumor angiogenesis, and Kikuchi et al. reported that ginsenoside Rh-2 inhibited the human ovarian cancer growth in nude mice. Recently, ginsenoside Rg-3 was produced as an anti-angiogenic anti-cancer drug in China. The aforementioned reports suggest that less glycosylated protopanaxadiol derivatives are effective in cancer prevention. Apart from Ginseng tetracyclic triterpenoid saponins, some oleanane-type pentacyclic triterpenoid compounds showed the anti-carcinogenic activity in the two-stage anti-cancer-promotion experiments in vitro and in vivo. PMID:11748374

  15. Compound power plant

    SciTech Connect

    Smith, R.R.

    1991-02-05

    This patent describes a compound motor for a vehicle. It comprises: an engine defining therein a chamber for the combustion of fuel, an intake passage leading to the combustion chamber and an exhaust passage leading from the combustion chamber; a drive shaft extending from the engine; means in the engine for rotating the drive shaft in response to the combustion of fuel in the chamber; a rotary compressor at the entry end of the intake passage; a turbine at the exit end of the exhaust passage, the turbine being drivable by exhaust gases from the combustion chamber; means for selectively transferring rotational motion of the turbine to the compressor, the transferring means including a clutch for mechanically connecting or disconnecting the compressor from the turbine; a planetary gear set having a sun gear member, a ring gear member surrounding the sun gear member, a planet gear member rotatable about its own axis and meshed between the sun gear member and the ring gear member, and a planet carrier member upon which the planet gear member is mounted for revolution about the sun gear member; a gear train between one of the members of the planetary gear set and the turbine; another one of the members of the planetary gear set being driven by the shaft extending from the engine; and a final output shaft driven by a third member of the planetary gear set.

  16. Public chemical compound databases.

    PubMed

    Williams, Anthony J

    2008-05-01

    The internet has rapidly become the first port of call for all information searches. The increasing array of chemistry-related resources that are now available provides chemists with a direct path to the information that was previously accessed via library services and was limited by commercial and costly resources. The diversity of the information that can be accessed online is expanding at a dramatic rate, and the support for publicly available resources offers significant opportunities in terms of the benefits to science and society. While the data online do not generally meet the quality standards of manually curated sources, there are efforts underway to gather scientists together and 'crowdsource' an improvement in the quality of the available data. This review discusses the types of public compound databases that are available online and provides a series of examples. Focus is also given to the benefits and disruptions associated with the increased availability of such data and the integration of technologies to data mine this information.

  17. Compounding with Silicones.

    PubMed

    Allen, Loyd V

    2015-01-01

    Since the 1940s, methylchlorosilanes have been used to treat glassware to prevent blood from clotting. The use of silicones in pharmaceutical and medical applications has grown to where today they are used in many life-saving devices (pacemakers, hydrocephalic shunts) and pharmaceutical applications from tubing, to excipients in topical formulations, to adhesives to affix transdermal drug delivery systems, and are also being used in products as active pharmaceutical ingredients, such as antiflatulents. About 60% of today's skin-care products now contain some type of silicone where they are considered safe and are known to provide a pleasant "silky-touch," non-greasy, and non-staining feel. Silicones exhibit many useful characteristics, and the safety of these agents supports their numerous applications; their biocompatibility is partially due to their low-chemical reactivity displayed by silicones, low-surface energy, and their hydrophobicity. Silicones are used both as active ingredients and as excipients. In addition is their use for "siliconization," or surface treatment, of many parenteral packaging components. Dimethicone and silicone oil are used as lubricants on stoppers to aid machineability, in syringes to aid piston movement, or on syringe needles to reduce pain upon injection. Silicones are also useful in pharmaceutical compounding as is discussed in this artiele included with this article are in developing formulations with silicones.

  18. Pluto's Nonvolatile Chemical Compounds

    NASA Astrophysics Data System (ADS)

    Grundy, William M.; Binzel, Richard; Cook, Jason C.; Cruikshank, Dale P.; Dalle Ore, Cristina M.; Earle, Alissa M.; Ennico, Kimberly; Jennings, Donald; Howett, Carly; Kaiser, Ralf-Ingo; Linscott, Ivan; Lunsford, A. W.; Olkin, Catherine B.; Parker, Alex Harrison; Parker, Joel Wm.; Philippe, Sylvain; Protopapa, Silvia; Quirico, Eric; Reuter, D. C.; Schmitt, Bernard; Singer, Kelsi N.; Spencer, John R.; Stansberry, John A.; Stern, S. Alan; Tsang, Constantine; Verbiscer, Anne J.; Weaver, Harold A.; Weigle, G. E.; Young, Leslie

    2016-10-01

    Despite the migration of Pluto's volatile ices (N2, CO, and CH4) around the surface on seasonal timescales, the planet's non-volatile materials are not completely hidden from view. They occur in a variety of provinces formed over a wide range of timescales, including rugged mountains and chasms, the floors of mid-latitude craters, and an equatorial belt of especially dark and reddish material typified by the informally named Cthulhu Regio. NASA's New Horizons probe observed several of these regions at spatial resolutions as fine as 3 km/pixel with its LEISA imaging spectrometer, covering wavelengths from 1.25 to 2.5 microns. Various compounds that are much lighter than the tholin-like macromolecules responsible for the reddish coloration, but that are not volatile at Pluto surface temperatures such as methanol (CH3OH) and ethane (C2H6) have characteristic absorption bands within LEISA's wavelength range. This presentation will describe their geographic distributions and attempt to constrain their origins. Possibilities include an inheritance from Pluto's primordial composition (the likely source of H2O ice seen on Pluto's surface) or ongoing production from volatile precursors through photochemistry in Pluto's atmosphere or through radiolysis on Pluto's surface. New laboratory data inform the analysis.This work was supported by NASA's New Horizons project.

  19. Method of preparing metallocene compounds

    DOEpatents

    Rosenblum, Myron; Matchett, Stephen A.

    1992-01-01

    This invention describes a novel method of preparing metallocene compounds. The invention is based on synthesis of novel bis cyclopentadienides that, under appropriate conditions, will either encapsulate a transition metal to produce a metallocene such as ferrocene, or ferrocene derivative, or will yield a polymeric metallocene. Compounds produced by this process are useful as catalysts in propulsion systems, or as anti-knock compounds in gasolines.

  20. Biomedical Compounds from Marine organisms

    PubMed Central

    Jha, Rajeev Kumar; Zi-rong, Xu

    2004-01-01

    The Ocean, which is called the ‘mother of origin of life’, is also the source of structurally unique natural products that are mainly accumulated in living organisms. Several of these compounds show pharmacological activities and are helpful for the invention and discovery of bioactive compounds, primarily for deadly diseases like cancer, acquired immuno-deficiency syndrome (AIDS), arthritis, etc., while other compounds have been developed as analgesics or to treat inflammation, etc. The life-saving drugs are mainly found abundantly in microorganisms, algae and invertebrates, while they are scarce in vertebrates. Modern technologies have opened vast areas of research for the extraction of biomedical compounds from oceans and seas.

  1. Organic Compounds in Carbonaceous Meteorites

    NASA Technical Reports Server (NTRS)

    Cooper, Grorge

    2001-01-01

    Carbonaceous meteorites are relatively enriched in soluble organic compounds. To date, these compounds provide the only record available to study a range of organic chemical processes in the early Solar System chemistry. The Murchison meteorite is the best-characterized carbonaceous meteorite with respect to organic chemistry. The study of its organic compounds has related principally to aqueous meteorite parent body chemistry and compounds of potential importance for the origin of life. Among the classes of organic compounds found in Murchison are amino acids, amides, carboxylic acids, hydroxy acids, sulfonic acids, phosphonic acids, purines and pyrimidines (Table 1). Compounds such as these were quite likely delivered to the early Earth in asteroids and comets. Until now, polyhydroxylated compounds (polyols), including sugars (polyhydroxy aldehydes or ketones), sugar alcohols, sugar acids, etc., had not been identified in Murchison. Ribose and deoxyribose, five-carbon sugars, are central to the role of contemporary nucleic acids, DNA and RNA. Glycerol, a three-carbon sugar alcohol, is a constituent of all known biological membranes. Due to the relative lability of sugars, some researchers have questioned the lifetime of sugars under the presumed conditions on the early Earth and postulated other (more stable) compounds as constituents of the first replicating molecules. The identification of potential sources and/or formation mechanisms of pre-biotic polyols would add to the understanding of what organic compounds were available, and for what length of time, on the ancient Earth.

