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Sample records for strong antitumor activity

  1. Evaluation of antibacterial, antitumor, antioxidant activities and ...

    African Journals Online (AJOL)

    Results: Generally, yellow loosestrife extracts demonstrated antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, S. epidermidis and Streptococcus pyogenes). Strong antitumor activity of yellow loosestrife was observed via potato disc diffusion bioassay. Nine different phenolics were also determined ...

  2. Antitumoral activity of marine organism

    International Nuclear Information System (INIS)

    Valdes Iglesias, O; Perez Gil, R; Colom, Y

    2010-01-01

    The study of the natural products from marine organism constitute a relatively recent scientific researcher field with high potentialities tanking in consideration that the oceans cover the three of the four parts of the earth. Poryphera and Bryozoans have been the Phylum more studied owning to the vulnerability, their soft body, their habitat on rocks, their slow movement and bright colors, for these reason these organisms are able to produce chemical substances as defense methods against depredators. Same mechanism is exhibit by the seaweeds with the production of secondary metabolites . In the present communication are exposed the main results obtained on the world a Cuba until the present in the looking for of substances with antitumor action from marine organism

  3. Characterization and antitumor activity of camptothecin from ...

    African Journals Online (AJOL)

    Xueqin Ran1, Gen Zhang2, Sheng Li2, Jiafu Wang2,3. 1. College of Animal Science, ... Cite as: Ran X, Zhang G, Li S, Wang J. Characterization and antitumor activity of camptothecin from endophytic fungus Fusarium solani isolated from Camptotheca ... Camptotheca acuminata has been used as tradition- ally Chinese ...

  4. Antitumor and immunomodulatory activity of Inonotus obliquus

    Directory of Open Access Journals (Sweden)

    Staniszewska Justyna

    2017-06-01

    Full Text Available The article presents the antitumor and immunomodulatory activity of compounds and extracts from Inonotus obliquus. Polysaccharides isolated from sclerotium have a direct antitumor effect due to protein synthesis inhibition in tumor cells. Polysaccharides derived from the mycelium function by activating the immune system. Due to the limited toxicity of these substances, both extracts as well as isolated and purified chemicals may be a good alternative to current chemotherapy and play a role in cancer prevention. In vitro experiments have shown the inhibition of inflammation with the influence of action of I. obliquus extracts; however, in vivo experiments on animals implanted with tumor cells of different types have shown the activation of the host immune system. This led to decrease in tumor mass and prolonged survival. The immunomodulatory mechanism of action is complex and it seems that stimulation of macrophages and induction of apoptosis in cancer cells is of great importance.

  5. Antitumor activity of Annona squamosa seed oil.

    Science.gov (United States)

    Chen, Yong; Chen, Yayun; Shi, Yeye; Ma, Chengyao; Wang, Xunan; Li, Yue; Miao, Yunjie; Chen, Jianwei; Li, Xiang

    2016-12-04

    Custard apple (Annona squamosa Linn.) is an edible tropical fruit, and its seeds have been used to treat "malignant sore" (cancer) and other usage as insecticide. A comparison of extraction processes, chemical composition analysis and antitumor activity of A. squamosa seed oil (ASO) were investigated. The optimal extraction parameters of ASO were established by comparing percolation, soxhlet, ultrasonic and SFE-CO 2 extraction methods. The chemical composition of fatty acid and content of total annonaceous acetogenins (ACGs) of ASO was investigated by GC-MS and colorimetric assay, and anti-tumor activity of ASO was tested using H 22 xenografts bearing mice. The optimal extraction parameters of ASO were obtained as follows: using soxhlet extraction method with extraction solvent of petroleum ether, temperature of 80°C, and extraction time of 90min. Under these conditions, the yield of ASO was 22.65%. GC-MS analysis results showed that the main chemical compositions of fatty acid of ASO were palmitic acid (9.92%), linoleic acid (20.49%), oleic acid (56.50%) and stearic acid (9.14%). The total ACGs content in ASO was 41.00mg/g. ASO inhibited the growth of H 22 tumor cells in mice with a maximum inhibitory rate of 53.54% by oral administration. Furthermore, it was found that ASO exerted an antitumor effect via decreasing interleukin-6 (IL-6), janus kinase (Jak) and phosphorylated signal transducers and activators of transcription (p-Stat3) expression. The results demonstrated that ASO suppressed the H 22 solid tumor development may due to its main chemical constituents unsaturated fatty acid and ACGs via IL-6/Jak/Stat3 pathway. ASO may be a potential candidate for the treatment of cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Onconase: A ribonuclease with antitumor activity

    Directory of Open Access Journals (Sweden)

    Małgorzata Zwolińska

    2010-02-01

    Full Text Available Onconase (ranpirnase is a homologous protein obtained from [i]Rana pipiens [/i]frog eggs. The activity of onconase, and particularly its antitumor effect, is strictly connected with ribonuclease (RN-ase activity. Onconase induces cell death through the decomposition of inner cellular RNA, inhibition of protein synthesis, and inhibition of cell growth and proliferation and it also specifically triggers tumor cell apoptosis. A very important mechanisms of its cytotoxicity is also its antioxidant activity. The results of preclinical trials demonstrated a high activity of onconase against tumor cells, also those resistant to cytostatics. Moreover, onconase showed synergic activity with other commonly used anticancer drugs. Several clinical trials were performed on patients suffering from kidney, breast, and pancreatic cancers. Most recently a phase III study of onconase in patients with mesothelioma was completed. There are also ongoing phase I and II clinical trials with non-small-cell lung cancer (NSCLC.

  7. Structural Antitumoral Activity Relationships of Synthetic Chalcones

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    Cesar Echeverria

    2009-01-01

    Full Text Available Relationships between the structural characteristic of synthetic chalcones and their antitumoral activity were studied. Treatment of HepG2 cells for 24 h with synthetic 2’-hydroxychalcones resulted in apoptosis induction and dose-dependent inhibition of cell proliferation. The calculated reactivity indexes and the adiabatic electron affinities using the DFT method including solvent effects, suggest a structure-activity relationship between the Chalcones structure and the apoptosis in HepG2 cells. The absence of methoxy substituents in the B ring of synthetic 2’-hydroxychalcones, showed the mayor structure-activity pattern along the series.

  8. Evaluation of Antitumor Activity of Cuscuta Reflexa Roxb ...

    African Journals Online (AJOL)

    On day 21, six animals in each group were sacrificed for observation of antitumor activity and the remaining animals were observed to determine host the life span. Antitumor effect was determined by evaluating tumor volume, viable and nonviable tumor cell count and hematological parameters of the host. The standard ...

  9. Antitumor Activity of Propolis on Differantiated Cancer Cell Lines

    OpenAIRE

    , Neşe Ersöz Gülçelik, Dilara Zeybek, Fige

    2012-01-01

    Propolis is a natural bee product with several pharmacological activities. Nowadays, it is also investigated for its antitumor properties. There are contraversies on the antitumor activity of propolis, not all tumour cells seem to respond to propolis treatment. The aim of our study is to evaluate the activity of propolis on differantiated thyroid cancer cell lines. Tyripan blue test and MTT assay were performed to evaluate the cell viability of B-CPAP cells after propolis treatment and compar...

  10. Assessment of in vitro antitumoral and antimicrobial activities of ...

    African Journals Online (AJOL)

    Assessment of in vitro antitumoral and antimicrobial activities of marine algae harvested from the eastern Mediterranean sea. ... African Journal of Biotechnology ... algal extracts obtained from the marine algae Scytosiphon lomentaria, Padina pavonica, Cystoseira mediterranea (Phaeophyceae), Hypnea musciformis and ...

  11. Antitumor active polysaccharides from the Chinese mushroom Songshan lingzhi, the fruiting body of Ganoderma tsugae.

    Science.gov (United States)

    Wang, G; Zhang, J; Mizuno, T; Zhuang, C; Ito, H; Mayuzumi, H; Okamoto, H; Li, J

    1993-06-01

    A systematic method of extraction, fractionation, and purification of polysaccharides from Songshan Lingzhi (Ganoderma tsugae) with antitumor activity was established. Seven glycans with strong antitumor activities were obtained from 14 water-soluble, and 15 water-insoluble fractions: FIo-a, FA-1, FII-1, FIII-2, and FIII-2-a, -b, and -c. FIo-a and FA-1 were protein-containing glucogalactans associated with mannose and fucose. FII-1 was a (1-->3)-beta-D-glucan having a lower protein content. The water-insoluble fractions FIII-2-a, -b, and -c were extracted with alkali, and were found to be protein-containing (1-->3)-beta-D-glucans showing the strongest activity. Chemical properties and structure of each antitumor polysaccharide were compared with three fungi of the Ganoderma family, Kofukitake (G. applanatum), Mannentake (G. lucidum), and Songshan Lingzhi (G. tsugae).

  12. Targeting G-quadruplex DNA Structures by EMICORON has a strong antitumor efficacy against advanced models of human colon cancer

    DEFF Research Database (Denmark)

    Porru, Manuela; Artuso, Simona; Salvati, Erica

    2015-01-01

    similar blood levels in humans. Moreover, EMICORON showed a marked therapeutic efficacy, as it inhibited the growth of patient-derived xenografts (PDX) and orthotopic colon cancer and strongly reduced the dissemination of tumor cells to lymph nodes, intestine, stomach, and liver. Finally, activation...... of human colon cancer that could adequately predict human clinical outcomes. Our results showed that EMICORON was well tolerated in mice, as no adverse effects were reported, and a low ratio of sensitivity across human and mouse bone marrow cells was observed, indicating a good potential for reaching...... of DNA damage and impairment of proliferation and angiogenesis are proved to be key determinants of EMICORON antitumoral activity. Altogether, our results, performed on advanced experimental models of human colon cancer that bridge the translational gap between preclinical and clinical studies...

  13. Antiviral and antitumor activities of the protein fractions from the ...

    African Journals Online (AJOL)

    AJL

    2012-05-15

    May 15, 2012 ... (2004). The chitosan, extracted from M. domestica was found to have effect on fungus and bacteria (Ai et al., 2008, 2012) while the extract from the larvae of the housefly exhibited antibacterial activity and in vitro anti-tumor activity (Hou et al., 2007a). In addition, Hf-1, a novel antibacterial peptide, was also.

  14. Study on the antioxidant and antitumoral activity of propolis

    Directory of Open Access Journals (Sweden)

    Elisa del Río del Rosal

    Full Text Available ABSTRACT Introduction: Propolis is the substance that protects the hive, a resin of complex and viscous composition bees use in the repair and protection of the hive. The material from which propolis arises are the resins, shoots and petioles of the leaves of different plants, so it has a very complex chemical composition that varies depending on the flora of the bees collection. It offers an antimicrobial, anti-inflammatory capacity related to its antioxidant, immunomodulatory power, among others. Aims: In this work, antioxidant and antitumoral activities of different propolis collected from different areas of the province of Malaga, comparing them with one from the Bohemian region to the south of the Czech Republic are studied. Material and methods: Antioxidant activity was determined according to the ABTS+/S2O8K2 method. In addition, the quantity of total proteins from the nitrogen content and subsequently the cytotoxicity and antitumoral activity of the propolis of Puerto de la Torre, north of Malaga, are measured according to the 3-(4,5-dimetiltiazol-2-il-2,5-diphenyl tetrazolium bromide method. Results: It was observed that propolis has high antioxidant activity, although it has a lower amount of proteins. Propolis has high toxicity and higher antitumoral activity against colon cancer than leukemia. Discussion: With all these data, it can be concluded that propolis offers different activities of interest, for the food and cosmetic industry, among which the high antioxidant and antitumoral capacity.

  15. A novel, polymer-coated oncolytic measles virus overcomes immune suppression and induces robust antitumor activity

    Directory of Open Access Journals (Sweden)

    Kaname Nosaki

    2016-01-01

    Full Text Available Although various therapies are available to treat cancers, including surgery, chemotherapy, and radiotherapy, cancer has been the leading cause of death in Japan for the last 30 years, and new therapeutic modalities are urgently needed. As a new modality, there has recently been great interest in oncolytic virotherapy, with measles virus being a candidate virus expected to show strong antitumor effects. The efficacy of virotherapy, however, was strongly limited by the host immune response in previous clinical trials. To enhance and prolong the antitumor activity of virotherapy, we combined the use of two newly developed tools: the genetically engineered measles virus (MV-NPL and the multilayer virus-coating method of layer-by-layer deposition of ionic polymers. We compared the oncolytic effects of this polymer-coated MV-NPL with the naked MV-NPL, both in vitro and in vivo. In the presence of anti-MV neutralizing antibodies, the polymer-coated virus showed more enhanced oncolytic activity than did the naked MV-NPL in vitro. We also examined antitumor activities in virus-treated mice. Complement-dependent cytotoxicity and antitumor activities were higher in mice treated with polymer-coated MV-NPL than in mice treated with the naked virus. This novel, polymer-coated MV-NPL is promising for clinical cancer therapy in the future.

  16. Evaluation of Antibacterial and Antitumor Activities of Some Turkish ...

    African Journals Online (AJOL)

    Purpose: To investigate the antibacterial and antitumor activities of the aerial parts of 8 different Turkish endemic plants (Phlomis russeliana, Phlomis armeniaca, Astragalus brachypterus, Astrantia maxima, Ptilostemon afer, Senecio castagneanus, Echium orientale and Arum euxinum). Methods: Two different bioassays ...

  17. In vitro Antitumor Activities of Platycarya strobilacea Sieb et Zucc ...

    African Journals Online (AJOL)

    Purpose: To evaluate the antitumor activities of Platycarya strobilacea infructescence extracts in A549, HepG2, SH-SY-5Y, HCT116, and U2OS-NKFB cell lines. Methods: The total amount of phenolics in P. strobilacea infructescence based on three solvent extracts (methanol, ethyl acetate and water) was measured using ...

  18. Antitumor activity of physcion 8-o-β-glucopyranoside against ...

    African Journals Online (AJOL)

    In vivo, PSG also had significant anti-tumor activity in nude mouse xenograft model (p < 0.05), inhibiting tumor growth. Furthermore, the results showed that treatment with PSG (20, 40 and 60 μg/mL) for 24 h resulted in significantly increased apoptosis in HeLa cells (p < 0.05). Additionally, Western blot analysis revealed that ...

  19. In vitro Antitumor Activities of Platycarya strobilacea Sieb et Zucc ...

    African Journals Online (AJOL)

    1Institute of Chemical Industry of Forest Products, Chinese Academy of Forestry, National Engineering Lab. for Biomass. Chemical Utilization ... Conclusion: The study confirms the antitumor activities of ethyl acetate and methanol extracts of P. strobilacea ..... The authors are grateful to the Natural Science. Foundation of ...

  20. Antitumor activity of doxorubicine-loaded nanoemulsion against ...

    African Journals Online (AJOL)

    Purpose: To evaluate the antitumor activity of doxorubicine (DOX) loaded nanoemulsion (NE) on Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Methods: The mice were divided into five groups (n = 20) according to the administered drug. Groups I - V were labeled as negative control (normal), positive control ...

  1. Comparison in antioxidant and antitumor activities of pine polyphenols and its seven biotransformation extracts by fungi

    OpenAIRE

    Hui Li; Zhenyu Wang

    2017-01-01

    Microbial transformation can strengthen the antioxidant and antitumor activities of polyphenols. Polyphenols contents, antioxidant and antitumor activities of pine polyphenols and its biotransformation extracts by Aspergillus niger, Aspergillus oryzae, Aspergillus carbonarius, Aspergillus candidus, Trichodermas viride, Mucor wutungkiao and Rhizopus sp were studied. Significant differences were noted in antioxidant and antitumor activities. The highest antioxidant activities in Trolox equivale...