  2. Structure-based tailoring of compound libraries for high-throughput screening: discovery of novel EphB4 kinase inhibitors.

    PubMed

    Kolb, Peter; Kipouros, Catherine Berset; Huang, Danzhi; Caflisch, Amedeo

    2008-10-01

    High-throughput docking is a computational tool frequently used to discover small-molecule inhibitors of enzymes or receptors of known three-dimensional structure. Because of the large number of molecules in chemical libraries, automatic procedures to prune multimillion compound collections are useful for high-throughput docking and necessary for in vitro screening. Here, we propose an anchor-based library tailoring approach (termed ALTA) to focus a chemical library by docking and prioritizing molecular fragments according to their binding energy which includes continuum electrostatics solvation. In principle, ALTA does not require prior knowledge of known inhibitors, but receptor-based pharmacophore information (hydrogen bonds with the hinge region) is additionally used here to identify molecules with optimal anchor fragments for the ATP-binding site of the EphB4 receptor tyrosine kinase. The 21,418 molecules of the focused library (from an initial collection of about 730,000) are docked into EphB4 and ranked by force-field-based energy including electrostatic solvation. Among the 43 compounds tested in vitro, eight molecules originating from two different anchors show low-micromolar activity in a fluorescence-based enzymatic assay. Four of them are active in a cell-based assay and are potential anti-angiogenic compounds.

  3. Integrating computational and chemical biology tools in the discovery of antiangiogenic small molecule ligands of FGF2 derived from endogenous inhibitors

    PubMed Central

    Foglieni, Chiara; Pagano, Katiuscia; Lessi, Marco; Bugatti, Antonella; Moroni, Elisabetta; Pinessi, Denise; Resovi, Andrea; Ribatti, Domenico; Bertini, Sabrina; Ragona, Laura; Bellina, Fabio; Rusnati, Marco; Colombo, Giorgio; Taraboletti, Giulia

    2016-01-01

    The FGFs/FGFRs system is a recognized actionable target for therapeutic approaches aimed at inhibiting tumor growth, angiogenesis, metastasis, and resistance to therapy. We previously identified a non-peptidic compound (SM27) that retains the structural and functional properties of the FGF2-binding sequence of thrombospondin-1 (TSP-1), a major endogenous inhibitor of angiogenesis. Here we identified new small molecule inhibitors of FGF2 based on the initial lead. A similarity-based screening of small molecule libraries, followed by docking calculations and experimental studies, allowed selecting 7 bi-naphthalenic compounds that bound FGF2 inhibiting its binding to both heparan sulfate proteoglycans and FGFR-1. The compounds inhibit FGF2 activity in in vitro and ex vivo models of angiogenesis, with improved potency over SM27. Comparative analysis of the selected hits, complemented by NMR and biochemical analysis of 4 newly synthesized functionalized phenylamino-substituted naphthalenes, allowed identifying the minimal stereochemical requirements to improve the design of naphthalene sulfonates as FGF2 inhibitors. PMID:27000667

  4. 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.

  5. Saturn's Stratospheric Oxygen Compounds

    NASA Astrophysics Data System (ADS)

    Romani, Paul N.; Delgado Díaz, Héctor E.; Bjoraker, Gordon; Hesman, Brigette; Achterberg, Richard

    2016-10-01

    There are three known oxygenated species present in Saturn's upper atmosphere: H2O, CO and CO2. The ultimate source of the water must be external to Saturn as Saturn's cold tropopause effectively prevents any internal water from reaching the upper atmosphere. The carbon monoxide and dioxide source(s) could be internal, external, produced by the photochemical interaction of water with Saturn's stratospheric hydrocarbons or some combination of all of these. At this point it is not clear what the external source(s) are.Cassini's Composite InfraRed Spectrometer (CIRS) has detected emission lines of H2O and CO2 (Hesman et al., DPS 2015, 311.16 & Abbas et al. 2013, Ap. J. doi:10.1088/0004-637X/776/2/73) on Saturn. CIRS also retrieves the temperature of the stratosphere using CH4 lines at 7.7 microns. Using CIRS retrieved temperatures, the mole fraction of H2O at the 0.5-5 mbar level can be retrieved and the CO2 mole fraction at ~1-10 mbar. Coupled with ground based observations of CO (Cavalié et al., 2010, A&A, DOI: 10.1051/0004-6361/200912909) these observations provide a complete oxygen compound data set to test photochemical models.Preliminary results will be presented with an emphasis on upper limit analysis to determine the percentage of stratospheric CO and CO2 that can be produced photochemically from CIRS observational constraints on the H2O profile.

  6. Antimicrobial Compounds in Tears

    PubMed Central

    McDermott, Alison M.

    2013-01-01

    The tear film coats the cornea and conjunctiva and serves several important functions. It provides lubrication, prevents drying of the ocular surface epithelia, helps provide a smooth surface for refracting light, supplies oxygen and is an important component of the innate defense system of the eye providing protection against a range of potential pathogens. This review describes both classic antimicrobial compounds found in tears such as lysozyme and some more recently identified such as members of the cationic antimicrobial peptide family and surfactant protein-D as well as potential new candidate molecules that may contribute to antimicrobial protection. As is readily evident from the literature review herein, tears, like all mucosal fluids, contain a plethora of molecules with known antimicrobial effects. That all of these are active in vivo is debatable as many are present in low concentrations, may be influenced by other tear components such as the ionic environment, and antimicrobial action may be only one of several activities ascribed to the molecule. However, there are many studies showing synergistic/additive interactions between several of the tear antimicrobials and it is highly likely that cooperativity between molecules is the primary way tears are able to afford significant antimicrobial protection to the ocular surface in vivo. In addition to effects on pathogen growth and survival some tear components prevent epithelial cell invasion and promote the epithelial expression of innate defense molecules. Given the protective role of tears a number of scenarios can be envisaged that may affect the amount and/or activity of tear antimicrobials and hence compromise tear immunity. Two such situations, dry eye disease and contact lens wear, are discussed here. PMID:23880529

  7. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble VEGF receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small-for-gestational-age neonate

    PubMed Central

    Romero, Roberto; Nien, Jyh Kae; Espinoza, Jimmy; Todem, David; Fu, Wenjiang; Chung, Hwan; Kusanovic, Juan Pedro; Gotsch, Francesca; Erez, Offer; Mazaki-tovi, Shali; Gomez, Ricardo; Edwin, Sam; Chaiworapongsa, Tinnakorn; Levine, Richard J.; Karumanchi, Ananth