  2. Intermittent Metronomic Drug Schedule Is Essential for Activating Antitumor Innate Immunity and Tumor Xenograft Regression

    Directory of Open Access Journals (Sweden)

    Chong-Sheng Chen

    2014-01-01

    Full Text Available Metronomic chemotherapy using cyclophosphamide (CPA is widely associated with antiangiogenesis; however, recent studies implicate other immune-based mechanisms, including antitumor innate immunity, which can induce major tumor regression in implanted brain tumor models. This study demonstrates the critical importance of drug schedule: CPA induced a potent antitumor innate immune response and tumor regression when administered intermittently on a 6-day repeating metronomic schedule but not with the same total exposure to activated CPA administered on an every 3-day schedule or using a daily oral regimen that serves as the basis for many clinical trials of metronomic chemotherapy. Notably, the more frequent metronomic CPA schedules abrogated the antitumor innate immune and therapeutic responses. Further, the innate immune response and antitumor activity both displayed an unusually steep dose-response curve and were not accompanied by antiangiogenesis. The strong recruitment of innate immune cells by the 6-day repeating CPA schedule was not sustained, and tumor regression was abolished, by a moderate (25% reduction in CPA dose. Moreover, an ~20% increase in CPA dose eliminated the partial tumor regression and weak innate immune cell recruitment seen in a subset of the every 6-day treated tumors. Thus, metronomic drug treatment must be at a sufficiently high dose but also sufficiently well spaced in time to induce strong sustained antitumor immune cell recruitment. Many current clinical metronomic chemotherapeutic protocols employ oral daily low-dose schedules that do not meet these requirements, suggesting that they may benefit from optimization designed to maximize antitumor immune responses.

  3. Antitumor metallothiosemicarbazonates: structure and antitumor activity of palladium complex of phenanthrenequinone thiosemicarbazone.

    Science.gov (United States)

    Padhye, Subhash; Afrasiabi, Zahra; Sinn, Ekk; Fok, Jansina; Mehta, Kapil; Rath, Nigam

    2005-03-07

    The crystal structure of the potential antitumor metal compound, viz. chloro, mono(phenanthrenequinone thiosemicarbazonato) palladium(II) dimethyl formamide solvate, is reported. The central palladium(II) atom is in a square planar environment provided by the tridentate, monoanionic thiosemicarbazone ligand and the ancillary chloride ion. The compound exhibited remarkable activity against drug-sensitive and drug-resistant breast cancer cell lines and was relatively nontoxic toward the normal mammary epithelial cells. The drug-induced killing effect against breast cancer cell lines was predominantly mediated via apoptosis, a physiologic form of cell death.

  4. Woodfruticosin (woodfordin C), a new inhibitor of DNA topoisomerase II. Experimental antitumor activity.

    Science.gov (United States)

    Kuramochi-Motegi, A; Kuramochi, H; Kobayashi, F; Ekimoto, H; Takahashi, K; Kadota, S; Takamori, Y; Kikuchi, T

    1992-11-17

    Woodfruticosin (woodfordin C) (WFC), a new inhibitor of DNA topoisomerase II (topo-II), was isolated from methanol extract of Woodfordia fruticosa Kurz (Lythraceae) and studied for in vitro and in vivo antitumor activities in comparison with Adriamycin (ADR) and etoposide (ETP), well known inhibitors of topo-II. The inhibitory activity against DNA topo-II shown by WFC was much stronger than that shown by ETP or ADR. WFC inhibited strongly intracellular DNA synthesis but not RNA and protein synthesis. On the other hand, WFC had a weaker growth inhibitory activity against various human tumor cells than ETP or ADR, but it showed remarkable activity against PC-1 cells and moderate activity against MKN45 and KB cells. Furthermore, WFC had in vivo growth inhibitory activity against s.c. inoculated colon38. These results indicate that the mechanism by which WFC exhibits antitumor activity may be through inhibition of topo-II.

  5. In Vitro Antitumor Activity of Sesquiterpene Lactones from Lychnophora trichocarpha

    Directory of Open Access Journals (Sweden)

    D.A. Saúde-Guimarães

    2014-06-01

    Full Text Available The sesquiterpene lactones lychnopholide and eremantholide C were isolated from Lychnophora trichocarpha Spreng. (Asteraceae, which is a plant species native to the Brazilian Savannah or Cerrado and popularly known as arnica. Sesquiterpene lactones are known to present a variety of biological activities including antitumor activity. The present paper reports on the evaluation of the in vitro antitumor activity of lychnopholide and eremantholide C, in the National Cancer Institute, USA (NCI, USA, against a panel of 52 human tumor cell lines of major human tumors derived from nine cancer types. Lychnopholide disclosed significant activity against 30 cell lines of seven cancer types with IC100 (total growth concentration inhibition values between 0.41 µM and 2.82 µM. Eremantholide C showed significant activity against 30 cell lines of eight cancer types with IC100 values between 21.40 µM and 53.70 µM. Lychnopholide showed values of lethal concentration 50% (LC50 for 30 human tumor cell lines between 0.72 and 10.00 µM, whereas eremantholide C presented values of LC50 for 21 human tumor cell lines between 52.50 and 91.20 µM. Lychnopholide showed an interesting profile of antitumor activity. The α-methylene-γ-lactone present in the structure of lychnopholide, besides two α,β- unsaturated carbonyl groups, might be responsible for the better activity and higher cytotoxicity of this compound in relation to eremantholide C.

  6. Antitumor Activity of Monoterpenes Found in Essential Oils

    Directory of Open Access Journals (Sweden)

    Marianna Vieira Sobral

    2014-01-01

    Full Text Available Cancer is a complex genetic disease that is a major public health problem worldwide, accounting for about 7 million deaths each year. Many anticancer drugs currently used clinically have been isolated from plant species or are based on such substances. Accumulating data has revealed anticancer activity in plant-derived monoterpenes. In this review the antitumor activity of 37 monoterpenes found in essential oils is discussed. Chemical structures, experimental models, and mechanisms of action for bioactive substances are presented.

  7. Antibacterial and Antitumor Activities of Biscoumarin and Dihydropyran Derivatives

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    Yun-Peng Sui

    2015-09-01

    Full Text Available A novel series of biscoumarin (1–4 and dihydropyran (5–13 derivatives were synthesized via a one-pot multicomponent condensation reaction and evaluated for antibacterial and antitumor activity in vitro. The X-ray crystal structure analysis of four representative compounds, 3, 7, 9 and 11, confirmed the structures of these compounds. Compounds 1–4 showed the most potent antitumor activity among the total 13 derivatives; especially for compounds 1 and 2, they also emerged as promising antibacterial members with better antibacterial activity. In addition, the results of density functional theory (DFT showed that compared with compounds 3 and 4, biscoumarins 1 and 2 had lower intramolecular hydrogen bonds (HB energy in their structures.

  8. Silybin-mediated inhibition of Notch signaling exerts antitumor activity in human hepatocellular carcinoma cells.

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    Song Zhang

    Full Text Available Hepatocellular carcinoma (HCC is a global health burden that is associated with limited treatment options and poor patient prognoses. Silybin (SIL, an antioxidant derived from the milk thistle plant (Silybum marianum, has been reported to exert hepatoprotective and antitumorigenic effects both in vitro and in vivo. While SIL has been shown to have potent antitumor activity against various types of cancer, including HCC, the molecular mechanisms underlying the effects of SIL remain largely unknown. The Notch signaling pathway plays crucial roles in tumorigenesis and immune development. In the present study, we assessed the antitumor activity of SIL in human HCC HepG2 cells in vitro and in vivo and explored the roles of the Notch pathway and of the apoptosis-related signaling pathway on the activity of SIL. SIL treatment resulted in a dose- and time-dependent inhibition of HCC cell viability. Additionally, SIL exhibited strong antitumor activity, as evidenced not only by reductions in tumor cell adhesion, migration, intracellular glutathione (GSH levels and total antioxidant capability (T-AOC but also by increases in the apoptotic index, caspase3 activity, and reactive oxygen species (ROS. Furthermore, SIL treatment decreased the expression of the Notch1 intracellular domain (NICD, RBP-Jκ, and Hes1 proteins, upregulated the apoptosis pathway-related protein Bax, and downregulated Bcl2, survivin, and cyclin D1. Notch1 siRNA (in vitro or DAPT (a known Notch1 inhibitor, in vivo further enhanced the antitumor activity of SIL, and recombinant Jagged1 protein (a known Notch ligand in vitro attenuated the antitumor activity of SIL. Taken together, these data indicate that SIL is a potent inhibitor of HCC cell growth that targets the Notch signaling pathway and suggest that the inhibition of Notch signaling may be a novel therapeutic intervention for HCC.

  9. Snake venoms components with antitumor activity in murine melanoma cells

    International Nuclear Information System (INIS)

    Queiroz, Rodrigo Guimaraes

    2012-01-01

    Despite the constant advances in the treatment of cancer, this disease remains one of the main causes of mortality worldwide. So, the development of new treatment modalities is imperative. Snake venom causes a variety of biological effects because they constitute a complex mixture of substances as disintegrins, proteases (serine and metalo), phospholipases A2, L-amino acid oxidases and others. The goal of the present work is to evaluate a anti-tumor activity of some snake venoms fractions. There are several studies of components derived from snake venoms with this kind of activity. After fractionation of snake venoms of the families Viperidae and Elapidae, the fractions were assayed towards murine melanoma cell line B16-F10 and fibroblasts L929. The results showed that the fractions of venom of the snake Notechis ater niger had higher specificity and potential antitumor activity on B16-F10 cell line than the other studied venoms. Since the components of this venom are not explored yet coupled with the potential activity showed in this work, we decided to choose this venom to develop further studies. The cytotoxic fractions were evaluated to identify and characterize the components that showed antitumoral activity. Western blot assays and zymography suggests that these proteins do not belong to the class of metallo and serine proteinases. (author)

  10. Jungle Honey Enhances Immune Function and Antitumor Activity

    Science.gov (United States)

    Fukuda, Miki; Kobayashi, Kengo; Hirono, Yuriko; Miyagawa, Mayuko; Ishida, Takahiro; Ejiogu, Emenike C.; Sawai, Masaharu; Pinkerton, Kent E.; Takeuchi, Minoru

    2011-01-01

    Jungle honey (JH) is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal). After seven injections, peritoneal cells (PC) were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2) cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS) producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW) of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261. PMID:19141489

  11. Jungle Honey Enhances Immune Function and Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Miki Fukuda

    2011-01-01

    Full Text Available Jungle honey (JH is collected from timber and blossom by wild honey bees that live in the tropical forest of Nigeria. JH is used as a traditional medicine for colds, skin inflammation and burn wounds as well as general health care. However, the effects of JH on immune functions are not clearly known. Therefore, we investigated the effects of JH on immune functions and antitumor activity in mice. Female C57BL/6 mice were injected with JH (1 mg/mouse/day, seven times intra-peritoneal. After seven injections, peritoneal cells (PC were obtained. Antitumor activity was assessed by growth of Lewis Lung Carcinoma/2 (LL/2 cells. PC numbers were increased in JH-injected mice compared to control mice. In Dot Plot analysis by FACS, a new cell population appeared in JH-injected mice. The percent of Gr-1 surface antigen and the intensity of Gr-1 antigen expression of PC were increased in JH-injected mice. The new cell population was neutrophils. JH possessed chemotactic activity for neutrophils. Tumor incidence and weight were decreased in JH-injected mice. The ratio of reactive oxygen species (ROS producing cells was increased in JH-injected mice. The effective component in JH was fractionized by gel filtration using HPLC and had an approximate molecular weight (MW of 261. These results suggest that neutrophils induced by JH possess potent antitumor activity mediated by ROS and the effective immune component of JH is substrate of MW 261.

  12. Antitumor Activity of Isosteroidal Alkaloids from the Plants in the Genus Veratrum and Fritillaria.

    Science.gov (United States)

    Shang, Yuanhong; Du, Qingdan; Liu, Simei; Staadler, Maksorvor; Wang, Shu; Wang, Dongdong

    2018-01-01

    Isosteroidal alkaloids are a category of promising bioactive compounds which mostly exist in plants of genus Veratrum and Fritillaria. The pharmacological activities of isosteroidal alkaloids include antihypertensive, antitussive, anti-inflammatory, antithrombosis, among others. Recently, some studies show that this kind of alkaloids exhibited significant antitumor activity. To the best of our knowledge, there is no review focusing on their antitumor activity and mechanism of their antitumor activity. To fill the gap, in this review, we summarized antitumor effects of the isosteroidal alkaloids from genus Veratrum and Fritillaria on different tumors and the mechanisms of their antitumor activity. In conclusion, this kind of alkaloids has extensive antitumor activity, and there are several main mechanisms of their antitumor activity, including the Hedgehog signaling pathway, caspase-3 dependent apoptosis, cell cycle, and autophagy. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  13. The anti-tumor effect and biological activities of the extract JMM6 ...

    African Journals Online (AJOL)

    Juglans mandshurica Maxim is a traditional herbal medicines in China, and its anti-tumor bioactivities are of research interest. Bioassay-guided fractionation method was employed to isolate anti-tumor compounds from the stem barks of the Juglans mandshurica Maxim. The anti-tumor effect and biological activities of the ...

  14. Separation, antitumor activities, and encapsulation of polypeptide from Chlorella pyrenoidosa.

    Science.gov (United States)

    Wang, Xiaoqin; Zhang, Xuewu

    2013-01-01

    Chlorella pyrenoidosa is a unicellular green algae and has been a popular foodstuff worldwide. However, no reports on the antitumor peptides from such a microalgae are available in the literature. In this study, using low-temperature high-pressure extraction, enzymatic hydrolysis, ion exchange, and gel filtration chromatography, we separated a polypeptide that exhibited inhibitory activity on human liver cancer HepG2 cells, and named the polypeptide CPAP (C. pyrenoidosa antitumor polypeptide). Furthermore, the micro- and nanoencapsulation of CPAP were investigated by using two methods: complex coacervation and ionotropic gelation. The in vitro release tests revealed that CPAP was well preserved against gastric enzymatic degradation after micro/nanoencapsulation and the slowly controlled release in the intestine could be potentially achieved. These results suggest that CPAP may be a useful ingredient in food, nutraceutical, and pharmaceutical applications. © 2013 American Institute of Chemical Engineers.

  15. Characterization and antitumor activity of camptothecin from ...

    African Journals Online (AJOL)

    Background: Camptothecin (CPT) is a potent drug against cancers, originally from plants. The endophytic fungi could produce the secondary metabolite same as the host and is used as medicine. Objectives: The aim of this paper was to investigate an endophytic fungal CPT with anti-neoplastic activity. Methods: Endophytic ...

  16. compounds: Structure–antitumor activity considerations

    Indian Academy of Sciences (India)

    Administrator

    human colon, gastric and prostate carcinomas. New strategies in ligand design, coordination chemistry with coinage metals (Au and Ag) and structure-biological activity considerations are presented. References. 1. Katti K V, Gali H, Smith C J and Berning D E 1999 Acc. Chem. Res. 32 9. 2. Gali H, Karra S R, Reddy V S and ...

  17. Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds.

    Science.gov (United States)

    Chen, Ling; Zhang, Qiao-Yan; Jia, Min; Ming, Qian-Liang; Yue, Wei; Rahman, Khalid; Qin, Lu-Ping; Han, Ting

    2016-05-01

    Plant endophytic fungi have been recognized as an important and novel resource of natural bioactive products, especially in anticancer application. This review mainly deals with the research progress on the production of anticancer compounds by endophytic fungi between 1990 and 2013. Anticancer activity is generally associated with the cytotoxicity of the compounds present in the endophytic fungi. All strains of endophytes producing antitumor chemicals were classified taxonomically and the genera of Pestalotiopsis and Aspergillus as well as the taxol producing endophytes were focused on. Classification of endophytic fungi producing antitumor compounds has received more attention from mycologists, and it can also lead to the discovery of novel compounds with antitumor activity due to phylogenetic relationships. In this review, the structures of the anticancer compounds isolated from the newly reported endophytes between 2010 and 2013 are discussed including strategies for the efficient production of the desired compounds. The purpose of this review is to provide new directions in endophytic fungi research including integrated information relating to its anticancer compounds.