    2008-01-01

    Introduction Accumulating evidence suggests that an imbalance between pro-angiogenic [i.e. vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)] and anti-angiogenic factors [i.e. soluble VEGF receptor-1 (sVEGFR-1, also referred to as sFlt1) is involved in the pathophysiology of preeclampsia (PE). Endoglin is a protein that regulates the pro-angiogenic effects of transforming growth factor β, and its soluble form has been recently implicated in the pathophysiology of PE. The objective of this study was to determine if changes in maternal plasma concentration of these angiogenic and anti-angiogenic factors differ prior to development of disease among patients with normal pregnancies, and those destined to develop PE (preterm and term) or to deliver an SGA neonate. Methods This longitudinal nested case-control study included 144 singleton pregnancies in the following groups: 1) patients with uncomplicated pregnancies who delivered appropriate for gestational age (AGA) neonates (n=46); 2) patients who delivered an SGA neonate but did not develop PE (n=56); and 3) patients who developed PE (n=42). Longitudinal samples were collected at each prenatal visit, which was scheduled at four-week intervals from the first or early second trimester until delivery. Plasma concentrations of soluble endoglin (s-Eng), sVEGFR-1 and PlGF were determined by specific and sensitive ELISA. Results 1) Patients destined to deliver an SGA neonate had higher plasma concentrations of s-Eng throughout gestation than those with normal pregnancies; 2) patients destined to develop preterm PE and term PE had significantly higher concentrations of s-Eng than those with normal pregnancies at 23 and 30 weeks, respectively (for preterm PE: p<0.036 and for term PE: 0=0.002); 3) patients destined to develop PE (term or preterm) and those who delivered an SGA neonate had lower plasma concentrations of PlGF than those with normal pregnancy throughout gestation, and the maternal

  8. THE CHANGE IN CONCENTRATIONS OF ANGIOGENIC AND ANTI-ANGIOGENIC FACTORS IN MATERNAL PLASMA BETWEEN THE FIRST AND SECOND TRIMESTERS IN RISK ASSESSMENT FOR THE SUBSEQUENT DEVELOPMENT OF PREECLAMPSIA AND SGA

    PubMed Central

    Erez, Offer; Romero, Roberto; Espinoza, Jimmy; Fu, Wenjiang; Todem, David; Kusanovic, Juan Pedro; Gotsch, Francesca; Edwin, Samuel; Nien, Jyh Kae; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Mazaki-Tovi, Shali; Than, Nandor Gabor; Gomez, Ricardo; Hassan, Sonia

    2009-01-01

    Introduction An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascual endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of preeclampsia and/or delivery of an SGA neonate. Methods This longitudinal case-control study included 402 singleton pregnancies in the following groups: 1) normal pregnancies with appropiate for gestational age (AGA) neonates (n=201); 2) patients who delivered an SGA neonate (n=145); and 3) patients who developed PE (n=56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: 1) first sample obtained between 6 and 15 weeks of gestation (“first trimester” sample); and 2) second sample obtained between 20 and 25 weeks of gestation (“second trimester” sample). Plasma concentrations of s-Eng, sVEGFR-1 and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity and body mass index (BMI). General linear

  9. Testing of Experimental Antileishmanial Compounds.

    DTIC Science & Technology

    1994-10-19

    administrative and clerical assistance and Ms. Barbara L. Harris, Laboratory Technician II, for technical assistance with this study. Their efforts are appreciated...braziliensis) leishmaniasis . Although several new compounds have been identified with activity against L. (V.) braziliensis, none have shown adequate promise...to warrant initiation of clinical trials. However, among the most promising active compounds found against visceral leishmaniasis during these

  10. Bilingual Reading of Compound Words

    ERIC Educational Resources Information Center

    Ko, In Yeong; Wang, Min; Kim, Say Young

    2011-01-01

    The present study investigated whether bilingual readers activate constituents of compound words in one language while processing compound words in the other language via decomposition. Two experiments using a lexical decision task were conducted with adult Korean-English bilingual readers. In Experiment 1, the lexical decision of real English…

  11. METHOD OF REDUCING PLUTONIUM COMPOUNDS

    DOEpatents

    Johns, I.B.

    1958-06-01

    A method is described for reducing plutonium compounds in aqueous solution from a higher to a lower valence state. This reduction of valence is achieved by treating the aqueous solution of higher valence plutonium compounds with hydrogen in contact with an activated platinum catalyst.

  12. Morphological Dynamics in Compound Processing

    ERIC Educational Resources Information Center

    Kuperman, Victor; Bertram, Raymond; Baayen, R. Harald

    2008-01-01

    This paper explores the time-course of morphological processing of trimorphemic Finnish compounds. We find evidence for the parallel access to full-forms and morphological constituents diagnosed by the early effects of compound frequency, as well as early effects of left constituent frequency and family size. We also observe an interaction between…

  13. Bismuth compounds in medicinal chemistry.

    PubMed

    Salvador, Jorge A R; Figueiredo, Sandra A C; Pinto, Rui M A; Silvestre, Samuel M

    2012-07-01

    In recent years, the chemical potential of bismuth and bismuth compounds has been actively exploited. Bismuth salts are known for their low toxicity, making them potential valuable reagents for large-scale synthesis, which becomes more obvious when dealing with products such as active pharmaceutical ingredients or synthetic intermediates. Conversely, bismuth compounds have been widely used in medicine. After extensive use in the treatments of syphilis and other bacterial infections before the advent of modern antibiotics, bismuth compounds remain important for the treatment of several gastrointestinal disorders and also exhibit antimicrobial properties and cytotoxic activity, among others. This review updates relevant advances in the past few years, concerning the application of bismuth reagents and catalysts in innovative synthetic processes for the preparation of compounds of medicinal interest, as well as the preparation, biological evaluation and potential medicinal uses of bismuth compounds.

  14. Current Research on Antiepileptic Compounds.

    PubMed

    Wei, Cheng-Xi; Bian, Ming; Gong, Guo-Hua

    2015-11-20

    Epilepsy affects about 1% of the world's population. Due to the fact all antiepileptic drugs (AEDs) have some undesirable side effects and about 30% of epileptic patients are not seizure-free with the existing AEDs, there is still an urgent need for the development of more effective and safer AEDs. Based on our research work on antiepileptic compounds and other references in recent years, this review covers the reported work on antiepileptic compounds which are classified according to their structures. This review summarized 244 significant anticonvulsant compounds which are classified by functional groups according to the animal model data, although there are some limitations in the data. This review highlights the properties of new compounds endowed with promising antiepileptic properties, which may be proven to be more effective and selective, and possibly free of unwanted side effects. The reviewed compounds represent an interesting possibility to overcome refractory seizures and to reduce the percentage of patients with a poor response to drug therapy.

  15. Complex chemistry with complex compounds

    NASA Astrophysics Data System (ADS)

    Eichler, Robert; Asai, M.; Brand, H.; Chiera, N. M.; Di Nitto, A.; Dressler, R.; Düllmann, Ch. E.; Even, J.; Fangli, F.; Goetz, M.; Haba, H.; Hartmann, W.; Jäger, E.; Kaji, D.; Kanaya, J.; Kaneya, Y.; Khuyagbaatar, J.; Kindler, B.; Komori, Y.; Kraus, B.; Kratz, J. V.; Krier, J.; Kudou, Y.; Kurz, N.; Miyashita, S.; Morimoto, K.; Morita, K.; Murakami, M.; Nagame, Y.; Ooe, K.; Piguet, D.; Sato, N.; Sato, T. K.; Steiner, J.; Steinegger, P.; Sumita, T.; Takeyama, M.; Tanaka, K.; Tomitsuka, T.; Toyoshima, A.; Tsukada, K.; Türler, A.; Usoltsev, I.; Wakabayashi, Y.; Wang, Y.; Wiehl, N.; Wittwer, Y.; Yakushev, A.; Yamaki, S.; Yano, S.; Yamaki, S.; Qin, Z.

    2016-12-01

    In recent years gas-phase chemical studies assisted by physical pre-separation allowed for the investigation of fragile single molecular species by gas-phase chromatography. The latest success with the heaviest group 6 transactinide seaborgium is highlighted. The formation of a very volatile hexacarbonyl compound Sg(CO)6 was observed similarly to its lighter homologues molybdenum and tungsten. The interactions of these gaseous carbonyl complex compounds with quartz surfaces were investigated by thermochromatography. Second-generation experiments are under way to investigate the intramolecular bond between the central metal atom of the complexes and the ligands addressing the influence of relativistic effects in the heaviest compounds. Our contribution comprises some aspects of the ongoing challenging experiments as well as an outlook towards other interesting compounds related to volatile complex compounds in the gas phase.

  16. Assimilation of Unusual Carbon Compounds

    NASA Astrophysics Data System (ADS)

    Middelhoven, Wouter J.

    Yeast taxa traditionally are distinguished by growth tests on several sugars and organic acids. During the last decades it became apparent that many yeast species assimilate a much greater variety of naturally occurring carbon compounds as sole source of carbon and energy. These abilities are indicative of a greater role of yeasts in the carbon cycle than previously assumed. Especially in acidic soils and other habitats, yeasts may play a role in the degradation of carbon compounds. Such compounds include purines like uric acid and adenine, aliphatic amines, diamines and hydroxyamines, phenolics and other benzene compounds and polysaccharides. Assimilation of purines and amines is a feature of many ascomycetes and basidiomycetes. However, benzene compounds are degraded by only a few ascomycetous yeasts (e.g. the Stephanoascus/ Blastobotrys clade and black yeastlike fungi) but by many basidiomycetes, e.g. Filobasidiales, Trichosporonales, red yeasts producing ballistoconidia and related species, but not by Tremellales. Assimilation of polysaccharides is wide-spread among basidiomycetes

  17. Devices for collecting chemical compounds

    DOEpatents

    Scott, Jill R; Groenewold, Gary S

    2013-12-24

    A device for sampling chemical compounds from fixed surfaces and related methods are disclosed. The device may include a vacuum source, a chamber and a sorbent material. The device may utilize vacuum extraction to volatilize the chemical compounds from a fixed surface so that they may be sorbed by the sorbent material. The sorbent material may then be analyzed using conventional thermal desorption/gas chromatography/mass spectrometry (TD/GC/MS) instrumentation to determine presence of the chemical compounds. The methods may include detecting release and presence of one or more chemical compounds and determining the efficacy of decontamination. The device may be useful in collection and analysis of a variety of chemical compounds, such as residual chemical warfare agents, chemical attribution signatures and toxic industrial chemicals.

  18. Novel bioactive compounds from actinomycetes.

    PubMed

    Sanglier, J J; Wellington, E M; Behal, V; Fiedler, H P; Ellouz Ghorbel, R; Finance, C; Hacene, M; Kamoun, A; Kelly, C; Mercer, D K

    1993-10-01

    Actinomycetes form an enormous reservoir of secondary metabolites and enzymes. The potential for exploiting rare actinomycetes is highlighted by the discovery of novel compounds from strains of Spirillospora and Nocardioides. Novel compounds of well known classes of antibiotics, such as polyenes, continue to be discovered. For compounds containing a chromophore, the analysis by high-performance liquid chromatography coupled with a diode-array detector enables the elimination of producers of known compounds and facilitates the discovery of novel compounds or derivatives. The complexity of the regulatory mechanisms is illustrated by glutamine synthetase. The characterization of thermostable amylolytic, lignolytic, peroxidase and neuramidase activities, and the isolation of novel cellulolytic actinomycetes clearly demonstrate the potential of Actinomycetes as producers of enzymes.

  19. A Prospective Cohort Study of the Value of Maternal Plasma Concentrations of Angiogenic and Anti-angiogenic Factors in Early Pregnancy and Midtrimester in the Identification of Patients Destined to Develop Preeclampsia

    PubMed Central

    Kusanovic, Juan Pedro; Romero, Roberto; Chaiworapongsa, Tinnakorn; Erez, Offer; Mittal, Pooja; Vaisbuch, Edi; Mazaki-Tovi, Shali; Gotsch, Francesca; Edwin, Samuel S.; Gomez, Ricardo; Yeo, Lami; Conde-Agudelo, Agustin; Hassan, Sonia S.

    2012-01-01

    OBJECTIVE Changes in the maternal plasma concentrations of angiogenic (such as PlGF and VEGF) and anti-angiogenic factors (such as sEng and sVEGFR-1) precede the clinical presentation of preeclampsia. This study was conducted to examine the role of maternal plasma PlGF, sEng and sVEGFR-1 concentrations in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. METHODS This longitudinal cohort study included 1,622 consecutive singleton pregnant women. Plasma samples were obtained in early pregnancy (6–15 weeks) and midtrimester (20–25 weeks). Maternal plasma PlGF, sEng and sVEGFR-1 concentrations were determined using sensitive and specific immunoassays. The primary outcome was the development of preeclampsia. Secondary outcomes included term, preterm and early-onset preeclampsia. Receiving operating characteristic (ROC) curves, sensitivity, specificity, positive and negative likelihood ratios, and multivariable logistic regression were used for statistical analyses. A p-value of <0.05 was considered significant. RESULTS 1) The prevalence of preeclampsia, term, preterm (<37 weeks) and early-onset preeclampsia (<34 weeks) was 3.8% (62/1,622), 2.5% (40/1,622), 1.4% (22/1,622) and 0.6% (9/1,622), respectively; 2) Higher likelihood ratios were provided by ratios of midtrimester plasma concentrations of PlGF, sEng, and sVEGFR-1 than single analytes; 3) Individual angiogenic and anti-angiogenic factors did not perform well in the identification of preeclampsia as a whole; in particular, they perform poorly in the prediction of term preeclampsia; 4) In contrast, a combination of these analytes such as the PlGF/sEng ratio, its delta and slope had the best predictive performance with a sensitivity of 100%, a specificity of 98%–99%, and likelihood ratios for a positive test of 57.6, 55.6 and 89.6, respectively, for predicting early-onset preeclampsia. CONCLUSIONS 1) The PlGF/sEng ratio and its delta and slope had an excellent

  20. 68Ga-TRAP-(RGD)3 Hybrid Imaging for the In Vivo Monitoring of αvß3-Integrin Expression as Biomarker of Anti-Angiogenic Therapy Effects in Experimental Breast Cancer

    PubMed Central

    Kazmierczak, Philipp M.; Todica, Andrei; Gildehaus, Franz-Josef; Hirner-Eppeneder, Heidrun; Brendel, Matthias; Eschbach, Ralf S.; Hellmann, Magdalena; Nikolaou, Konstantin; Reiser, Maximilian F.; Wester, Hans-Jürgen; Kropf, Saskia; Rominger, Axel; Cyran, Clemens C.

    2016-01-01

    Objectives To investigate 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. Materials and Methods Human breast cancer (MDA-MB-231) xenografts were implanted orthotopically into the mammary fat pads of n = 25 SCID mice. Transmission/emission scans (53 min to 90 min after i.v. injection of 20 MBq 68Ga-TRAP-(RGD)3) were performed on a dedicated small animal PET before (day 0, baseline) and after (day 7, follow-up) a 1-week therapy with the VEGF antibody bevacizumab or placebo (imaging cohort n = 13; therapy n = 7, control n = 6). The target-to-background ratio (TBR, VOImaxtumor/VOImeanmuscle) served as semiquantitative measure of tumor radiotracer uptake. Unenhanced CT data sets were subsequently acquired for anatomic coregistration and morphology-based tumor response assessments (CT volumetry). The imaging results were validated by multiparametric ex vivo immunohistochemistry (αvß3-integrin, microvascular density–CD31, proliferation–Ki-67, apoptosis–TUNEL) conducted in a dedicated immunohistochemistry cohort (n = 12). Results 68Ga-TRAP-(RGD)3 binding was significantly reduced under VEGF inhibition and decreased in all bevacizumab-treated animals (ΔTBRfollow-up/baseline: therapy -1.07±0.83, control +0.32±1.01, p = 0.022). No intergroup difference in tumor volume development between day 0 and day 7 was observed (Δvolumetherapy 134±77 μL, Δvolumecontrol 132±56 μL, p = 1.000). Immunohistochemistry revealed a significant reduction of αvß3-integrin expression (308±135 vs. 635±325, p = 0.03), microvascular density (CD31, 168±108 vs. 432±70, p = 0.002), proliferation (Ki-67, 5,195±1,002 vs. 7,574±418, p = 0.004) and significantly higher apoptosis (TUNEL, 14,432±1,974 vs. 3,776±1,378, p = 0.002) in the therapy compared to the control group. Conclusions 68Ga-TRAP-(RGD)3 hybrid imaging allows for the in vivo assessment of αvß3