  18. Radiometric prescreen for antitumor activity with Saccharomyces cerevisiae mutant strain.

    Science.gov (United States)

    Speedie, M K; Fique, D V; Blomster, R N

    1980-07-01

    After modification, a technique for radiometrically measuring bacterial growth has been applied to a mutant strain of Saccharomyces cerevisiae. The assay is based on inhibition of 14CO2 release from [14C]glucose, which provides an extremely sensitive measure of cellular respiratory activity and growth. The criterion for antitumor activity is the differential inhibition of wild-type and mutant (distorted cell membrane) strains of the yeast. The system was optimized for medium, time of incubation, temperature, and size of inoculum. Known antitumor agents, including bleomycin, actinomycin D, adriamycin, and ellipticine were tested in the system, and differential inhibition was observed. Vincristine showed no inhibitory effects at the concentrations tried. The sensitivity for 20% inhibition ranged from 0.8 micrograms of adriamycin per ml to 0.14 mg of ellipticine per ml. Antifungal agents such as amphotericin B exhibited no differential inhibition. Antibacterial agents were inactive. This method may provide a rapid, sensitive, in vitro quantitative assay for antitumor agents which could be applied to a variety of assay needs and which can be run with facilities and equipment available in most laboratories.

  19. Gamma-irradiated bacterial preparation having anti-tumor activity

    International Nuclear Information System (INIS)

    Vass, A.A.; Tyndall, R.L.; Terzaghi-Howe, P.

    1999-01-01

    This application describes a bacterial preparation from Pseudomonas species isolated number s ign15 ATCC 55638 that has been exposed to gamma radiation exhibits cytotoxicity that is specific for neoplastic carcinoma cells. A method for obtaining a bacterial preparation having antitumor activity consists of suspending a bacterial isolate in media and exposing the suspension to gamma radiation. A bacterial preparation of an aged culture of an amoeba-associated bacteria exhibits anti-reverse transcriptase activity. A method for obtaining a bacterial preparation having anti-reverse transcriptase activity from an amoeba-associated bacterial isolate grown to stationary phase is disclosed

  20. Aragusterol C: a novel halogenated marine steroid from an Okinawan sponge, Xestospongia sp., possessing potent antitumor activity.

    Science.gov (United States)

    Shimura, H; Iguchi, K; Yamada, Y; Nakaike, S; Yamagishi, T; Matsumoto, K; Yokoo, C

    1994-02-15

    A novel chlorinated steroid, aragusterol C, was isolated from an Okinawan marine sponge of the genus Xestospongia. The compound strongly inhibited the proliferation of KB cells in vitro, and also showed potent in vivo antitumor activity against L1210 cells in mice. The complete structure of aragusterol C was determined by spectroscopic analysis and X-ray crystallographic analysis.

  1. High antitumor activity of pladienolide B and its derivative in gastric cancer

    Science.gov (United States)

    Sato, Momoko; Muguruma, Naoki; Nakagawa, Tadahiko; Okamoto, Koichi; Kimura, Tetsuo; Kitamura, Shinji; Yano, Hiromi; Sannomiya, Katsutaka; Goji, Takahiro; Miyamoto, Hiroshi; Okahisa, Toshiya; Mikasa, Hiroaki; Wada, Satoshi; Iwata, Masao; Takayama, Tetsuji

    2014-01-01

    The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction. PMID:24635824

  2. Antitumor activity of C-phycocyanin from Arthronema africanum (Cyanophyceae

    Directory of Open Access Journals (Sweden)

    Elena Gardeva

    2014-10-01

    Full Text Available Pure C-phycocyanin (C-PC was isolated from Arthronema africanumto evaluate its potential antitumor effects in vivo and in vitro. Experimental myeloid Graffi tumor in hamsters was used as a model. The cell proliferation assay showed that C-PC treatment, at concentration of 100 µg mL-1 for 24 h, significantly inhibited the growth of Graffi tumor cells (51.4% viability. Agarose gel electrophoresis of the genomic DNA of treated cells displayed time-and concentration-dependent fragmentation pattern, typical for apoptosis. Apoptotic process was related to the increase in cellular manganese and copper/zinc superoxide dismutases and glutathione reductase activities, coupled with a low catalase activity. In vivo C-PC administration (5.0 mg kg-1 body weight suppressed the tumor transplantability and growth, while the mean survival time of the tumor-bearing hamsters was increased. The results revealed promising antitumor activities of A. africanum C-PC and suggested the potential of this natural biliprotein pigment for future pharmacological and medical applications. The study provided new data on the mechanism of the C-PC induced apoptosis in which the imbalance of antioxidant enzymes that favoured hydrogen peroxide accumulation might play a leading role.

  3. Ganoderma applanatum: a promising mushroom for antitumor and immunomodulating activity.

    Science.gov (United States)

    Jeong, Yong-Tae; Yang, Byung-Keun; Jeong, Sang-Chul; Kim, Sang-Min; Song, Chi-Hyun

    2008-05-01

    The antitumor effect of exo-biopolymer (EXP) produced by Ganoderma applanatum was investigated using sarcoma-180 bearing mice. EXP, when administered (10-80 mg/kg body weight: BW) intraperitoneally, significantly inhibited the growth of solid tumor and increased the natural killer (NK) cell activity. A dose of 40 mg/kg BW was found to be highly effective, as it reduced the tumor formation by 39.7%, and increased the NK cell activity of splenocytes by 51.6% compared with the control group. The complement activity of EXP was increased in accordance with an increase in concentration. The phosphatase activity of macrophages was increased by 0.7-fold (200 microg/mL) compared with the control group. This EXP contained 58.9% carbohydrate and 17.1% protein. The major sugar of EXP was composed of mannose and glucose, while the protein mainly consisted of serine, glycine and aspartic acid.

  4. Antitumor Activity of Fascaplysin Derivatives on Glioblastoma Model In Vitro.

    Science.gov (United States)

    Lyakhova, I A; Bryukhovetsky, I S; Kudryavtsev, I V; Khotimchenko, Yu S; Zhidkov, M E; Kantemirov, A V

    2018-03-01

    Antitumor efficiency of fascaplysin synthetic derivatives (7-phenylfascaplysin, 3-chlorofascaplysin, 3-bromofascaplysin, and 10-bromofascaplysin) was compared out in vitro on C6 glioma cells. The cytotoxic efficiency of all tested compounds was higher than that of unsubstituted fascaplysin; 3-bromofascaplysin and 7-phenylfascaplysin exhibited the best capacity to kill glioma C6 cells. Apoptosis was the main mechanism of glioma cell death. The cytotoxic activity of these compounds increased with prolongation of exposure to the substance and increase of its concentration. Fascaplysin derivatives modified all phases of glioma cell vital cycle. The count of viable tumor cell in G0 phase remained minimum by the end of experiment under the effects of 3-bromofascaplysin and 7-phenylfascaplysin.

  5. Antitumor and Antiviral Activity of Colombian Medicinal Plant Extracts

    Directory of Open Access Journals (Sweden)

    Betancur-Galvis LA

    1999-01-01

    Full Text Available Extracts of nine species of plants traditionally used in Colombia for the treatment of a variety of diseases were tested in vitro for their potential antitumor (cytotoxicity and antiherpetic activity. MTT (Tetrazolium blue and Neutral Red colorimetric assays were used to evaluate the reduction of viability of cell cultures in presence and absence of the extracts. MTT was also used to evaluate the effects of the extracts on the lytic activity of herpes simplex virus type 2 (HSV-2. The 50% cytotoxic concentration (CC50 and the 50% inhibitory concentration of the viral effect (EC50 for each extract were calculated by linear regression analysis. Extracts from Annona muricata, A. cherimolia and Rollinia membranacea, known for their cytotoxicity were used as positive controls. Likewise, acyclovir and heparin were used as positive controls of antiherpetic activity. Methanolic extract from Annona sp. on HEp-2 cells presented a CC50 value at 72 hr of 49.6x103mg/ml. Neither of the other extracts examined showed a significant cytotoxicity. The aqueous extract from Beta vulgaris, the ethanol extract from Callisia grasilis and the methanol extract Annona sp. showed some antiherpetic activity with acceptable therapeutic indexes (the ratio of CC50 to EC50. These species are good candidates for further activity-monitored fractionation to identify active principles.

  6. Anti-Tumor Activity of a Polysaccharide from Blueberry

    Directory of Open Access Journals (Sweden)

    Xiyun Sun

    2015-02-01

    Full Text Available Blueberries (Vaccinium spp. are rich in bioactive compounds. However, the biological activity of polysaccharides from blueberry has not been reported so far. This study evaluated the anti-tumor and immunological activities of a polysaccharide (BBP3-1 from blueberry in S180-bearing mice. The experimental results indicated that BBP3-1 (100 mg·kg−1·d−1 inhibited the tumor growth rate by 73.4%. Moreover, this group, compared with the model control, had shown an effect of increasing both the spleen and thymus indices (p < 0.05, increasing phagocytosis by macrophages (p < 0.05, boosting the proliferation and transformation of lymphocytes (p < 0.01, promoting the secretion of TNF-α, IFN-γ, and IL-2 (p < 0.05 and improving NK cell activity (p < 0.01. From this study, we could easily conclude that BBP3-1 has the ability to inhibit tumor progression and could act as a good immunomodulator.

  7. [Study on the chemical components, antimicrobial and antitumor activities of the essential oil from the leaves of Zanthoxylum avicennae].

    Science.gov (United States)

    Zhang, Da-Shuai; Zhong, Qiong-Xin; Song, Xin-Ming; Liu, Wen-Jie; Wang, Jing; Zhang, Qiong-Yu

    2012-08-01

    To study the chemical constituents, antimicrobial activity and antitumor activity of the essential oil from Zanthoxylum avicennae. The essential oil from the leaves of Zanthoxylum avicennae was extracted by steam distillation. The components of the essential oil were separated and identified by GC-MS. 72 components were identified and accounted for 98.15% of the all peak area. The essential oil exhibited strong antitumor activity against K-562 human tumor cell lines with IC50 of 1.76 microg/mL. It also exhibited moderate antimicrobial activity against three bacteria. The essential oil of Zanthoxylum avicennae contains various active constituents. This result provides scientific reference for the pharmacological further research of Zanthoxylum avicennae.

  8. Antioxidant and anti-tumor activity of a polysaccharide from freshwater clam, Corbicula fluminea.

    Science.gov (United States)

    Liao, Ningbo; Chen, Shiguo; Ye, Xingqian; Zhong, Jianjun; Wu, Nian; Dong, Shilei; Yang, Bo; Liu, Donghong

    2013-04-25

    The fresh water clam Corbicula fluminea is currently one of the most economically important aquatic species in China because of its nutritional value and pharmacological activity. In order to explore the potential of C. fluminea as a natural resource of bioactive compounds, a papain-released polysaccharide designated CFPS-2 was isolated. Chemical composition analysis indicated that CFPS-2 contained glucosamine, glucose, galactose, fucose, protein and sulfate groups, with an average molecular weight of about 22 kDa. Furthermore, the antioxidant and antitumor activities, in vitro, of the polysaccharide fractions (crude CFPS and purified CFPS-2) were evaluated. CFPS-2, which exhibited strong antioxidant activities in a dose dependent manner also showed significant inhibitory effects on growth of human gastric cancer cells (SGC7901) and human ovarian carcinoma cells (SKOV3 and A2780). The present results suggest that CFPS-2 could be a potential candidate for the development of novel functional food ingredient.

  9. Experimental study of anti-tumor activity of direct current

    International Nuclear Information System (INIS)

    Ito, Hisao; Hashimoto, Shozo

    1989-01-01

    The anti-tumor activity of direct current combined with radiation was studied. The experiments were performed with fibrosarcomas (FSA, NFSA) syngenetic to C3H mice. Direct current (0.6mA, 120min) alone was effective to reduce the tumor sizes, but could not cure the tumors. When the direct current therapy (DC therapy) was combined with radiation the DC therapy following radiation was more effective than that before radiation. Using TCD 50 assay, the DC therapy enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.2. However, tumor control rates by the combination therapy were more improved at the smaller doses of radiation than at the larger ones. When the single DC therapy (0.6mA, 120min) was applied immediately after the first radiation of fractionated one the combination therapy still showed the enhanced effect. However, both DC therapy and the radiation therapy were divided in three fractions, and the DC therapy (0.6mA, 40min) was applied after each radiation. Tumor growth retardation by the combination therapy was no different from that by radiation alone. This result suggests that there might be a minimum required dose of coulombs to show the effect of the combination therapy. (author)

  10. Oridonin Loaded Solid Lipid Nanoparticles Enhanced Antitumor Activity in MCF-7 Cells

    Directory of Open Access Journals (Sweden)

    Lu Wang

    2014-01-01

    Full Text Available Oridonin (ORI, a famous diterpenoid from Chinese herbal medicine, has drawn rising attention for its remarkable apoptosis and autophagy-inducing activity in human cancer therapy, while clinical application of ORI is limited by its strong hydrophobicity and rapid plasma clearance. The purpose of this study was to evaluate whether the antitumor activity of ORI could be enhanced by loading into solid lipid nanoparticles (SLNs. ORI-loaded SLNs were prepared by hot high pressure homogenization with narrow size distribution and good entrapment efficacy. MTT assay indicated that ORI-loaded SLNs enhanced the inhibition of proliferation against several human cancer cell lines including breast cancer MCF-7 cells, hepatocellular carcinoma HepG 2 cells, and lung carcinoma A549 cells compared with free ORI, while no significant enhancement of toxicity to human mammary epithelial MCF-10A cells was shown. Meanwhile, flow cytometric analysis demonstrated that ORI-SLNs induced more significant cell cycle arrest at S and decreased cell cycle arrest at G1/G0 phase in MCF-7 cells than bulk ORI solution. Hoechst 33342 staining and Annexin V/PI assay indicated that apoptotic rates of cells treated with ORI-loaded SLNs were higher compared with free ORI. In summary, our data indicated that SLNs may be a potential carrier for enhancing the antitumor effect of hydrophobic drug ORI.

  11. Carboxylate groups play a major role in antitumor activity of Ganoderma applanatum polysaccharide.

    Science.gov (United States)

    Sun, Xiaobo; Zhao, Chen; Pan, Wei; Wang, Jinping; Wang, Weijun

    2015-06-05

    In this paper, the structure difference between the polysaccharides isolated from fruit bodies (FGAP) and submerged fermentation system (SGAP) of Ganoderma applanatum was investigated by means of GPC, HPLC and IR, respectively. And their antitumor activities were evaluated against Sarcoma 180 in vivo. The results showed that FGAP and SGAP were typical polysaccharides with different molecular weights, monosaccharide components, and functional groups. Closely related to the distinct structures, FGAP exhibited a better antitumor activity than SGAP. Moreover, since FGAP contained carboxylate groups rather than SGAP, such groups were chemically introduced into SGAP (CSGAP) by carboxymethylation in order to identify their contribution to antitumor activity. The results demonstrated that the inhibition of CSGAP against Sarcoma 180 in vivo was significantly enhanced by comparison to the native SGAP and even higher than that of FGAP, suggesting that the carboxylate groups played a major role in antitumor activity of G. applanatum polysaccharide. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Preclinical antitumor activity and pharmacological properties of deoxyspergualin.

    Science.gov (United States)

    Plowman, J; Harrison, S D; Trader, M W; Griswold, D P; Chadwick, M; McComish, M F; Silveira, D M; Zaharko, D

    1987-02-01

    A new antibiotic, deoxyspergualin (DSG), demonstrated antitumor activity against L1210 leukemia in mice. The life span of mice bearing either i.p. or s.c.-implanted L1210 increased greater than 150% following i.p. administration of 25 mg/kg DSG on days 1-9. Activity obtained with i.p. bolus treatments was schedule dependent. The tumor burden in mice bearing the s.c. implanted L1210 was reduced by 4-6 log10 units at the end of treatment when DSG was administered every 3 h for 8 injections on days 1, 5, and 9. By contrast, single injections of DSG on days 1, 5, and 9 allowed the tumor burden to increase at least 100-fold during treatment and daily single injections for 9 days reduced the tumor burden by 2 log10 units. The therapeutic advantage for i.p.-implanted L1210 of maintaining plasma concentrations of DSG was indicated further by infusion studies using s.c.-implanted Alzet osmotic pumps. Tumor burden was reduced by 3.5 and 6 log10 units following s.c. bolus treatments every 3 h on day 1 and a 24 h-infusion, respectively. The optimal infusion time for an infusion rate in mice of 179 mg/kg/day appeared to be 72 h. Pharmacokinetic studies following bolus i.v. injection revealed a rapid plasma clearance of parent drug (20.8 ml/min/kg) and a beta half-life of approximately 12 min. The bolus dose kinetics was used to predict the steady state plasma concentrations resulting from s.c. infusion; good agreement was observed between predicted values and experimental results. Based on these preclinical data, DSG has been developed to clinical trial. Initial Phase I protocols involve a 120-h infusion schedule.

  13. Anti-tumor activity of polysaccharides extracted from Senecio ...

    African Journals Online (AJOL)

    Purpose: To optimize the extraction conditions of polysaccharides from the root of Senecio scandens. Buch,-Ham. (PRS) and evaluate its anti-tumor effect on hepatocellular carcinoma. Methods: Response surface methodology (RSM) applied with a Box-Behnken design (BBD, three levels and three factors) was employed to ...

  14. Anti-tumor activity of polysaccharides extracted from Senecio ...

    African Journals Online (AJOL)

    Purpose: To optimize the extraction conditions of polysaccharides from the root of Senecio scandens Buch,-Ham. (PRS) and evaluate its anti-tumor effect on hepatocellular carcinoma. Methods: Response surface methodology (RSM) applied with a Box-Behnken design (BBD, three levels and three factors) was employed to ...

  15. Enavatuzumab, a Humanized Anti-TWEAK Receptor Monoclonal Antibody, Exerts Antitumor Activity through Attracting and Activating Innate Immune Effector Cells

    Directory of Open Access Journals (Sweden)

    Shiming Ye

    2017-01-01

    Full Text Available Enavatuzumab is a humanized IgG1 anti-TWEAK receptor monoclonal antibody that was evaluated in a phase I clinical study for the treatment of solid malignancies. The current study was to determine whether and how myeloid effector cells were involved in postulated mechanisms for its potent antitumor activity in xenograft models. The initial evidence for a role of effector cells was obtained in a subset of tumor xenograft mouse models whose response to enavatuzumab relied on the binding of Fc of the antibody to Fcγ receptor. The involvement of effector cells was further confirmed by immunohistochemistry, which revealed strong infiltration of CD45+ effector cells into tumor xenografts in responding models, but minimal infiltration in nonresponders. Consistent with the xenograft studies, human effector cells preferentially migrated toward in vivo-responsive tumor cells treated by enavatuzumab in vitro, with the majority of migratory cells being monocytes. Conditioned media from enavatuzumab-treated tumor cells contained elevated levels of chemokines, which might be responsible for enavatuzumab-triggered effector cell migration. These preclinical studies demonstrate that enavatuzumab can exert its potent antitumor activity by actively recruiting and activating myeloid effectors to kill tumor cells. Enavatuzumab-induced chemokines warrant further evaluation in clinical studies as potential biomarkers for such activity.

  16. Investigation of antitumor activities of trastuzumab delivered by PLGA nanoparticles.

    Science.gov (United States)

    Colzani, Barbara; Pandolfi, Laura; Hoti, Ada; Iovene, Pietro Alessandro; Natalello, Antonino; Avvakumova, Svetlana; Colombo, Miriam; Prosperi, Davide

    2018-01-01

    We report the development of an efficient antibody delivery system for the incorporation of trastuzumab (TZ) into poly(lactic- co -glycolic) acid nanoparticles (PLGA NPs). The aim of the work was to overcome the current limitations in the clinical use of therapeutic antibodies, including immunogenicity, poor pharmacokinetics, low tumor penetration and safety issues. Trastuzumab-loaded PLGA NPs (PLGA-TZ) were synthesized according to a double emulsion method. The same protocol was used to produce control batches of nonspecific IgG-loaded NPs and empty PLGA NPs. After release of TZ from PLGA NPs, the effects on the main biological activities of the antibody were evaluated on SKBR3 (human epidermal growth factor receptor 2 [HER2]-positive breast cancer cell line), including specific binding to HER2, phosphorylation of HER2 (Y1248), degradation of HER2 protein and antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism. In addition, an MTT assay was performed for treating SKBR3 cells with PLGA NPs loaded with TZ and doxorubicin to evaluate the cytotoxic activity of the combined treatment. TZ was gradually released in a prolonged way over 30 days. The physical characterization performed with circular dichroism, Fourier transform infrared and fluorescence spectroscopy of TZ after release demonstrated that no structural alterations occurred compared to the native antibody. In vitro experiments using SKBR3 cells showed that TZ released from PLGA NPs maintained the same biological activity of native TZ. PLGA NPs allowed a good co-encapsulation efficiency of TZ and doxorubicin resulting in improved therapy. With the TZ case study, we demonstrate that the distinctive features of therapeutic monoclonal antibodies, including molecular targeting efficiency, capability to inhibit or properly affect the regulatory signaling pathways of cancer cells and stimulation of the ADCC, are fully preserved after loading into and release from PLGA NPs. In addition, PLGA NPs are shown

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

    Science.gov (United States)

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

    2016-05-02

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

  18. Tumor Antigen-Dependent and Tumor Antigen-Independent Activation of Antitumor Activity in T Cells by a Bispecific Antibody-Modified Tumor Vaccine

    Directory of Open Access Journals (Sweden)

    Philippe Fournier

    2010-01-01

    Full Text Available New approaches of therapeutic cancer vaccination are needed to improve the antitumor activity of T cells from cancer patients. We studied over the last years the activation of human T cells for tumor attack. To this end, we combined the personalized therapeutic tumor vaccine ATV-NDV—which is obtained by isolation, short in vitro culture, irradiation, and infection of patient's tumor cells by Newcastle Disease Virus (NDV—with bispecific antibodies (bsAbs binding to this vaccine and introducing anti-CD3 (signal 1 and anti-CD28 (signal 2 antibody activities. This vaccine called ATV-NDV/bsAb showed the unique ability to reactivate a preexisting potentially anergized antitumor memory T cell repertoire. But it also activated naive T cells to have antitumor properties in vitro and in vivo. This innovative concept of direct activation of cancer patients' T cells via cognate and noncognate interactions provides potential for inducing strong antitumor activities aiming at overriding T cell anergy and tumor immune escape mechanisms.

  19. Comparative antitumor and anti-proliferative activities of Hippophae rhamnoides L. leaves extracts

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    Javid Ali

    2015-03-01

    Full Text Available Objective: To evaluate the antitumor and anti-proliferative activities of methanol, aqueous, acetone, ethyl acetate, ethanol, chloroform and n-hexane extracts of Hippophae rhamnoides leaves. Methods: Antitumor activities were evaluated by using the antitumor potato disc assay by using inoculums (Agrobacterium tumefaciens with three different concentrations of test samples (10, 100 and 1 000 mg/L. Anti-proliferative activity was evaluated by the given method of methyl thiazolyl tetrazolium assay. The concentrations of the extract ranging from 0.039 to 10 mg/mL were tested against HeLa cells. Results: Highest tumors inhibition activity (60.9% and 55.8% was shown by methanol and ethanol extracts, with EC50 values of 424.41 and 434.61 mg/L respectively. At 10 mg/mL, The highest cell inhibition 75.61% was observed in methanol extract and the lowest 36.59% were calculated in n-hexane extract. The difference in tumor and cell inhibition (% may be due to the different concentration of active compounds responsible for antitumor and anti-proliferative activities. All extracts have considerable level of tumor and cell inhibitiory effect in a dose dependent manner. Conclusions: Our finding showed that Hippophae rhamnoides leaves are a potent natural source of antitumor and antiproliferative agent.

  20. Adenosine can thwart antitumor immune responses elicited by radiotherapy. Therapeutic strategies alleviating protumor ADO activities

    Energy Technology Data Exchange (ETDEWEB)

    Vaupel, Peter [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Multhoff, Gabriele [Klinikum rechts der Isar, Technische Universitaet Muenchen (TUM), Department of Radiation Oncology, Munich (Germany); Helmholtz Zentrum Muenchen, Institute for innovative Radiotherapy (iRT), Experimental Immune Biology, Neuherberg (Germany)

    2016-05-15

    By studying the bioenergetic status we could show that the development of tumor hypoxia is accompanied, apart from myriad other biologically relevant effects, by a substantial accumulation of adenosine (ADO). ADO has been shown to act as a strong immunosuppressive agent in tumors by modulating the innate and adaptive immune system. In contrast to ADO, standard radiotherapy (RT) can either stimulate or abrogate antitumor immune responses. Herein, we present ADO-mediated mechanisms that may thwart antitumor immune responses elicited by RT. An overview of the generation, accumulation, and ADO-related multifaceted inhibition of immune functions, contrasted with the antitumor immune effects of RT, is provided. Upon hypoxic stress, cancer cells release ATP into the extracellular space where nucleotides are converted into ADO by hypoxia-sensitive, membrane-bound ectoenzymes (CD39/CD73). ADO actions are mediated upon binding to surface receptors, mainly A2A receptors on tumor and immune cells. Receptor activation leads to a broad spectrum of strong immunosuppressive properties facilitating tumor escape from immune control. Mechanisms include (1) impaired activity of CD4 + T and CD8 + T, NK cells and dendritic cells (DC), decreased production of immuno-stimulatory lymphokines, and (2) activation of Treg cells, expansion of MDSCs, promotion of M2 macrophages, and increased activity of major immunosuppressive cytokines. In addition, ADO can directly stimulate tumor proliferation and angiogenesis. ADO mechanisms described can thwart antitumor immune responses elicited by RT. Therapeutic strategies alleviating tumor-promoting activities of ADO include respiratory hyperoxia or mild hyperthermia, inhibition of CD39/CD73 ectoenzymes or blockade of A2A receptors, and inhibition of ATP-release channels or ADO transporters. (orig.) [German] Untersuchungen des bioenergetischen Status ergaben, dass Tumorhypoxie neben vielen anderen bedeutsamen biologischen Effekten zu einem starken

  1. Antitumor activity of orally administered maitake α-glucan by stimulating antitumor immune response in murine tumor.

    Directory of Open Access Journals (Sweden)

    Yuki Masuda

    Full Text Available Maitake α-glucan, YM-2A, isolated from Grifola frondosa, has been characterized as a highly α-1,6-branched α-1,4 glucan. YM-2A has been shown to possess an anti-virus effect in mice; however, it does not directly inhibit growth of the virus in vitro, indicating that the anti-virus effect of YM-2A might be associated with modulation of the host immune system. In this study, we found that oral administration of YM-2A could inhibit tumor growth and improve survival rate in two distinct mouse models of colon-26 carcinoma and B16 melanoma. Orally administered YM-2A enhanced antitumor immune response by increasing INF-γ-expressing CD4+ and CD8+ cells in the spleen and INF-γ-expressing CD8+ cells in tumor-draining lymph nodes. In vitro study showed that YM-2A directly activated splenic CD11b+ myeloid cells, peritoneal macrophages and bone marrow-derived dendritic cells, but did not affect splenic CD11b- lymphocytes or colon-26 tumor cells. YM-2A is more slowly digested by pancreatic α-amylase than are amylopectin and rabbit liver glycogen, and orally administered YM-2A enhanced the expression of MHC class II and CD86 on dendritic cells and the expression of MHC class II on macrophages in Peyer's patches. Furthermore, in vitro stimulation of YM-2A increased the expression of pro-inflammatory cytokines in Peyer's patch CD11c+ cells. These results suggest that orally administered YM-2A can activate dendritic cells and macrophages in Peyer's patches, inducing systemic antitumor T-cell response. Thus, YM-2A might be a candidate for an oral therapeutic agent in cancer immunotherapy.

  2. Toxic effect of nonylphenol on the marine macroalgae Gracilaria lemaneiformis (Gracilariales, Rhodophyta): antioxidant system and antitumor activity.

    Science.gov (United States)

    Zhong, Mingqin; Yin, Pinghe; Zhao, Ling

    2017-04-01

    The objective of the present work was to evaluate the toxic effect of nonylphenol (NP) on the antioxidant response and antitumor activity of Gracilaria lemaneiformis. An obvious oxidative damage was observed in this study. The thallus exposed to NP showed 1.2-2.0-fold increase in lipid peroxide and displayed a maximum level of 16.58 μmol g -1 Fw on 0.6 mg L -1 for 15-day exposure. The activities of antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT) enhanced significantly by 1.1-3.2-fold and subsequently diminished at the high concentrations and prolonged exposure. The results of DNA damage in comet assay also supported that NP was obviously toxic on G. lemaneiformis with increasing the percentage of tail DNA in a dose-dependent manner. Furthermore, the ethanol extract of G. lemaneiformis (EEGL) did exhibit antitumor potential against HepG-2 cells. While decreased in cell inhibition, ROS generation, apoptosis, and caspase-3 in HepG-2 cells treated with the EEGL were observed when G. lemaneiformis was exposed to NP for 15 days, and which were related to exposure concentration of NP. These suggested that NP has strongly toxic effect on the antitumor activity of G. lemaneiformis. The results revealed in this study imply that macroalgae can be useful biomarkers to evaluate marine pollutions.

  3. Synthesis and Antitumor Activity of Triazole-Containing Sorafenib Analogs

    Directory of Open Access Journals (Sweden)

    Wenjing Ye

    2017-10-01

    Full Text Available Using a highly effective binuclear Cu complex as the catalyst, the 1,3-dipolar cycloaddition reactions between 16 alkynes and two azides were successfully performed and resulted in the production of 25 new triazole-containing sorafenib analogs. Several compounds were evaluated as potent antitumor agents. Among them, 4-(4-(4-(3-fluorophenyl-1H-1,2,3-triazol-1-ylphenoxy-N-methylpicolinamide (8f potently suppressed the proliferation of HT-29 cancer cells by inducing apoptosis and almost completely inhibited colony formation at a low micromolar concentration.

  4. Semisynthesis and antitumoral activity of 2-acetylfuranonaphthoquinone and other naphthoquinone derivatives from lapachol.

    Science.gov (United States)

    Eyong, Kenneth O; Kumar, Ponminor S; Kuete, Victor; Folefoc, Gabriel N; Nkengfack, Ephriam A; Baskaran, Sundarababu

    2008-10-15

    Ozonolysis of lapachol (1), resulting in an unusual formation of a potent antitumor agent 2-acetylfuranonaphthoquinone (3) along with the expected aldehyde 6, is described. The reaction of lapachol (1) with CAN in dry acetonitrile leading to biologically active furanonaphthoquinones is also reported. The antitumoral activity of the tested compounds on human DU-145 prostate carcinoma cells was evaluated following XTT assay. The results revealed that 2-(1-methylethenyl)-2,3-dihydronaphtho[2,3-b]furan-4,9-dione (5), beta-lapachone (10) and dehydro-beta-lapachone diacetate (11) showed 100% inhibition at 25 microg/ml. All the tested samples showed dose-dependent activity.

  5. QSAR analysis of antitumor activities of 3,4-ethylenedioxythiphene derivatives

    Science.gov (United States)

    Rastija, Vesna; Bajić, Miroslav; Stolić, Ivana; Krstulović, Luka; Jukić, Marijana; Glavaš-Obrovac, Ljubica

    2015-12-01

    QSAR analysis was performed for the antitumor activity of 27 derivatives of 3,4-ethylenedioxythiophene against six carcinoma cell lines. The best models were obtained with surface area (SAG) in combination with lipohilicity (log P) as descriptors. Results have shown that molecules with smaller solvent accessible surface area and higher lipophilicy should have higher biological activity against carcinoma cell.

  6. Anti-tumor activity of tetrodotoxin extracted from the Masked Puffer ...

    African Journals Online (AJOL)

    Anti-tumor activity of tetrodotoxins extracted from the skin of the Masked Puffer fish (Arothron diadematus) from the Red Sea was evaluated using the Ehrlich ascite carcinoma tumor model in mice. Activity was assessed using a variety of cellular and liver biochemical parameters. Experimental mice were divided into 4 equal ...