  1. Photoprotective compounds from marine organisms.

    PubMed

    Rastogi, Rajesh P; Richa; Sinha, Rajeshwar P; Singh, Shailendra P; Häder, Donat-P

    2010-06-01

    The substantial loss in the stratospheric ozone layer and consequent increase in solar ultraviolet radiation on the earth's surface have augmented the interest in searching for natural photoprotective compounds in organisms of marine as well as freshwater ecosystems. A number of photoprotective compounds such as mycosporine-like amino acids (MAAs), scytonemin, carotenoids and several other UV-absorbing substances of unknown chemical structure have been identified from different organisms. MAAs form the most common class of UV-absorbing compounds known to occur widely in various marine organisms; however, several compounds having UV-screening properties still need to be identified. The synthesis of scytonemin, a predominant UV-A-photoprotective pigment, is exclusively reported in cyanobacteria. Carotenoids are important components of the photosynthetic apparatus that serve both light-harvesting and photoprotective functions, either by direct quenching of the singlet oxygen or other toxic reactive oxygen species or by dissipating the excess energy in the photosynthetic apparatus. The production of photoprotective compounds is affected by several environmental factors such as different wavelengths of UVR, desiccation, nutrients, salt concentration, light as well as dark period, and still there is controversy about the biosynthesis of various photoprotective compounds. Recent studies have focused on marine organisms as a source of natural bioactive molecules having a photoprotective role, their biosynthesis and commercial application. However, there is a need for extensive work to explore the photoprotective role of various UV-absorbing compounds from marine habitats so that a range of biotechnological and pharmaceutical applications can be found.

  2. Membrane rejection of nitrogen compounds

    NASA Technical Reports Server (NTRS)

    Lee, S.; Lueptow, R. M.

    2001-01-01

    Rejection characteristics of nitrogen compounds were examined for reverse osmosis, nanofiltration, and low-pressure reverse osmosis membranes. The rejection of nitrogen compounds is explained by integrating experimental results with calculations using the extended Nernst-Planck model coupled with a steric hindrance model. The molecular weight and chemical structure of nitrogen compounds appear to be less important in determining rejection than electrostatic properties. The rejection is greatest when the Donnan potential exceeds 0.05 V or when the ratio of the solute radius to the pore radius is greater than 0.8. The transport of solute in the pore is dominated by diffusion, although convective transport is significant for organic nitrogen compounds. Electromigration contributes negligibly to the overall solute transport in the membrane. Urea, a small organic compound, has lower rejection than ionic compounds such as ammonium, nitrate, and nitrite, indicating the critical role of electrostatic interaction in rejection. This suggests that better treatment efficiency for organic nitrogen compounds can be obtained after ammonification of urea.

  3. Selected ebselen analogs reduce mechlorethamine toxicity in vitro.

    PubMed

    Pino, Maria A; Pietka-Ottlik, Magdalena; Billack, Blase

    2014-03-01

    Sulfur mustard (SM) is a potent vesicant. The lack of an effective antidote makes SM a continued threat to both military and civilian settings. A surrogate agent, namely mechlorethamine (HN2), was used here to mimic the toxicity of SM, and the main objective of this study was to demonstrate if selected organoselenium analogs could protect cultured A-431 skin cells from HN2 toxicity. Test compounds included ebselen (EB-1) and three related organoselenium analogs (EB-2, EB-3 and EB-4). In the absence of test compound, a reproducible and robust cell death was observed in the cells following incubation with HN2 (25 µM, 24 or 48 h) while cells treated with test compound alone (15, 30 or 60 µM) for similar periods of time were generally not affected. When incubated in the presence of both HN2 and test compound for 24 or 48 h, it was found that EB-1, EB-2, EB-3 and EB-4 could spare the cells from death, with the EB-4 compound being the most effective at reducing HN2 toxicity. Light microscopy confirmed these findings. The organoseleniums were also examined for their effects on reducing lipid peroxidation in the A-431 skin cells. Among the test compounds, EB-4 reduced lipid peroxidation by HN2 to the greatest extent. These studies, taken together, validate that the organoselenium antioxidants tested here may serve a purpose in the discovery of medical countermeasures to vesicants.

  4. Selenium- and Tellurium-Based Antioxidants for Modulating Inflammation and Effects on Osteoblastic Activity

    PubMed Central

    Lu, Xi; Mestres, Gemma; Singh, Vijay Pal; Effati, Pedram; Poon, Jia-Fei; Engman, Lars; Karlsson Ott, Marjam

    2017-01-01

    Increased oxidative stress plays a significant role in the etiology of bone diseases. Heightened levels of H2O2 disrupt bone homeostasis, leading to greater bone resorption than bone formation. Organochalcogen compounds could act as free radical trapping agents or glutathione peroxidase mimetics, reducing oxidative stress in inflammatory diseases. In this report, we synthesized and screened a library of organoselenium and organotellurium compounds for hydrogen peroxide scavenging activity, using macrophagic cell lines RAW264.7 and THP-1, as well as human mono- and poly-nuclear cells. These cells were stimulated to release H2O2, using phorbol 12-myristate 13-acetate, with and without organochalogens. Released H2O2 was then measured using a chemiluminescent assay over a period of 2 h. The screening identified an organoselenium compound which scavenged H2O2 more effectively than the vitamin E analog, Trolox. We also found that this organoselenium compound protected MC3T3 cells against H2O2-induced toxicity, whereas Trolox did not. The organoselenium compound exhibited no cytotoxicity to the cells and had no deleterious effects on cell proliferation, viability, or alkaline phosphatase activity. The rapidity of H2O2 scavenging and protection suggests that the mechanism of protection is due to the direct scavenging of extracellular H2O2. This compound is a promising modulators of inflammation and could potentially treat diseases involving high levels of oxidative stress. PMID:28216602

  5. MEASUREMENT OF INFRARED SPECTRA AND CHEMICAL BONDING OF INORGANIC COMPOUNDS.

    DTIC Science & Technology

    CHROMATES, SELENIUM COMPOUNDS, PERMANGANATES, FLUOBORATES , LITHIUM FLUORIDES, BELGIUM...CRYSTAL STRUCTURE, SODIUM CHLORIDE, LITHIUM COMPOUNDS, BARIUM COMPOUNDS, ALKALINE EARTH COMPOUNDS, ALKALI METAL COMPOUNDS, SULFATES, PERCHLORATES

  6. Polishing compound for plastic surfaces

    DOEpatents

    Stowell, M.S.

    1995-08-22

    A polishing compound for plastic surfaces is disclosed. The compound contains by weight approximately 4 to 17 parts at least one petroleum distillate lubricant, 1 to 6 parts mineral spirits, 2.5 to 15 parts abrasive particles, and 2.5 to 10 parts water. The abrasive is tripoli or a similar material that contains fine particles silica. Preferably, most of the abrasive particles are less than approximately 10 microns, more preferably less than approximately 5 microns in size. The compound is used on PLEXIGLAS{trademark}, LEXAN{trademark}, LUCITE{trademark}, polyvinyl chloride (PVC) and similar plastic materials whenever a smooth, clear polished surface is desired. 5 figs.

  7. Polishing compound for plastic surfaces

    DOEpatents

    Stowell, M.S.