  7. Antitumor and antimicrobial activities and inhibition of in-vitro lipid ...

    African Journals Online (AJOL)

    The antitumor activity was measured in DLA cell line induced mice. Inhibition of in vitro lipid peroxidation activity of the D. nobile in both liver homogenate and RBC ghosts was also carried out. The aqueous extracts of stem and flower of D. nobile showed better zone of bacterial inhibition than that of ethanol and chloroform

  8. Alkyl caffeates improve the antioxidant activity, antitumor property and oxidation stability of edible oil.

    Directory of Open Access Journals (Sweden)

    Jun Wang

    Full Text Available Caffeic acid (CA is distributed widely in nature and possesses strong antioxidant activity. However, CA has lower solubility in non-polar media, which limits its application in fat-soluble food. To increase the lipophilicity of natural antioxidant CA, a series of alkyl caffeates were synthesized and their antioxidant and antitumor activities were investigated. The antioxidant parameters, including the induction period, acid value and unsaturated fatty acid content, of the alkyl caffeates in edible oil were firstly investigated. The results indicated that alkyl caffeates had a lower DPPH IC₅₀ (14-23 µM compared to CA, dibutyl hydroxy toluene (BHT and Vitamin C (24-51 µM, and significantly inhibited four human cancer cells (SW620, SW480, SGC7901 and HepG2 with inhibition ratio of 71.4-78.0% by a MTT assay. With regard to the induction period and acid value assays, methyl and butyl caffeates had higher abilities than BHT to restrain the oxidation process and improve the stability of edible oil. The addition of ethyl caffeate to oil allowed maintenance of a higher unsaturated fatty acid methyl ester content (68.53% at high temperatures. Overall, the alkyl caffeats with short chain length (n<5 assessed better oxidative stability than those with long chain length. To date, this is the first report to the correlations among the antioxidant activity, anticancer activity and oxidative stability of alkyl caffeates.

  9. A novel engineered VEGF blocker with an excellent pharmacokinetic profile and robust anti-tumor activity

    International Nuclear Information System (INIS)

    Liu, Lily; Yu, Haijia; Huang, Xin; Tan, Hongzhi; Li, Song; Luo, Yan; Zhang, Li; Jiang, Sumei; Jia, Huifeng; Xiong, Yao; Zhang, Ruliang; Huang, Yi; Chu, Charles C; Tian, Wenzhi

    2015-01-01

    Relatively poor penetration and retention in tumor tissue has been documented for large molecule drugs including therapeutic antibodies and recombinant immunoglobulin constant region (Fc)-fusion proteins due to their large size, positive charge, and strong target binding affinity. Therefore, when designing a large molecular drug candidate, smaller size, neutral charge, and optimal affinity should be considered. We engineered a recombinant protein by molecular engineering the second domain of VEGFR1 and a few flanking residues fused with the Fc fragment of human IgG1, which we named HB-002.1. This recombinant protein was extensively characterized both in vitro and in vivo for its target-binding and target-blocking activities, pharmacokinetic profile, angiogenesis inhibition activity, and anti-tumor therapeutic efficacy. HB-002.1 has a molecular weight of ~80 kDa, isoelectric point of ~6.7, and an optimal target binding affinity of <1 nM. The pharmacokinetic profile was excellent with a half-life of 5 days, maximal concentration of 20.27 μg/ml, and area under the curve of 81.46 μg · days/ml. When tested in a transgenic zebrafish embryonic angiogenesis model, dramatic inhibition in angiogenesis was exhibited by a markedly reduced number of subintestinal vessels. When tested for anti-tumor efficacy, HB-002.1 was confirmed in two xenograft tumor models (A549 and Colo-205) to have a robust tumor killing activity, showing a percentage of inhibition over 90% at the dose of 20 mg/kg. Most promisingly, HB-002.1 showed a superior therapeutic efficacy compared to bevacizumab in the A549 xenograft model (tumor inhibition: 84.7% for HB-002.1 versus 67.6% for bevacizumab, P < 0.0001). HB-002.1 is a strong angiogenesis inhibitor that has the potential to be a novel promising drug for angiogenesis-related diseases such as tumor neoplasms and age-related macular degeneration

  10. Anti-tumor activity of triterpenoid-rich extract from bamboo shavings ...

    African Journals Online (AJOL)

    GREGORY

    2010-09-20

    Sep 20, 2010 ... especially on anti-tumor. The reports on the biological activities of triterpenoids ... Helium was used as a carrier gas at a flow rate of 1. mL/min. 1 µL EBS sample dissolved in dichloromethane was ... The Silica Gel Column Chromatography and Countercurrent Chro- matography preparation techniques were ...

  11. In vitro antioxidant, antibacterial and anti-tumor activities of total ...

    African Journals Online (AJOL)

    In vitro antioxidant, antibacterial and anti-tumor activities of total flavonoids from Elsholtzia densa Benth. Ren Qiu-Rong, Li Jiao, Wang Ya-Nan, Gou Xun, Xin Wen-Yuan, Ma Dan-Wei, Xiong Xiu-Hong, Zhou Yu-Jun ...

  12. In vitro antioxidant, antibacterial and anti-tumor activities of total ...

    African Journals Online (AJOL)

    Purpose: To investigate the in vitro antioxidant, antibacterial and anti-tumor activities of total flavonoids from Elsholtzia densa Benth of Sichuan Province, China. Methods: The total flavonoids of Elsholtzia densa Bent were extracted utilizing the ultrasonic extraction method, and purified by D101 macroporous adsorption resin ...

  13. PEGylation of α-momorcharin retained its anti-tumor activity with ...

    African Journals Online (AJOL)

    user

    α-Momorcharin (α-MMC) is the ribosome inactivating protein (RIPs) found to possess antitumor activity. However, acute toxicity and short plasma ... milder immunological reaction in rabbits when α-MMC is conjugated with PEG (Bian et al., ... tunneled 1 to 2 cm to prevent leakage of cell inoculum. For each strain of mouse, 80 ...

  14. Anti-tumor activity of triterpenoid-rich extract from bamboo shavings ...

    African Journals Online (AJOL)

    Bamboo shavings are a kind of Chinese traditional medicine, which have been certificated as a material of functional food by the Ministry of Health in China. The anti-tumor activities of a triterpenoid-rich extract of bamboo shavings (EBS) and its main component, friedelin were evaluated in the present study. It was proved ...

  15. Study on in vitro anti-tumor activity of Bidens bipinnata L. extract ...

    African Journals Online (AJOL)

    We studied the in vitro anti-tumor activity of Bidens Bipinnata L. extract. MTT assay was used to investigate the inhibitory effect of different concentrations of the extracts on human hepatocellular carcinoma (HepG2) cell lines and human cervical carcinoma (Hela) cell lines, and the IC50 values were calculated. The Bidens ...

  16. Camelliin B and nobotanin I, macrocyclic ellagitannin dimers and related dimers, and their antitumor activity.

    Science.gov (United States)

    Yoshida, T; Chou, T; Haba, K; Okano, Y; Shingu, T; Miyamoto, K; Koshiura, R; Okuda, T

    1989-11-01

    Camelliin B and nobotanin I, dimeric hydrolyzable tannins of a new class having macrocyclic structures, were isolated from Camellia japonica and Heterocentron roseum, respectively. Nobotanin G and H of the structures related to nobotanin I, were also obtained from H. roseum. Camelliin B and also woodfordin C, a macrocyclic dimer from Woodfordia fruticosa, exhibited marked host-mediated antitumor activities.

  17. Fraction From Lycium barbarum Polysaccharides Reduces Immunotoxicity and Enhances Antitumor Activity of Doxorubicin in Mice.

    Science.gov (United States)

    Deng, Xiangliang; Luo, Shuang; Luo, Xia; Hu, Minghua; Ma, Fangli; Wang, Yuanyuan; Zhou, Lian; Huang, Rongrong

    2018-01-01

    The aim of the present study was to investigate whether fraction from Lycium barbarum polysaccharide (LBP) could reduce immunotoxicity and enhance antitumor activity of doxorubicin (Dox) in mice. A water-soluble LBP fraction, designated LBP3, was isolated from edible Chinese herbal Lycium barbarum and used in this study. To investigate the effect of LBP3 on Dox-induced immunotoxicity, tumor-free mice were used and treated with either normal saline, Dox, or Dox plus LBP3. To investigate the effect of LBP3 on antitumor activity of Dox, H22 tumor-bearing mice were used and treated with either normal saline, Dox, LBP3, or Dox plus LBP3. The results showed that LBP3 did not protect against the body weight loss caused by Dox, but it promoted the recovery of body weight starting at day 5 after Dox treatment in tumor-free mice. LBP3 also improved peripheral blood lymphocyte counts, promoted cell cycle recovery in bone marrow cells, and restored the cytotoxicity of natural killer cells. Furthermore, in H22 tumor-bearing mice, LBP3 enhanced antitumor activity of Dox and improved peripheral blood lymphocyte counts and the cytotoxicity of splenocytes. In brief, our results demonstrated that LBP3 could reduce the immunotoxicity and enhance antitumor activity of Dox.

  18. Cytotoxic, antitumor and leukocyte migration activities of resveratrol and sitosterol present in the hidroalcoholic extract of Cissus sicyoides L., Vitaceae, leaves

    Directory of Open Access Journals (Sweden)

    Flávia R. S. Lucena

    2010-05-01

    Full Text Available Cissus sicyoides L. pertains to the Vitaceae family. It is popularly known as "insulina, cipo-pucá, bejuco caro, puci, anil trepador". A vasoconstrictor effect and an antibacterial activity have also been allocated to it. In Brazil, C. sicyoides was evaluated for its anticonvulsant and anti-diabetc properties. Phytochemistry studies identified and isolated sitosterol and resveratrol compounds from its aerial parts which are pointed out as having antitumor activities. The goal of this study was to investigate the cytotoxic and antitumor activities of Cissus sicyoides hydroalcoholic extract as well as its ability to repair leukocytes cells to injured tissue. Cissus sicyoides did not demonstrate cytotoxic activity but showed an inhibition of tumor growth in face of the tumors tested. The extract had a strong chemotactic effect on the twenty four hours period after treatment. The hidroalchoolic extract of Cissus sicyoides presented antitumor activity which was prompted by T lymphocytes recruitment to the local lesion and suggests a new pathway to antitumor activity by activation of lymphoid lineage.

  19. Meroterpenoids with Antitumor Activities from Guava (Psidium guajava).

    Science.gov (United States)

    Qin, Xu-Jie; Yu, Qian; Yan, Huan; Khan, Afsar; Feng, Mi-Yan; Li, Pan-Pan; Hao, Xiao-Jiang; An, Lin-Kun; Liu, Hai-Yang

    2017-06-21

    Psidium guajava L., a species native to South America, has been widely cultivated in the tropical and subtropical areas of China for its popular fruits. The preliminary analysis by liquid chromatography-ultraviolet (LC-UV) indicated the presence of meroterpenoids in the fruits of P. guajava (guava). Subsequent fractionation of the petroleum ether extract resulted in the identification of two new meroterpenoids, psiguajavadials A (1) and B (2), together with 14 previously described meroterpenoids (3-16). Their structures were fully elucidated by comprehensive spectroscopic techniques and theoretical calculations. All of the meroterpenoids showed cytotoxicities against five human cancer cell lines, with guajadial B (12) being the most effective having an IC 50 value of 150 nM toward A549 cells. Furthermore, biochemical topoisomerase I (Top1) assay revealed that psiguajavadial A (1), psiguajavadial B (2), guajadial B (12), guajadial C (14), and guajadial F (16) acted as Top1 catalytic inhibitors and delayed Top1 poison-mediated DNA damage. The flow cytometric analysis indicated that the new meroterpenoids psiguajavadials A (1) and B (2) could induce apoptosis of HCT116 cells. These data suggest that meroterpenoids from guava fruit could be used for the development of antitumor agents.

  20. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells.

    Science.gov (United States)

    Gao, Yuxiu; Shan, Ning; Zhao, Cheng; Wang, Yunhai; Xu, Fuliang; Li, Jiacun; Yu, Xiaoqian; Gao, Lifeng; Yi, Zhengjun

    2015-01-01

    Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin. SKOV3, OV-90 and SKOV3(DDP) cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models. LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models. Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients.

  1. Activation of the Unfolded Protein Response Contributes toward the Antitumor Activity of Vorinostat

    Directory of Open Access Journals (Sweden)

    Soumen Kahali

    2010-01-01

    Full Text Available Histone deacetylase (HDAC inhibitors represent an emerging class of anticancer agents progressing through clinical trials. Although their primary target is thought to involve acetylation of core histones, several nonhistone substrates have been identified, including heat shock protein (HSP 90, which may contribute towards their antitumor activity. Glucose-regulated protein 78 (GRP78 is a member of the HSP family of molecular chaperones and plays a central role in regulating the unfolded protein response (UPR. Emerging data suggest that GRP78 is critical in cellular adaptation and survival associated with oncogenesis and may serve as a cancer-specific therapeutic target. On the basis of shared homology with HSP family proteins, we sought to determine whether GRP78 could serve as a molecular target of the HDAC inhibitor vorinostat. Vorinostat treatment led to GRP78 acetylation, dissociation, and subsequent activation of its client protein double-stranded RNA-activated protein-like endoplasmic reticulum kinase (PERK. Investigations in a panel of cancer cell lines identified that UPR activation after vorinostat exposure is specific to certain lines. Mass spectrometry performed on immunoprecipitated GRP78 identified lysine-585 as a specific vorinostat-induced acetylation site of GRP78. Downstream activation of the UPR was confirmed, including eukaryotic initiating factor 2α phosphorylation and increase in ATF4 and C/EBP homologous protein expression. To determine the biologic relevance of UPR activation after vorinostat, RNA interference of PERK was performed, demonstrating significantly decreased sensitivity to vorinostat-induced cytotoxicity. Collectively, these findings indicate that GRP78 is a biologic target of vorinostat, and activation of the UPR through PERK phosphorylation contributes toward its antitumor activity.

  2. [Screening of the anti-tumor active fraction from Ipomoea batatas Lam. (cv.simon) leaves].

    Science.gov (United States)

    Lü, Shuhe; Lin, Cong; Xu, Pingsheng

    2015-05-01

    Three fractions (SM, SM-A, SM-B) were prepared from different polarity parts of Ipomoea batatas Lam. (cv.simon) leaves and the anti-tumor potency as well as the dose-response relations were evaluated. The anti-tumor activities of fraction SM, SM-A or SM-B were screened by MTS in human hepatic cancer Hep3B cells, lung cancer A549 cells or gastric carcinoma MGC803 cells, respectively. The three fractions all showed anti-tumor activities in three cancer cells with different sensitivity. Among them, SM-B was the most potent fraction with IC50 values at 15.17 mg/L, 72.64 mg/L or 165.47 mg/L in MGC803 cells, A549 cells or Hep3B cells, respectively (P<0.05). Th e extraction of Brazil sweet potato leaves displayed anti-tumor activity and SM-B was the most potent fraction.

  3. Effect of linalool as a component of Humulus lupulus on doxorubicin-induced antitumor activity.

    Science.gov (United States)

    Miyashita, Michiko; Sadzuka, Yasuyuki

    2013-03-01

    As malignant neoplasm is a major public health problem, there is a need for the development of a novel modulator that enhances antitumor activity and reduces adverse reactions to antitumor agents. In this study, the effects of some volatile oil components in Humulus lupulus on doxorubicin (DOX) permeability in tumor cells and DOX-induced antitumor activity were examined. In vitro, DOX levels in tumor cells by combined linalool as its component significantly increased in the DOX influx system, and the increased effect by linalool on DOX cytotoxicity was shown. In vivo, the combination of DOX with linalool significantly decreased tumor weight compared with that of DOX alone treated group. The promotion of DOX influx level by combined linalool did not depend on energy, whereas it was suppressed by the absence of Na(+). This promoting effect was suppressed by the presence of S-(4-nitrobenzyl)-6-thioinosine and inhibited dependently on phlorizin concentration. It is considered that linalool promoted DOX influx in tumor cells because of its action on DOX transport through concentrative Na(+)-dependent nucleoside transporter 3, which increased DOX concentration in tumor cells and thus enhanced the antitumor activity of DOX. Therefore, linalool as a food component is anticipated to be an effective DOX modulator. Copyright © 2012 Elsevier Ltd. All rights reserved.

  4. A profile of the in vitro antitumor activity of lissoclinolide

    International Nuclear Information System (INIS)

    Richardson, Adam D.; Ireland, Chris M.

    2004-01-01

    Lissoclinolide is a small non-nitrogenous lactone isolated from the marine ascidian Lissoclinum patella. Previous studies of lissoclinolide (isolated from a fungus and an actinomycete) have identified varying activity against both Gram-negative and Gram-positive bacteria. In this study, lissoclinolide was able to inhibit cell growth in various mammalian tumor lines at an average IC 50 of 395 nM (determined by MTT conversion after 48-h treatment). Treatment of HCT 116 human colon tumor cells with 2.4 μM lissoclinolide resulted in a strong arrest in the G 2 /M phase of the cell cycle after 24-h exposure. A daughter cell line lacking p53 showed an identical response while there was a slight increase in cytotoxicity towards a p21 null cell line. Although treatment with 2.4 μM lissoclinolide did not result in apoptosis after 48 h, this arrest was not reversible when drug wash out was attempted. The mechanism of action does not appear to involve tubulin, ubiquitin-specific isopeptidases, p53 or p21. COMPARE analysis in the NCI 60 cell line tumor panel revealed a moderate selectivity towards colon tumor cell lines

  5. Total phenolics, antioxidant, antitumor, and enzyme inhibitory activity of Indian medicinal and aromatic plants extracted with different extraction methods.

    Science.gov (United States)

    Nile, Shivraj Hariram; Nile, Arti Shivraj; Keum, Young-Soo

    2017-05-01

    The phenolic content, antioxidant, antitumor, and enzyme inhibitory activities of commonly used medicinal herbs from a Unani system of medicine were investigated using four different extraction methods. Among the plants studied, the Hyssopus officinalis L, Origanum vulgare L, and Portulaca oleracea L. extracts showed the highest amount of total phenolics (64.40, 60.35, and 58.81 mg GAE/g) and revealed significant antioxidant activities. The plants also showed a maximum cytotoxic activity as indicated by H. officinalis (82%), O. vulgare (75%), and P. oleracea (72%) showed more than 70% cytotoxicity for breast cancer cells, 82% of the cells were dead at the concentration of 500 mg/mL. The plants H. officinalis, P. oleracea, O. vulgare, and Rubia cordifolia L. revealed more than 80% inhibition towards xanthine oxidase and comprising maximum 70% of inhibition for superoxide dismutase. From results we conclude that there is a strong correlation between phenolic content, antioxidant, and enzyme inhibitory activity among these plants, indicating phenolics are the major compounds for these biological activities. Furthermore, this study provides the basis for the therapeutic importance of studied plants as latent inhibitors of oxidative stress and antitumor cell proliferation which correlate with the ethnobotanical data contained in the Unani system of medicine.

  6. EVALUATION OF THE ANTITUMOR AND ANTICACHEXIA ACTIVITY OF GRATIOLA OFFICINALIS L. EXTRACT IN RATS WITH TRANSPLANTED SARCOMA 45

    Directory of Open Access Journals (Sweden)

    N. A. Navolokin

    2016-01-01

    Full Text Available Cachexia is a severe complication of cancer and currently there are no drugs that would effectively deal with exhaustion and intoxication in various diseases.Materials and methods. In this paper a study and evaluation of the antitumor and anticachexia activities of the extract of Gratiola officinalis l. in rats with transplanted sarcoma 45 in experiment in vivo was conducted. Gratiola officinalis l. extract is received by patented method and is not toxic to animals. The study was conducted on 40 white male rats line Wistar weighing 150 ± 50 g. Animals were divided into 4 groups (10 rats per group: control group, comparison group with sarcoma without affecting, group with sarcoma with intramuscular and group with sarcoma with oral administration of the extract in a dosage of 110 mg/kg. The extract was administered intramuscularly or orally 72 hours after transplantation of sarcoma 45. The tumor volume and the weight of the animals were assessed daily.Results. The extract of leaves and flowers of Gratiola officinalis l. obtained by patented method has a strong antitumor activity, reducing the growth rate of the tumor and causing marked changes in the tumor, as well as providing stable anticachexia effect. Index of tumor weight inhibition was 70.6 % on average. Intramuscular administration was more effective in reducing of tumor growth, but less effectively increases the weight of animals than oral administration. In both administration methods Gratiola officinalis extract has no toxic effect on peripheral blood. We have previously found that the extract has antioxidant activity so that anticachexia effect is pathogenic, meaning it occurs by reducing toxicity.Conclusions. Gratiola officinalis extract has a broad spectrum of biological activity, in particular antitumor, anticachexia, it is not toxic, so it is advisable to investigate as a promising tool for the treatment of tumor diseases and cancer cachexia, and cachexia caused by other chronic

  7. Antitumor activity of Bulgarian herb Tribulus terrestris L. on human breast cancer cells

    Directory of Open Access Journals (Sweden)

    Svetla Angelova

    2013-01-01

    Full Text Available Medicinal plants have been intensively studied as a source of antitumor compounds. Due to the beneficial climate conditions Bulgarian herbs have high pharmacological potential. Currently, the antitumor effect of the Bulgarian medicinal plant Tribulus terrestris L. on human cancer cell lines is not studied. The main active compounds of the plant are the steroid saponins.The present study aims to analyze the effect on cell viability and apoptotic activity of total extract and saponin fraction of Bulgarian Tribulus terrestris L. on human breast cancer (MCF7 and normal (MCF10A cell lines. Antitumor effect was established by МТТ cell viability assay and assessment of apoptotic potential was done through analysis of genomic integrity (DNA fragmentation assay and analysis of morphological cell changes (Fluorescence microscopy. The results showed that total extract of the herb has a marked dose-dependent inhibitory effect on viability of MCF7 cells (half maximal inhibitory concentration is 15 μg/ml. Cell viability of MCF10A was moderately decreased without visible dose-dependent effect. The saponin fraction has increased inhibitory effect on breast cancer cells compared to total extract. Morphological changes and DNA fragmentation were observed as markers for early and late apoptosis predominantly in tumor cells after treatment. Apoptotic processes were intensified with the increase of treatment duration.The obtained results are the first showing selective antitumor activity of Bulgarian Tribulus terrestris L. on human cancer cells in vitro. Apoptotic processes are involved in the antitumor mechanisms induced by the herb. This results give directions for future investigations concerning detailed assessment of its pharmacological potential.

  8. Synthesis of tigogenin MeON-Neoglycosides and their antitumor activity.

    Science.gov (United States)

    Li, Guo-Long; Xu, Hong-Jiang; Xu, Shao-Hua; Wang, Wei-Wei; Yu, Bo-Yang; Zhang, Jian

    2018-03-01

    To discover new potent cytotoxic steroidal saponins, a series of tigogenin neoglycosides were synthesized via oxyamine neoglycosylation for the first time. The preliminary bioassays for their in vitro antitumor activities against five human cancer cell lines (A375, A-549, HCT-116, HepG2 and MCF-7) were conducted. The results revealed a sugar-dependent activity profile of their cytotoxicity, the glycoconjugation converted the non-active tigogenin to the most potential product Tg29 ((3R)-N-methoxyamino-tigogenin-β-2-deoxy-d-galactoside) with IC 50 value of 2.7μM and 4.6μM against HepG2 and MCF-7 cells respectively. And the 3R-tigogenin neoglycosides exhibited enhanced antitumor activity while the 3S-tigogenin almost showed no activity. Among the five cell lines, HepG2 and MCF-7 cells showed more sensitive cytotoxic responses to the products. Therefore, the neoglycosylation could be a promising strategy for the synthesis of antitumor steroidal saponins and it also proved the essential role of carbohydrate moiety of steroidal saponins in the biological activity. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Recent advance on the antitumor and antioxidant activity of grape seed extracts

    Directory of Open Access Journals (Sweden)

    Zhu FM

    2015-05-01

    Full Text Available Fengmei Zhu, Bin Du, Jun Li College of Food Science and Technology, Hebei Normal University of Science and Technology, Qinhuangdao, Hebei Province, People's Republic of China Abstract: The grape pomace (including seeds and stems poses potential disposal and pollution problems along with loss of valuable biomass and nutrients. The utilization of grape seeds processing as a source of functional ingredients is a promising field. Grape seed extract provides a concentrated source of polyphenols. Grape seed extract is known as an effective antioxidant that protects the body from premature aging and disease. A number of phytochemicals including resveratrol, proanthocyanidins, etc, have demonstrated significant benefits in cancer chemoprevention. In this review, we summarize the existing knowledge on the antitumor and antioxidant activity of grape seeds polyphenols. Keywords: grape seed, antitumor activity, antioxidant activity, polyphenol, proanthocyanidin

  10. Antitumor Activity of Prosopis glandulosa Torr. on Ehrlich Ascites Carcinoma (EAC) Tumor Bearing Mice.

    Science.gov (United States)

    Senthil Kumar, Raju; Rajkapoor, Balasubramanian; Perumal, Perumal; Dhanasekaran, Thangavel; Alvin Jose, Manonmani; Jothimanivannan, Chennakesavalu

    2011-01-01

    The antitumor activity of ethanol extract of Prosopis glandulosa Torr. (EPG) was evaluated against Ehrlich ascites carcinoma (EAC) tumor model in Swiss albino mice on dose dependent manner. The activity was assessed using survival time, average increase in body weight, hematological parameters and solid tumor volume. Oral administration of EPG at the dose of 100, 200 and 400 mg/Kg, significantly (p < 0.001) increased the survival time and decreased the average body weight of the tumor bearing mice. After 14 days of inoculation, EPG was able to reverse the changes in the hematological parameters, protein and PCV consequent to tumor inoculation. Oral administration of EPG was effective in reducing solid tumor mass development induced by EAC cells. The results indicate that EPG possess significant antitumor activity on dose dependent manner.

  11. MUC1-specific immune therapy generates a strong anti-tumor response in a MUC1-tolerant colon cancer model.

    Science.gov (United States)

    Mukherjee, P; Pathangey, L B; Bradley, J B; Tinder, T L; Basu, G D; Akporiaye, E T; Gendler, S J

    2007-02-19

    A MUC1-based vaccine was used in a preclinical model of colon cancer. The trial was conducted in a MUC1-tolerant immune competent host injected with MC38 colon cancer cells expressing MUC1. The vaccine included: MHC class I-restricted MUC1 peptides, MHC class II-restricted pan-helper-peptide, unmethylated CpG oligodeoxynucleotide, and granulocyte macrophage-colony stimulating factor. Immunization was successful in breaking MUC1 self-tolerance, and in eliciting a robust anti-tumor response. The vaccine stimulated IFN-gamma-producing CD4(+) helper and CD8(+) cytotoxic T cells against MUC1 and other undefined MC38 tumor antigens. In the prophylactic setting, immunization caused complete rejection of tumor cells, while in the therapeutic regimen, tumor burden was significantly reduced.

  12. QSAR Study on the anti-tumor activity of levofloxacin-thiadiazole HDACi conjugates

    Science.gov (United States)

    Tang, Ziqiang; Feng, Hui; Chen, Yan; Yue, Wei; Feng, Changjun

    2017-12-01

    A molecular electronegativity distance vector(M t) based on 13atomic types is used to describe the structures of 19 conjugates(LHCc) of levofloxacin-thiadiazole HDAC inhibitor(HDACi) and related to the anti-tumor activity (M F and P C) of LHCc against MCF-7 and PC-3. The quantitative structure-activity relationships (QSAR) was established by using leaps-and-bounds regression analysis for the anti-tumor activities (M F and P C) of 19 above compounds to MCF-7and PC-3 along with the M t. The correlation coefficients (R 2) and the leave-one-out (LOO) cross validation R cv 2 for the M F and P C models were 0.792 and 0.679; 0.773 and 0.565, respectively. The QSAR models have favorable correlation, as well as robustness and good prediction capability by R 2, F, R cv 2, A IC F IT V IF tests. The results indicate that the molecular structural units: -CHg-(g=1, 2), -NH2, -NH-,-OH, O=, -O-, -S- and -X are main factors which can affect the anti-tumor activity M F and PC bioactivities of these compounds directly.

  13. Antitumor Activity and Toxicity of Salts of Inorganic Group IIIa Metals: Aluminum, Gallium, Indium, and Thallium

    Science.gov (United States)

    Hart, Michael M.; Adamson, Richard H.

    1971-01-01

    The toxicity and antitumor activity of salts of the Group IIIa metals aluminum, gallium, indium, and thallium were determined. With the (lethal dose)50 as a measure, the decreasing order of toxicity was TlCl3 ≥ In(NO3)3 > Ga(NO3)3 > Al(NO3)3. All four metals exhibited antitumor activity, but when the tumor was inoculated by a route different from that of the drug, only Ga+3 and, to a lesser extent, In+3 inhibited tumor growth. Ga(NO3)3 was found to inhibit the growth of three out of four rodent solid tumors. Gallium therefore has potential therapeutic usefulness for treatment of solid tumors in man. PMID:5283954

  14. Anti-tumor Activity of Toll-Like Receptor 7 Agonists

    Directory of Open Access Journals (Sweden)

    Huju Chi

    2017-05-01

    Full Text Available Toll-like receptors (TLRs are a class of pattern recognition receptors that play a bridging role in innate immunity and adaptive immunity. The activated TLRs not only induce inflammatory responses, but also elicit the development of antigen specific immunity. TLR7, a member of TLR family, is an intracellular receptor expressed on the membrane of endosomes. TLR7 can be triggered not only by ssRNA during viral infections, but also by immune modifiers that share a similar structure to nucleosides. Its powerful immune stimulatory action can be potentially used in the anti-tumor therapy. This article reviewed the anti-tumor activity and mechanism of TLR7 agonists that are frequently applied in preclinical and clinical investigations, and mainly focused on small synthetic molecules, including imiquimod, resiquimod, gardiquimod, and 852A, etc.

  15. Chemical composition, antitumor activity, and toxicity of essential oil from the leaves of Lippia microphylla.

    Science.gov (United States)

    Xavier, Aline L; Pita, João Carlos L R; Brito, Monalisa T; Meireles, Déborah R P; Tavares, Josean F; Silva, Marcelo S; Maia, José Guilherme S; Andrade, Eloisa H A; Diniz, Margareth F F M; Silva, Teresinha G; Pessoa, Hilzeth L F; Sobral, Marianna V

    2015-01-01

    The chemical composition, antitumor activity and toxicity of the essential oil from Lippia microphylla leaves (OEL) were investigated. The major constituents were thymol (46.5%), carvacrol (31.7%), p-cymene (9%), and γ-terpinene (2.9%). To evaluate the toxicity of OEL in non-tumor cells, the hemolytic assay with Swiss mice erythrocytes was performed. The concentration producing 50% hemolysis (HC50) was 300 μg/mL. Sarcoma 180 tumor growth was inhibited in vivo 38% at 50 mg/kg, and 60% at 100 mg/kg, whereas 5-FU at 50 mg/kg caused 86% inhibition. OEL displays moderate gastrointestinal and hematological toxicity along with causing some alteration in liver function and morphology. However, the changes were considered reversible and negligible in comparison to the effects of several anticancer drugs. In summary, OEL displays in vivo antitumor activity and a moderate toxicity, which suggests further pharmacological study.

  16. Antitumor activity of 3,4-ethylenedioxythiophene derivatives and quantitative structure-activity relationship analysis

    Science.gov (United States)

    Jukić, Marijana; Rastija, Vesna; Opačak-Bernardi, Teuta; Stolić, Ivana; Krstulović, Luka; Bajić, Miroslav; Glavaš-Obrovac, Ljubica

    2017-04-01

    The aim of this study was to evaluate nine newly synthesized amidine derivatives of 3,4- ethylenedioxythiophene (3,4-EDOT) for their cytotoxic activity against a panel of human cancer cell lines and to perform a quantitative structure-activity relationship (QSAR) analysis for the antitumor activity of a total of 27 3,4-ethylenedioxythiophene derivatives. Induction of apoptosis was investigated on the selected compounds, along with delivery options for the optimization of activity. The best obtained QSAR models include the following group of descriptors: BCUT, WHIM, 2D autocorrelations, 3D-MoRSE, GETAWAY descriptors, 2D frequency fingerprint and information indices. Obtained QSAR models should be relieved in elucidation of important physicochemical and structural requirements for this biological activity. Highly potent molecules have a symmetrical arrangement of substituents along the x axis, high frequency of distance between N and O atoms at topological distance 9, as well as between C and N atoms at topological distance 10, and more C atoms located at topological distances 6 and 3. Based on the conclusion given in the QSAR analysis, a new compound with possible great activity was proposed.