    1993-01-01

    A polishing compound for plastic surfaces is disclosed. The compound contains by weight approximately 4 to 17 parts at least one petroleum distillate lubricant, 1 to 6 parts mineral spirits, 2.5 to 15 parts abrasive particles, and 2.5 to 10 parts water. The abrasive is tripoli or a similar material that contains colloidal silica. Preferably, most of the abrasive particles are less than approximately 10 microns, more preferably less than approximately 5 microns in size. The compound is used on PLEXIGLAS{sup TM}, LEXAN{sup TM}, LUCITE{sup TM}, polyvinyl chloride (PVC) and similar plastic materials whenever a smooth, clear polished surface is desired.

  8. Polishing compound for plastic surfaces

    DOEpatents

    Stowell, Michael S.

    1995-01-01

    A polishing compound for plastic surfaces. The compound contains by weight approximately 4 to 17 parts at least one petroleum distillate lubricant, 1 to 6 parts mineral spirits, 2.5 to 15 parts abrasive particles, and 2.5 to 10 parts water. The abrasive is tripoli or a similar material that contains fine particles silica. Preferably, most of the abrasive particles are less than approximately 10 microns, more preferably less than approximately 5 microns in size. The compound is used on PLEXIGLAS.TM., LEXAN.TM., LUCITE.TM., polyvinyl chloride (PVC) and similar plastic materials whenever a smooth, clear polished surface is desired.

  9. THE FERROELECTRIC AND STRUCTURAL PROPERTIES OF HAFNIUM OXIDE COMPOUNDS,

    DTIC Science & Technology

    HAFNIUM COMPOUNDS, OXIDES), (* FERROELECTRICITY , HAFNIUM COMPOUNDS), (*CRYSTAL STRUCTURE, HAFNIUM COMPOUNDS), DIELECTRIC PROPERTIES, HYSTERESIS... FERROELECTRIC MATERIALS, SOLID SOLUTIONS, X RAY DIFFRACTION, CRYSTAL LATTICES, LOW TEMPERATURE, CALCIUM COMPOUNDS, STRONTIUM COMPOUNDS, LEAD COMPOUNDS, BARIUM COMPOUNDS

  10. Detection of chlorinated aromatic compounds

    DOEpatents

    Ekechukwu, Amy A.

    1996-01-01

    A method for making a composition for measuring the concentration of chloated aromatic compounds in aqueous fluids, and an optical probe for use with the method. The composition comprises a hydrophobic polymer matrix, preferably polyamide, with a fluorescent indicator uniformly dispersed therein. The indicator fluoresces in the presence of the chlorinated aromatic compounds with an intensity dependent on the concentration of these compounds in the fluid of interest, such as 8-amino-2-naphthalene sulfonate. The probe includes a hollow cylindrical housing that contains the composition in its distal end. The probe admits an aqueous fluid to the probe interior for exposure to the composition. An optical fiber transmits excitation light from a remote source to the composition while the indicator reacts with chlorinated aromatic compounds present in the fluid. The resulting fluorescence light signal is reflected to a second optical fiber that transmits the light to a spectrophotometer for analysis.

  11. Detection of chlorinated aromatic compounds

    DOEpatents

    Ekechukwu, A.A.

    1996-02-06

    A method for making a composition for measuring the concentration of chlorinated aromatic compounds in aqueous fluids, and an optical probe for use with the method are disclosed. The composition comprises a hydrophobic polymer matrix, preferably polyamide, with a fluorescent indicator uniformly dispersed therein. The indicator fluoresces in the presence of the chlorinated aromatic compounds with an intensity dependent on the concentration of these compounds in the fluid of interest, such as 8-amino-2-naphthalene sulfonate. The probe includes a hollow cylindrical housing that contains the composition in its distal end. The probe admits an aqueous fluid to the probe interior for exposure to the composition. An optical fiber transmits excitation light from a remote source to the composition while the indicator reacts with chlorinated aromatic compounds present in the fluid. The resulting fluorescence light signal is reflected to a second optical fiber that transmits the light to a spectrophotometer for analysis. 5 figs.

  12. MECHANICAL BEHAVIOR OF INTERMETALLIC COMPOUNDS.

    DTIC Science & Technology

    AGING(MATERIALS), AGING(MATERIALS), INTERMETALLIC COMPOUNDS, VANADIUM ALLOYS, COBALT ALLOYS, NICKEL ALLOYS, MECHANICAL PROPERTIES, TEMPERATURE, TIME ... CRYSTAL STRUCTURE, MICROSTRUCTURE, HARDNESS, TRANSFORMATIONS, ELECTRICAL RESISTANCE, MEASUREMENT, MICROSCOPY, ALLOYS, METALLOGRAPHY, X RAY DIFFRACTION.

  13. Compound cueing in free recall

    PubMed Central

    Lohnas, Lynn J.; Kahana, Michael J.

    2013-01-01

    According to the retrieved context theory of episodic memory, the cue for recall of an item is a weighted sum of recently activated cognitive states, including previously recalled and studied items as well as their associations. We show that this theory predicts there should be compound cueing in free recall. Specifically, the temporal contiguity effect should be greater when the two most recently recalled items were studied in contiguous list positions. A meta-analysis of published free recall experiments demonstrates evidence for compound cueing in both conditional response probabilities and inter-response times. To help rule out a rehearsal-based account of these compound cueing effects, we conducted an experiment with immediate, delayed and continual-distractor free recall conditions. Consistent with retrieved context theory but not with a rehearsal-based account, compound cueing was present in all conditions, and was not significantly influenced by the presence of interitem distractors. PMID:23957364

  14. Phenolic compounds in Brassica vegetables.

    PubMed

    Cartea, María Elena; Francisco, Marta; Soengas, Pilar; Velasco, Pablo

    2010-12-30

    Phenolic compounds are a large group of phytochemicals widespread in the plant kingdom. Depending on their structure they can be classified into simple phenols, phenolic acids, hydroxycinnamic acid derivatives and flavonoids. Phenolic compounds have received considerable attention for being potentially protective factors against cancer and heart diseases, in part because of their potent antioxidative properties and their ubiquity in a wide range of commonly consumed foods of plant origin. The Brassicaceae family includes a wide range of horticultural crops, some of them with economic significance and extensively used in the diet throughout the world. The phenolic composition of Brassica vegetables has been recently investigated and, nowadays, the profile of different Brassica species is well established. Here, we review the significance of phenolic compounds as a source of beneficial compounds for human health and the influence of environmental conditions and processing mechanisms on the phenolic composition of Brassica vegetables.

  15. Crystallographic properties of fertilizer compounds

    SciTech Connect

    Frazier, A.W.; Dillard, E.F.; Thrasher, R.D.; Waerstad, K.R.; Hunter, S.R.; Kohler, J.J.; Scheib, R.M.

    1991-02-01

    This bulletin is a compilation of crystallographic data collected at NFERC on 450 fertilizer-related compounds. In TVA's fertilizer R and D program, petrographic examination, XRD, and infrared spectroscopy are combined with conventional chemical analysis methods in identifying the individual compounds that occur in fertilizer materials. This handbook brings together the results of these characterization studies and supplemental crystallographic data from the literature. It is in one-compound-per-page, loose-leaf format, ordered alphabetically by IUPAC name. Indexes provided include IUPAC name, formula, group, alternate formula, synonyms, x-ray data, optical data. Tables are given for solids, compounds in commercial MAP and DAP, and matrix materials in phosphate rock.

  16. Polishing compound for plastic surfaces

    DOEpatents

    Stowell, M.S.

    1991-01-01

    This invention is comprised of a polishing compound for plastic materials. The compound includes approximately by approximately by weight 25 to 80 parts at least one petroleum distillate lubricant, 1 to 12 parts mineral spirits, 50 to 155 parts abrasive paste, and 15 to 60 parts water. Preferably, the compound includes approximately 37 to 42 parts at least one petroleum distillate lubricant, up to 8 parts mineral spirits, 95 to 110 parts abrasive paste, and 50 to 55 parts water. The proportions of the ingredients are varied in accordance with the particular application. The compound is used on PLEXIGLAS{trademark}, LEXAN{trademark}, LUCITE{trademark}, polyvinyl chloride (PVC), and similar plastic materials whenever a smooth, clear polished surface is desired.

  17. Photochemical dimerization of organic compounds

    DOEpatents

    Crabtree, Robert H.; Brown, Stephen H.; Muedas, Cesar A.; Ferguson, Richard R.

    1992-01-01

    At least one of selectivity and reaction rate of photosensitized vapor phase dimerizations, including dehydrodimerizations, hydrodimerizations and cross-dimerizations of saturated and unsaturated organic compounds is improved by conducting the dimerization in the presence of hydrogen or nitrous oxide.

  18. Fourth symposium on macrocyclic compounds

    SciTech Connect

    Christensen, J. J.; Izatt, R. M.

    1980-01-01

    Both theoretical and experimental aspects of the properties and behavior of synthetic and naturally occurring macrocyclic compounds are covered in this symposium. This document contains abstracts of the papers. (DLC)

  19. Two compounds from Peucedanum dissolutum.

    PubMed

    Wu, Xian-Li; Li, Yi; Kong, Ling-Yi; Min, Zhi-Da

    2004-12-01

    A new compound, 3'(R)-O-beta-D-glucopyranosyl-3',4'-dihydroxanthyletin (1), and a known compound, prim-O-glucosylcimifugin (2), were isolated from the roots of Peucedanum dissolutum. The structure of 1 was elucidated by spectral evidence and chemical reaction. The NMR signals of carbons and protons of 2 were assigned for the first time by analysis of (1)H-(1)H COSY, HMQC and HMBC spectra.

  20. The Multilinear Compound Gaussian Distribution

    DTIC Science & Technology

    2012-05-01

    which we call the Multilinear Compound Gaussian (MCG) distribution, subsumes both GSM [1] and the previously developed MICA [3-4] distributions as...modeling various natural phenomena of interest. Index Terms— GSM, MICA , MCG, Bayesian, Nonlinear I. INTRODUCTION The compound Gaussian (CG) model—also...We will see how the MCG model developed subsumes both CG and the previously developed multilinear ICA ( MICA ) distribution [3-4] as complementary

  1. Aza compounds as anion receptors

    DOEpatents

    Lee, Hung Sui; Yang, Xiao-Qing; McBreen, James

    1998-01-06

    A family of aza-ether based compounds including linear, multi-branched and aza-crown ethers is provided. When added to non-aqueous battery electrolytes, the family of aza-ether based compounds acts as neutral receptors to complex the anion moiety of the electrolyte salt thereby increasing the conductivity and the transference number of Li.sup.+ ion in alkali metal batteries.

  2. Aza compounds as anion receptors

    DOEpatents

    Lee, H.S.; Yang, X.Q.; McBreen, J.

    1998-01-06

    A family of aza-ether based compounds including linear, multi-branched and aza-crown ethers is provided. When added to non-aqueous battery electrolytes, the family of aza-ether based compounds acts as neutral receptors to complex the anion moiety of the electrolyte salt thereby increasing the conductivity and the transference number of Li{sup +} ion in alkali metal batteries. 3 figs.

  3. Miniature curved artificial compound eyes

    PubMed Central

    Floreano, Dario; Pericet-Camara, Ramon; Viollet, Stéphane; Ruffier, Franck; Brückner, Andreas; Leitel, Robert; Buss, Wolfgang; Menouni, Mohsine; Expert, Fabien; Juston, Raphaël; Dobrzynski, Michal Karol; L’Eplattenier, Geraud; Recktenwald, Fabian; Mallot, Hanspeter A.; Franceschini, Nicolas

    2013-01-01

    In most animal species, vision is mediated by compound eyes, which offer lower resolution than vertebrate single-lens eyes, but significantly larger fields of view with negligible distortion and spherical aberration, as well as high temporal resolution in a tiny package. Compound eyes are ideally suited for fast panoramic motion perception. Engineering a miniature artificial compound eye is challenging because it requires accurate alignment of photoreceptive and optical components on a curved surface. Here, we describe a unique design method for biomimetic compound eyes featuring a panoramic, undistorted field of view in a very thin package. The design consists of three planar layers of separately produced arrays, namely, a microlens array, a neuromorphic photodetector array, and a flexible printed circuit board that are stacked, cut, and curved to produce a mechanically flexible imager. Following this method, we have prototyped and characterized an artificial compound eye bearing a hemispherical field of view with embedded and programmable low-power signal processing, high temporal resolution, and local adaptation to illumination. The prototyped artificial compound eye possesses several characteristics similar to the eye of the fruit fly Drosophila and other arthropod species. This design method opens up additional vistas for a broad range of applications in which wide field motion detection is at a premium, such as collision-free navigation of terrestrial and aerospace vehicles, and for the experimental testing of insect vision theories. PMID:23690574

  4. Miniature curved artificial compound eyes.

    PubMed

    Floreano, Dario; Pericet-Camara, Ramon; Viollet, Stéphane; Ruffier, Franck; Brückner, Andreas; Leitel, Robert; Buss, Wolfgang; Menouni, Mohsine; Expert, Fabien; Juston, Raphaël; Dobrzynski, Michal Karol; L'Eplattenier, Geraud; Recktenwald, Fabian; Mallot, Hanspeter A; Franceschini, Nicolas

    2013-06-04

    In most animal species, vision is mediated by compound eyes, which offer lower resolution than vertebrate single-lens eyes, but significantly larger fields of view with negligible distortion and spherical aberration, as well as high temporal resolution in a tiny package. Compound eyes are ideally suited for fast panoramic motion perception. Engineering a miniature artificial compound eye is challenging because it requires accurate alignment of photoreceptive and optical components on a curved surface. Here, we describe a unique design method for biomimetic compound eyes featuring a panoramic, undistorted field of view in a very thin package. The design consists of three planar layers of separately produced arrays, namely, a microlens array, a neuromorphic photodetector array, and a flexible printed circuit board that are stacked, cut, and curved to produce a mechanically flexible imager. Following this method, we have prototyped and characterized an artificial compound eye bearing a hemispherical field of view with embedded and programmable low-power signal processing, high temporal resolution, and local adaptation to illumination. The prototyped artificial compound eye possesses several characteristics similar to the eye of the fruit fly Drosophila and other arthropod species. This design method opens up additional vistas for a broad range of applications in which wide field motion detection is at a premium, such as collision-free navigation of terrestrial and aerospace vehicles, and for the experimental testing of insect vision theories.

  5. Bioaccessibility testing of cobalt compounds.

    PubMed

    Stopford, Woodhall; Turner, John; Cappellini, Danielle; Brock, Tom

    2003-08-01

    Testing of metal compounds for solubility in artificial fluids has been used for many years to assist determining human health risk from exposure to specific compounds of concern. In lieu of obtaining bioavailability data from samples of urine, blood, or other tissues, these studies measured solubility of compounds in various artificial fluids as a surrogate for bioavailability. In this context, the measurement of metal "bioaccessibility" can be used as an in vitro substitute for measuring metal bioavailability. Bioaccessibility can be defined as a value representing the availability of metal for absorption when dissolved in in vitro surrogates of body fluids or juices. The aim of this study was to measure and compare the bioaccessibility of selected cobalt compounds in artificial human tissue fluids and human serum. A second aim was to initiate studies to experimentally validate an in vitro methodology that would provide a conservative estimate of cobalt bioavailability in the assessment of dose from human exposure to various species of cobalt compounds. This study evaluated the bioaccessibility of cobalt(II) from 11 selected cobalt compounds and an alloy in 2 physical forms in 5 surrogate human tissue fluids and human serum. Four (4) separate extraction times were used up to 72 hours. The effect of variables such as pH, dissolution time, and mass-ion effect on cobalt bioaccessibility were assessed as well. We found that the species of cobalt compound as well as the physico-chemical properties of the surrogate fluids, especially pH, had a major impact on cobalt solubility. Cobalt salts such as cobalt(II) sulfate heptahydrate were highly soluble, whereas cobalt alloys used in medical implants and cobalt aluminate spinels used as pigments, showed minimal dissolution over the period of the assay.