  17. Electron-topological investigation of the structure-antitumor activity relationship of thiosemicarbazone derivatives.

    Science.gov (United States)

    Dimoglo, A S; Chumakov, Y M; Dobrova, B N; Saracoglu, M

    1997-04-01

    In the frameworks of the electron-topological method (ETM) the structure-antitumor activity relationship was investigated for a series of thiosemicarbazone derivatives. The series included 70 compounds. Conformational analysis and quantum-chemical calculations were carried out for each compound. The revealed activity feature showed a satisfactory description of the class of active compounds according to two different parameters P and alpha estimating the probabilities of the feature realization in the class of active compounds (they are equal to 0.94 and 0.86, correspondingly). The results of testing demonstrated the high ability of ETM in predicting the activity investigated.

  18. Snake venoms components with antitumor activity in murine melanoma cells; Componentes derivados de venenos de serpentes com acao antitumoral em celulas de melanoma murino

    Energy Technology Data Exchange (ETDEWEB)

    Queiroz, Rodrigo Guimaraes

    2012-07-01

    Despite the constant advances in the treatment of cancer, this disease remains one of the main causes of mortality worldwide. So, the development of new treatment modalities is imperative. Snake venom causes a variety of biological effects because they constitute a complex mixture of substances as disintegrins, proteases (serine and metalo), phospholipases A2, L-amino acid oxidases and others. The goal of the present work is to evaluate a anti-tumor activity of some snake venoms fractions. There are several studies of components derived from snake venoms with this kind of activity. After fractionation of snake venoms of the families Viperidae and Elapidae, the fractions were assayed towards murine melanoma cell line B16-F10 and fibroblasts L929. The results showed that the fractions of venom of the snake Notechis ater niger had higher specificity and potential antitumor activity on B16-F10 cell line than the other studied venoms. Since the components of this venom are not explored yet coupled with the potential activity showed in this work, we decided to choose this venom to develop further studies. The cytotoxic fractions were evaluated to identify and characterize the components that showed antitumoral activity. Western blot assays and zymography suggests that these proteins do not belong to the class of metallo and serine proteinases. (author)

  19. Improved Antitumoral Activity of Extracts Derived from Cultured ...

    African Journals Online (AJOL)

    After 10, 20 and 30 days, alga samples were collected and their organic extracts prepared. Lipid and phenol contents were evaluated by standardized methods. Antiproliferative activity was assayed in four cancer cell lines (Hep-2, HeLa, SiHa, and KB) while cytotoxic activity was evaluated on a normal cell line (MDCK).

  20. Two new phenolic compounds and antitumor activities of asparinin A from Asparagus officinalis.

    Science.gov (United States)

    Li, Xue-Mei; Cai, Jin-Long; Wang, Le; Wang, Wen-Xiang; Ai, Hong-Lian; Mao, Zi-Chao

    2017-02-01

    Two new phenolic acid compounds, asparoffin C (1) and asparoffin D (2), together with four known compounds, asparenyol (3), gobicusin B (4), 1-methoxy-2-hydroxy-4-[5-(4-hydroxyphenoxy)-3-penten-1-ynyl] phenol (5), and asparinin A (6), have been isolated from the stems of Asparagus officinalis. The structures were established by extensive spectroscopic methods (MS and 1D and 2D NMR). Compound 6 has obvious antitumor activities both in vitro and in vivo.

  1. Non-ionic surfactant vesicles simultaneously enhance antitumor activity and reduce the toxicity of cantharidin

    Directory of Open Access Journals (Sweden)

    Han W

    2013-06-01

    Full Text Available Wei Han,1,* Shengpeng Wang,2,* Rixin Liang,1 Lan Wang,1 Meiwan Chen,2 Hui Li,1 Yitao Wang1,2 1Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, People’s Republic of China *These authors contributed equally to this work Objective: The objective of the present study was to prepare cantharidin-entrapped non-ionic surfactant vesicles (CTD-NSVs and evaluate their potential in enhancing the antitumor activities and reducing CTD’s toxicity. Methods and results: CTD-NSVs were prepared by injection method. 3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay and flow cytometry analysis showed that CTD-NSVs could significantly enhance in vitro toxicity against human breast cancer cell line MCF-7 and induce more significant cell-cycle arrest in G0/G1 phase. Moreover, Hoechst 33342 staining implicated that CTD-NSVs induced higher apoptotic rates in MCF-7 cells than free CTD solution. In vivo therapeutic efficacy was investigated in imprinting control region mice bearing mouse sarcoma S180. Mice treated with 1.0 mg/kg CTD-NSVs showed the most powerful antitumor activity, with an inhibition rate of 52.76%, which was significantly higher than that of cyclophosphamide (35 mg/kg, 40.23% and the same concentration of free CTD (1.0 mg/kg, 31.05%. In addition, the acute toxicity and liver toxicity of CTD were also distinctly decreased via encapsulating into NSVs. Conclusion: Our results revealed that NSVs could be a promising delivery system for enhancing the antitumor activity and simultaneously reducing the toxicity of CTD. Keywords: cantharidin, non-ionic surfactant vesicle, toxicity, antitumor activity

  2. Antitumor activity of a fungal glucan tylopilan and Propionibacterium acnes preparation

    Directory of Open Access Journals (Sweden)

    Jan Grzybek

    2014-01-01

    Full Text Available The study evaluated the antitumor activity of tylopilan, aβ- (1→3 (1→6 linked glucan isolated from fruiting bodies of Tylopilus felleus (Bull.: Fr. P. Karst. (Boletaceae, and Propionibacterium acnes (P.a. preparation. The antitumor effect of tylopilan and P.a. used alone or in combination was studied in NMRI mice inoculated i.p. with 106 180-TG Crocker tumor cells. All experiments were based on a pretreatment with tylopilan and/or P.a. 5 days and/or 2 h before tumor cell inoculation. Mean survival time (MST of tumor - bearing mice was significantly prolonged in comparison to control mice by a single injection of tylopilan (25 µg/mouse or 50 µg/mouse or P.a. (1 mg/mouse. MST was 23.6; 22.8 days in the tylopilan injected mice and 17.5 in the control animals. Tylopilan injected in conjunction with P.a. prolonged signifi-cantly MST in comparison to control mice as well as to tylopilan alone treated mice. We have found that P.a. which stimulate immune response enhanced significantly antitumor activity of tylopilan. The cytotoxicity of tylopilan at concentrations of 300, 150, 75 and 37.5 µg/ml towards 180-TG Crocker cells in vitro studies was evaluated. All examined tylopilan concentrations showed cytotoxic activity.

  3. GE11 Peptide as an Active Targeting Agent in Antitumor Therapy: A Minireview

    Directory of Open Access Journals (Sweden)

    Ida Genta

    2017-12-01

    Full Text Available A lot of solid tumors are characterized by uncontrolled signal transduction triggered by receptors related to cellular growth. The targeting of these cell receptors with antitumor drugs is essential to improve chemotherapy efficacy. This can be achieved by conjugation of an active targeting agent to the polymer portion of a colloidal drug delivery system loaded with an antitumor drug. The goal of this minireview is to report and discuss some recent results in epidermal growth factor receptor targeting by the GE11 peptide combined with colloidal drug delivery systems as smart carriers for antitumor drugs. The minireview chapters will focus on explaining and discussing: (i Epidermal growth factor receptor (EGFR structures and functions; (ii GE11 structure and biologic activity; (iii examples of GE11 conjugation and GE11-conjugated drug delivery systems. The rationale is to contribute in gathering information on the topic of active targeting to tumors. A case study is introduced, involving research on tumor cell targeting by the GE11 peptide combined with polymer nanoparticles.

  4. Activation of antitumor immune responses by Ganoderma formosanum polysaccharides in tumor-bearing mice.

    Science.gov (United States)

    Wang, Cheng-Li; Lu, Chiu-Ying; Hsueh, Ying-Chao; Liu, Wen-Hsiung; Chen, Chun-Jen

    2014-11-01

    Fungi of the genus Ganoderma are basidiomycetes that have been used as traditional medicine in Asia and have been shown to exhibit various pharmacological activities. We recently found that PS-F2, a polysaccharide fraction purified from the submerged culture broth of Ganoderma formosanum, stimulates the maturation of dendritic cells and primes a T helper 1 (Th1)-polarized adaptive immune response in vivo. In this study, we investigated whether the immune adjuvant function of PS-F2 can stimulate antitumor immune responses in tumor-bearing mice. Continuous intraperitoneal or oral administration of PS-F2 effectively suppressed the growth of colon 26 (C26) adenocarcinoma, B16 melanoma, and sarcoma 180 (S180) tumor cells in mice without adverse effects on the animals' health. PS-F2 did not cause direct cytotoxicity on tumor cells, and it lost the antitumor effect in mice with severe combined immunodeficiency (SCID). CD4(+) T cells, CD8(+) T cells, and serum from PS-F2-treated tumor-bearing mice all exhibited antitumor activities when adoptively transferred to naïve animals, indicating that PS-F2 treatment stimulates tumor-specific cellular and humoral immune responses. These data demonstrate that continuous administration of G. formosanum polysaccharide PS-F2 can activate host immune responses against ongoing tumor growth, suggesting that PS-F2 can potentially be developed into a preventive/therapeutic agent for cancer immunotherapy.

  5. Effects of cultural medium on the formation and antitumor activity of polysaccharides by Cordyceps gunnii.

    Science.gov (United States)

    Zhu, Zhen-Yuan; Liu, Xiao-Cui; Tang, Ya-Li; Dong, Feng-Ying; Sun, Hui-Qing; Chen, Lu; Zhang, Yong-Min

    2016-10-01

    The effects of culture medium composition (i.e., carbon and nitrogen sources) on the growth of mycelia, molecular weight distribution and antitumor activity of intracellular polysaccharides (IPS) from Cordyceps gunnii were investigated. Sucrose and peptone were proved to be the best carbon and nitrogen sources for mycelia growth and remarkably improved IPS production. When the sucrose concentration was 2.0%, the mycelium yield reached up to 15.94±1.26 g/L, but with lower IPS yield; whereas the sucrose concentration was 4.5%, IPS yield reached to a maximum of 138.78±3.89 mg/100 mL. The effects of different carbon/nitrogen (C/N) ratios with equal amounts of carbon source matter on the mycelia and IPS formation were optimized. It found that the yield of mycelia and IPS were both reached to the highest at a C/N ratio of 10:3. In addition, the IPS had the highest macro molecular polysaccharide content and antitumor activity when sucrose concentration was 3.5% and the C/N ratio was 10:1.5. Thus, there was a positive correlation between molecular weight distribution and antitumor activity of IPS by C. gunnii. Copyright © 2016 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  6. Improving anti-tumor activity of sorafenib tosylate by lipid- and polymer-coated nanomatrix.

    Science.gov (United States)

    Guo, Yang; Zhong, Ting; Duan, Xiao-Chuan; Zhang, Shuang; Yao, Xin; Yin, Yi-Fan; Huang, Dan; Ren, Wei; Zhang, Qiang; Zhang, Xuan

    2017-11-01

    In the present study, we select the Sylysia 350 (Sylysia) as mesoporous material, distearoylphosphatidylethanolamine-poly(ethylene glycol) 2000 (DSPE-PEG) as absorption enhancer and hydroxy propyl methyl cellulose (HPMC) as crystallization inhibitor to prepare sorafenib tosylate (SFN) nanomitrix (MSNM@SFN) for improving the anti-tumor activity of SFN. The MSNM@SFN was prepared by solvent evaporation method. The solubility, dissolution, and bioavailability of SFN in MSNM@SFN were also investigated. The anti-tumor activity of MSNM@SFN was evaluated in vitro and in vivo. Our results indicated that the solubility and dissolution of SFN in MSNM@SFN were significantly increased. The oral bioavailability of SFN in MSNM@SFN was greatly improved 7.7-fold compared with that in SFN suspension. The enhanced anti-tumor activity of MSNM@SFN was confirmed in vitro and in vivo experiments. This nanomatrix developed in this study could be a promising drug delivery platform for improving the therapeutic efficacy of poorly water-soluble drugs.

  7. Enhanced antitumoral activity of doxorubicin against lung cancer cells using biodegradable poly(butylcyanoacrylate nanoparticles

    Directory of Open Access Journals (Sweden)

    Melguizo C

    2015-12-01

    Full Text Available Consolación Melguizo1,2,* Laura Cabeza,1,* Jose Prados,1,2 Raúl Ortiz,1,3 Octavio Caba,1,3 Ana R Rama,1,3 Ángel V Delgado,4 José L Arias1,2,5 1Institute of Biopathology and Regenerative Medicine (IBIMER, Biomedical Research Center, 2Biosanitary Institute of Granada (IBS Granada, SAS Universidad de Granada, Granada, 3Department of Health Science, University of Jaén, Jaén, 4Department of Applied Physics, 5Department of Pharmacy and Pharmaceutical Technology, University of Granada, Granada, Spain *These authors contributed equally to this work Abstract: Doxorubicin (Dox is widely used for the combined chemotherapy of solid tumors. However, the use of these drug associations in lung cancer has low antitumor efficacy. To improve its efficacious delivery and activity in lung adenocarcinoma cells, we developed a biodegradable and noncytotoxic nanoplatform based on biodegradable poly(butylcyanoacrylate (PBCA. The reproducible formulation method was based on an anionic polymerization process of the PBCA monomer, with the antitumor drug being entrapped within the nanoparticle (NP matrix during its formation. Improved drug-entrapment efficiencies and sustained (biphasic drug-release properties were made possible by taking advantage of the synthesis conditions (drug, monomer, and surfactant-agent concentrations. Dox-loaded NPs significantly enhanced cellular uptake of the drug in the A549 and LL/2 lung cancer cell lines, leading to a significant improvement of the drug’s antitumoral activity. In vivo studies demonstrated that Dox-loaded NPs clearly reduced tumor volumes and increased mouse-survival rates compared to the free drug. These results demonstrated that PBCA NPs may be used to optimize the antitumor activity of Dox, thus exhibiting a potential application in chemotherapy against lung adenocarcinoma. Keywords: lung cancer, cancer chemotherapy, PBCA, polymeric nanoparticles, drug carrier

  8. Design, Synthesis and Antitumor Activity of Novel 4-Methyl-(3'S,4'S-cis-khellactone Derivatives

    Directory of Open Access Journals (Sweden)

    Taigang Liang

    2013-04-01

    Full Text Available An asymmetric synthesis of a series of novel 4-methyl-(3'S,4'S-cis-khellactone derivatives 3a–o is reported for the first time. Their structures were confirmed by 1H-NMR, 13C-NMR and MS. Their cytotoxic activity was evaluated by the MTT assay against three selected human cancer cell lines: HEPG-2 (human liver carcinoma, SGC-7901 (human gastric carcinoma, LS174T (human colon carcinoma. Some compounds showed high inhibitory activity against these human cancer cell lines. Among them, compound 3a exhibited strong cytotoxicity, with IC50 values ranging from 8.51 to 29.65 μM. The results showed that 4-methyl-cis-khellactone derivatives with S,S configuration could be a potential antitumor agents.

  9. Woodfordin C, a macro-ring hydrolyzable tannin dimer with antitumor activity, and accompanying dimers from Woodfordia fruticosa flowers.

    Science.gov (United States)

    Yoshida, T; Chou, T; Nitta, A; Miyamoto, K; Koshiura, R; Okuda, T

    1990-05-01

    Three new dimeric hydrolyzable tannins, woodfordins A, B and C, along with seven known hydrolyzable tannins, including oenothein B, a dimer exhibiting marked host-mediated antitumor activity, were isolated from an Indonesian crude drug, Sidowayah [dried flowers of Woodfordia fruticosa (L.) Kurz (Lythraceae)]. The structures of the new tannins were elucidated based on chemical and spectral evidence. Woodfordin C, having a macro-ring structure, was also found to exhibit a significant antitumor activity.