  6. Host compounds for red phosphorescent OLEDs

    DOEpatents

    Xia, Chuanjun; Cheon, Kwang -Ohk

    2015-08-25

    Novel compounds containing a triphenylene moiety linked to an .alpha..beta. connected binaphthyl ring system are provided. These compounds have surprisingly good solubility in organic solvents and are useful as host compounds in red phosphorescent OLEDs.

  7. Method for purifying bidentate organophosphorus compounds

    DOEpatents

    Schulz, Wallace W.

    1977-01-01

    Bidentate organophosphorus compounds useful for extracting actinide elements from acidic nuclear waste solutions are purified of undesirable acidic impurities by contacting the compounds with ethylene glycol which preferentially extracts the impurities found in technical grade bidentate compounds.

  8. Organoselenium bis selenide attenuates 3-nitropropionic acid-induced neurotoxicity in rats.

    PubMed

    Bortolatto, Cristiani F; Jesse, Cristiano R; Wilhelm, Ethel A; Chagas, Pietro M; Nogueira, Cristina W

    2013-04-01

    This study was designed to evaluate the effects of bis selenide on Huntington disease (HD)-like signs induced by 3-nitropropionic acid (3-NP) in rats. To this aim, rats were treated for 4 days with bis selenide (5 or 20 mg/kg/day, per oral) 30 min before 3-NP (20 mg/kg/day, intraperitoneally). The body weight gain, locomotor activity, motor coordination, and biochemical parameters in striatal preparations were assessed 24 h after the last injection of 3-NP. The highest dose of bis selenide was effective in protecting against body weight loss and motor coordination deficit induced by 3-NP. The impairment of locomotor activity caused by 3-NP was abolished by bis selenide at both doses. Bis selenide (5 and 20 mg/kg) partially restored succinate dehydrogenase activity inhibited after 3-NP exposure. The dose of 20 mg/kg of bis selenide recovered partially δ-aminolevulinic acid dehydratase activity, and totally Na(+), K(+)-ATPase activity, two sulfhydryl enzymes sensitive to oxidizing agents, which had their activities inhibited by 3-NP. Also, 3-NP led to an increase in protein carbonyl levels and glutathione reductase activity and inhibited catalase activity-alterations that were reversed by bis selenide administration at both doses. The highest dose of bis selenide was effective against the increase of RS levels, the depletion of reduced glutathione content, and the inhibition of glutathione peroxidase activity induced by 3-NP. Bis selenide was not effective against inhibition of SOD activity caused by 3-NP. These findings demonstrate that bis selenide elicited protective effects against HD-like signs induced by 3-NP in rats.

  9. Cytotoxic Compounds from Brucea mollis

    PubMed Central

    Tung, Mai Hung Thanh; Đuc, Ho Viet; Huong, Tran Thu; Duong, Nguyen Thanh; Phuong, Do Thi; Thao, Do Thi; Tai, Bui Huu; Kim, Young Ho; Bach, Tran The; Cuong, Nguyen Manh

    2013-01-01

    Ten compounds, including soulameanone (1), isobruceine B (2), 9-methoxy-canthin-6-one (3), bruceolline F (4), niloticine (5), octatriacontan-1-ol (6), bombiprenone (7), α-tocopherol (8), inosine (9), and apigenin 7-O-β-D-glucopyranoside (10), were isolated from the leaves, stems, and roots of Brucea mollis Wall. ex Kurz. Their structures were determined using one-and two-dimensional NMR spectroscopy and mass spectrometry. All compounds were evaluated for their cytotoxic activity against KB (human carcinoma of the mouth), LU-1 (human lung adenocarcinoma), LNCaP (human prostate adeno-carcinoma), and HL-60 (human promyelocytic leukemia) cancer cell lines. Compound 2 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values of 0.39, 0.40, 0.34, and 0.23 μg/mL, respectively. In addition, compounds 3 and 5 showed significant cytotoxic activity against KB, LU-1, LNCaP, and HL-60 cancer cells with IC50 values around 1–4 μg/mL. Compounds 9-methoxycanthin-6-one (3) and niloticine (5) have been discovered for the first time from the Brucea genus. PMID:24106661

  10. Extraterrestrial Organic Compounds in Meteorites

    NASA Technical Reports Server (NTRS)

    Botta, Oliver; Bada, Jeffrey L.; Meyer, Michael (Technical Monitor)

    2003-01-01

    Many organic compounds or their precursors found in meteorites originated in the interstellar or circumstellar medium and were later incorporated into planetesimals during the formation of the solar system. There they either survived intact or underwent further processing to synthesize secondary products on the meteorite parent body. The most distinct feature of CI and CM carbonaceous chondrites, two types of stony meteorites, is their high carbon content (up to 3% of weight), either in the form of carbonates or of organic compounds. The bulk of the organic carbon consists of an insoluble macromolecular material with a complex structure. Also present is a soluble organic fraction, which has been analyzed by several separation and analytical procedures. Low detection limits can be achieved by derivatization of the organic molecules with reagents that allow for analysis by gas chromatography/mass spectroscopy and high performance liquid chromatography. The CM meteorite Murchison has been found to contain more than 70 extraterrestrial amino acids and several other classes of compounds including carboxylic acids, hydroxy carboxylic acids, sulphonic and phosphonic acids, aliphatic, aromatic and polar hydrocarbons, fullerenes, heterocycles as well as carbonyl compounds, alcohols, amines and amides. The organic matter was found to be enriched in deuterium, and distinct organic compounds show isotopic enrichments of carbon and nitrogen relative to terrestrial matter.

  11. Volatile compounds from Melicope obscura.

    PubMed

    Smadja, Jacqueline; Strasberg, Dominique; Legoff, Géraldine; Gauvin-Bialecki, Anne

    2010-02-01

    To evaluate the interpopulation variability of volatile compounds in Melicope obscura, four samples representing four populations were collected all over the distribution area of the species in Reunion Island (Indian Ocean). The samples were extracted by hydrodistillation, and analyzed using GC/FID and GC/MS techniques. The study revealed that, in the four essential oils obtained, oxygenated sesquiterpenes were one of the major chemical classes (9.2-35.2%), mainly consisting of a new compound, (+)-6-ethenyl-2-hydroxy-6,10-dimethylundeca-2,9-dien-4-one (1), called melicopenol (8.6-30.1%). The compound was isolated by column chromatography and identified by spectral analyses including 1D- and 2D-NMR.

  12. Gallium-containing anticancer compounds.

    PubMed

    Chitambar, Christopher R

    2012-06-01

    There is an ever pressing need to develop new drugs for the treatment of cancer. Gallium nitrate, a group IIIa metal salt, inhibits the proliferation of tumor cells in vitro and in vivo and has shown activity against non-Hodgkin's lymphoma and bladder cancer in clinical trials. Gallium can function as an iron mimetic and perturb iron-dependent proliferation and other iron-related processes in tumor cells. Gallium nitrate lacks crossresistance with conventional chemotherapeutic drugs and is not myelosuppressive; it can be used when other drugs have failed or when the blood count is low. Given the therapeutic potential of gallium, newer generations of gallium compounds are now in various phases of preclinical and clinical development. These compounds hold the promise of greater anti-tumor activity against a broader spectrum of cancers. The development of gallium compounds for cancer treatment and their mechanisms of action will be discussed.