  10. Antitumor activity of doxorubicine-loaded nanoemulsion against ...

    African Journals Online (AJOL)

    wide scope of activity in human cancers, including acute lymphoblastic leukemia, ... were housed in large polypropylene cages with utmost of five animals per cage and .... vessels (B), and D) DOX/LNE group, revealing slight alteration in the morphology of the cardiomyocytes and considerably less cellular vacuolization and ...

  11. In-vitro Antimicrobial and Antitumor Activities of Stevia Rebaudiana ...

    African Journals Online (AJOL)

    subtilis, Aeromonas hydrophila and Vibrio cholerae by using agar well diffusion method. Candida albicans, Cryptococcus neoformans, Trichophyton mentagrophytes and Epidermophyton species were used to test anti-yeast and antifungal activity. The cytotoxic effects of the extracts on Vero and HEp2 cells were assayed ...

  12. Improved Antitumoral Activity of Extracts Derived from Cultured ...

    African Journals Online (AJOL)

    Erah

    with the total polyphenol content suggesting a causal link related to extract content of polyphenols and phenolic acids [8], while other authors have reported a variety of fatty acids and derivatives with ..... the effectiveness of anticancer therapy; some anticancer drugs show their anticancer activity by inducing apoptosis of ...

  13. Ficus umbellata Vahl. (Moraceae) Stem Bark Extracts Exert Antitumor Activities In Vitro and In Vivo.

    Science.gov (United States)

    Silihe, Kevine Kamga; Zingue, Stéphane; Winter, Evelyn; Awounfack, Charline Florence; Bishayee, Anupam; Desai, Nishil N; João Mello, Leônidas; Michel, Thomas; Tankeu, Francine Nzufo; Ndinteh, Derek Tantoh; Honorine Riwom, Sara; Njamen, Dieudonné; Creczynski-Pasa, Tânia Beatriz

    2017-05-23

    A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspases activities as well as Bcl-2 and Bcl-xL protein content were assessed in MDA-MB-231 cells. The 7,12-dimethylbenz(a)anthracene (DMBA)-induced carcinogenesis in rats were also used to investigate antitumor potential of F. umbellata extracts. The F. umbellata methanol extract exhibited a CC 50 of 180 μg/mL in MDA-MB-231 cells after 24 h. It induced apoptosis in MCF-7 and MDA-MB-231 cells, while it did not alter their cell cycle phases. Further, it induced a decrease in MMP, an increase in ROS levels and caspases activities as well as a downregulation in Bcl-2 and Bcl-xL protein contents in MDA-MB-231 cells. In vivo, F. umbellata aqueous (200 mg/kg) and methanol (50 mg/kg) extracts significantly ( p < 0.001) reduced ovarian tumor incidence (10%), total tumor burden (58% and 46%, respectively), average tumor weight (57.8% and 45.6%, respectively) as compared to DMBA control group. These results suggest antitumor potential of F. umbellata constituents possibly due to apoptosis induction mediated through ROS-dependent mitochondrial pathway.

  14. Ficus umbellata Vahl. (Moraceae Stem Bark Extracts Exert Antitumor Activities In Vitro and In Vivo

    Directory of Open Access Journals (Sweden)

    Kevine Kamga Silihe

    2017-05-01

    Full Text Available A Ficus umbellata is used to treat cancer. The present work was therefore designed to assess antitumor potentials of F. umbellata extracts in nine different cell lines. Cell cycle, apoptosis, cell migration/invasion, levels of reactive oxygen species (ROS, mitochondrial membrane potential (MMP, caspases activities as well as Bcl-2 and Bcl-xL protein content were assessed in MDA-MB-231 cells. The 7,12-dimethylbenz(aanthracene (DMBA-induced carcinogenesis in rats were also used to investigate antitumor potential of F. umbellata extracts. The F. umbellata methanol extract exhibited a CC50 of 180 μg/mL in MDA-MB-231 cells after 24 h. It induced apoptosis in MCF-7 and MDA-MB-231 cells, while it did not alter their cell cycle phases. Further, it induced a decrease in MMP, an increase in ROS levels and caspases activities as well as a downregulation in Bcl-2 and Bcl-xL protein contents in MDA-MB-231 cells. In vivo, F. umbellata aqueous (200 mg/kg and methanol (50 mg/kg extracts significantly (p < 0.001 reduced ovarian tumor incidence (10%, total tumor burden (58% and 46%, respectively, average tumor weight (57.8% and 45.6%, respectively as compared to DMBA control group. These results suggest antitumor potential of F. umbellata constituents possibly due to apoptosis induction mediated through ROS-dependent mitochondrial pathway.

  15. In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

    International Nuclear Information System (INIS)

    Menezes, C.B.A.; Silva, B.P.; Sousa, I.M.O.; Ruiz, A.L.T.G.; Spindola, H.M.; Cabral, E.; Eberlin, M.N.; Tinti, S.V.; Carvalho, J.E.; Foglio, M.A.; Fantinatti-Garboggini, F.

    2012-01-01

    Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed

  16. An HDAC inhibitor enhances the antitumor activity of a CMV promoter-driven DNA vaccine.

    Science.gov (United States)

    Lai, M-D; Chen, C-S; Yang, C-R; Yuan, S-Y; Tsai, J-J; Tu, C-F; Wang, C-C; Yen, M-C; Lin, C-C

    2010-03-01

    The cytomegalovirus (CMV) promoter is considered to be one of the strongest promoters for driving the in vivo expression of genes encoded by DNA vaccines. However, the efficacy of DNA vaccines has so far been disappointing (particularly in humans), and this might be explained in part by histone deacetylase (HDAC)-mediated chromatin condensation. Hence, we sought to investigate whether increasing the expression of DNA vaccine antigens with the HDAC inhibitor OSU-HDAC42 would enhance the efficacy of DNA vaccines in vivo. A luciferase assay was used to determine the effects of OSU-HDAC42 on CMV promoter-driven DNA plasmids in vitro and in vivo. Three HDAC inhibitors were able to activate expression from the CMV promoter in NIH3T3 cells and MBT-2 bladder cancer cells. The expression of luciferase was significantly enhanced by co-administration of pCMV-luciferase and OSU-HDAC42 in mice. To explore whether OSU-HDAC42 could enhance the specific antitumor activity of a neu DNA vaccine driven by the CMV promoter, we evaluated therapeutic effects and immune responses in a mouse tumor natively overexpressing HER2/neu. Mice receiving OSU-HDAC42 in combination with the CMV-promoter neu DNA vaccine exhibited stronger antitumor effects than mice given the DNA vaccine only. In addition, a correlation between the antitumor effects and the specific cellular immune responses was observed in the mice receiving the DNA vaccine and OSU-HDAC42.

  17. In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates

    Energy Technology Data Exchange (ETDEWEB)

    Menezes, C.B.A.; Silva, B.P. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Universidade de São Paulo, Interunidades em Biotecnologia, São Paulo, SP (Brazil); Sousa, I.M.O.; Ruiz, A.L.T.G.; Spindola, H.M. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Cabral, E.; Eberlin, M.N. [Instituto de Química, Universidade Estadual de Campinas, Laboratório Thomson Mass Spectrometry, Campinas, SP (Brazil); Tinti, S.V.; Carvalho, J.E. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Foglio, M.A.; Fantinatti-Garboggini, F. [Universidade Estadual de Campinas, Centro Pluridisciplinar de Pesquisas Químicas, Biológicas e Agrícolas, Campinas, SP (Brazil); Universidade de São Paulo, Interunidades em Biotecnologia, São Paulo, SP (Brazil)

    2012-10-23

    Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative β-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 µg/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed.

  18. Antitumor activity and carrier properties of novel hemocyanins coupled to a mimotope of GD2 ganglioside.

    Science.gov (United States)

    Palacios, Miriam; Tampe, Ricardo; Del Campo, Miguel; Zhong, Ta-Ying; López, Mercedes N; Salazar-Onfray, Flavio; Becker, María Inés

    2018-04-25

    Conjugation to carrier proteins is a way to improve the immunogenicity of peptides. Such is the case for peptides mimicking carbohydrate tumor-associated antigens in cancer vaccine development. The most used protein for this purpose is the keyhole limpet hemocyanin (KLH) from Megathura crenulata. Its limited bioavailability has prompted interest in finding new candidates; nevertheless, it is not known whether other hemocyanins might be equally efficient as carrier of carbohydrate peptide mimotopes to promotes anti-tumor responses. Here, we evaluated the carrier and antitumor activity of novel hemocyanins with documented immunogenicity obtained from Concholepas concholepas (CCH) and Fissurella latimarginata (FLH), coupled through sulfo-SMCC to P10, a mimetic peptide of GD2, the major ganglioside constituent of neuroectodermal tumors, and incorporating AddaVax as an adjuvant. The humoral immune responses of mice showed that CCH-P10 and FLH-P10 conjugates elicited specific IgM and IgG antibodies against P10 mimotope, similar to those obtained with KLH-P10, which was used as a positive control. The CCH-P10 and FLH-P10 antisera, exhibited cross-reactivity with murine and human melanoma cells, like anti-CCH and anti-FLH sera suggesting a cross-reaction of CCH and FLH glycosylations with carbohydrate epitopes on the tumor cell surfaces, similar to the KLH antisera. When mice were primed with each hemocyanin-P10 and challenged with melanoma cells, better antitumor effects were observed for FLH-P10 than for CCH-P10 and, as for KLH-P10, irrespective of conjugation. These data demonstrate that CCH and FLH are useful carriers of carbohydrate mimotopes; however, the best antitumor activity of FLH preparations, indicate that is a suitable candidate for further cancer vaccines research. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

  19. Comparative toxicity and efficacy of engineered anthrax lethal toxin variants with broad anti-tumor activities

    Energy Technology Data Exchange (ETDEWEB)

    Peters, Diane E. [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Program of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA (United States); Hoover, Benjamin [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Cloud, Loretta Grey [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Liu, Shihui [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Molinolo, Alfredo A. [Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States); Leppla, Stephen H. [Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (United States); Bugge, Thomas H., E-mail: thomas.bugge@nih.go [Proteases and Tissue Remodeling Section, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (United States)

    2014-09-01

    We have previously designed and characterized versions of anthrax lethal toxin that are selectively cytotoxic in the tumor microenvironment and which display broad and potent anti-tumor activities in vivo. Here, we have performed the first direct comparison of the safety and efficacy of three engineered anthrax lethal toxin variants requiring activation by either matrix-metalloproteinases (MMPs), urokinase plasminogen activator (uPA) or co-localized MMP/uPA activities. C57BL/6J mice were challenged with six doses of engineered toxins via intraperitoneal (I.P.) or intravenous (I.V.) dose routes to determine the maximum tolerated dose for six administrations (MTD6) and dose-limiting toxicities. Efficacy was evaluated using the B16-BL6 syngraft model of melanoma; mice bearing established tumors were treated with six I.P. doses of toxin and tumor measurements and immunohistochemistry, paired with terminal blood work, were used to elaborate upon the anti-tumor mechanism and relative efficacy of each variant. We found that MMP-, uPA- and dual MMP/uPA-activated anthrax lethal toxins exhibited the same dose-limiting toxicity; dose-dependent GI toxicity. In terms of efficacy, all three toxins significantly reduced primary B16-BL6 tumor burden, ranging from 32% to 87% reduction, and they also delayed disease progression as evidenced by dose-dependent normalization of blood work values. While target organ toxicity and effective doses were similar amongst the variants, the dual MMP/uPA-activated anthrax lethal toxin exhibited the highest I.P. MTD6 and was 1.5–3-fold better tolerated than the single MMP- and uPA-activated toxins. Overall, we demonstrate that this dual MMP/uPA-activated anthrax lethal toxin can be administered safely and is highly effective in a preclinical model of melanoma. This modified bacterial cytotoxin is thus a promising candidate for further clinical development and evaluation for use in treating human cancers. - Highlights: • Toxicity and anti-tumor

  20. Enhancement of intrinsic antitumor activity in spore-endotoxin mixtures of Bacillus thuringiensis by exposure to ultraviolet radiation

    International Nuclear Information System (INIS)

    Zamola, B.; Karminski-Zamola, G.; Fuks, Z.; Kubovic, M.; Wrishcer, M.

    1985-01-01

    Irradiation of spore-endotoxin mixtures from Bacillus thuringiensis cultures at 254 nm (60 μW cm -2 ) enhances their intrinsic antitumor potency as well as that of either component. The extent of enhancement depends on the length of exposure (optimum: 35 min) and may thus be due to photochemical changes of the endotoxin protein or/and to photoproduction of additional compounds with antitumor activity. Antitumor effects, expressed as survival rates of C57BL/6 mice inoculated with Lewis' mouse lung carcinoma and subjected to treatments 24 h later, depended on the number of doses of preparations administered (mixture, separated components). (author)

  1. Morphological and biochemical alterations activated by antitumor clerodane diterpenes.

    Science.gov (United States)

    Ferreira, Paulo Michel Pinheiro; Militão, Gardenia Carmen Gadelha; Lima, Daisy Jereissati Barbosa; Costa, Nagilla Daniela de Jesus; Machado, Kátia da Conceição; Santos, André Gonzaga Dos; Cavalheiro, Alberto José; Bolzani, Vanderlan da Silva; Silva, Dulce Helena Siqueira; Pessoa, Cláudia

    2014-10-05

    Casearia sylvestris Swartz (Salicaceae) is a plant commonly widespread in the Americas. It has oxygenated tricyclic bioactive clerodane diterpenes with antimicrobial, antiulcer, larvicidal, chemopreventive, anti-inflammatory, antioxidant and antiproliferative properties. Due to this requirement for the developing of new anticancer drugs, it was initially evaluated the cytotoxic activity of a fraction with Casearins (FC) and its clerodane diterpenes Casearin B (Cas B), D (Cas D), X (Cas X) and Caseargrewiin F (Cas F) isolated from C.sylvestris leaves against 7 tumor cell lines, Sarcoma 180 cells (S180) and on normal peripheral blood mononuclear cells (PBMC). All substances tested showed cytotoxic potential. Cas F and X were the most active compounds. Cell death analyzes with Cas F (0.5 and 1μM) and Cas X (0.7 and 1.5μM) using the HL-60 leukemia line as experimental model showed DNA synthesis and membrane integrity reduction, DNA fragmentation and mitochondrial depolarization, specially after 24h exposure, cell cycle arrest in G0/G1 phase caused by Cas X, activation of the initiator -8/-9 and effector -3/-7 caspases and phosphatidylserine externalization, all biochemical features of apoptosis corroborated by chromatinic condensation, karyorrhexis, cytoplasmic vacuolation and rarefaction and cellular shrinkage, morphological findings specially observed after 12 and 24h of incubation. Therefore, Cas X and F were the most functional molecules with more pronounced lethal and discriminating effects on tumor cells and antiproliferative action predominantly mediated by apoptosis, highlighting clerodane dipertenes as promising lead antineoplastic compounds. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  2. Synthesis and Antitumor Activity of New Group 3 Metallocene Complexes.

    Science.gov (United States)

    Caporale, Angelamaria; Palma, Giuseppe; Mariconda, Annaluisa; Del Vecchio, Vitale; Iacopetta, Domenico; Parisi, Ortensia Ilaria; Sinicropi, Maria Stefania; Puoci, Francesco; Arra, Claudio; Longo, Pasquale; Saturnino, Carmela

    2017-03-28

    The quest for alternative drugs with respect to the well-known cis -platin and its derivatives, which are still used in more than 50% of the treatment regimens for patients suffering from cancer, is highly needed. In this context, organometallic compounds, which are defined as metal complexes containing at least one direct covalent metal-carbon bond, have recently been found to be promising anticancer drug candidates. A series of new metallocene complexes with scandium, yttrium, and neodymium have been prepared and characterized. Some of these compounds show a very interesting anti-proliferative activity in triple negative breast cancer cell line (MDA.MB231) and the non-hormone sensitive prostate cancer cell line (DU145). Moreover, the interaction of some of them with biological membranes, evaluated using liposomes as bio-membrane mimetic model systems, seems to be relevant. The biological activity of these compounds, particularly those based on yttrium, already effective at low concentrations on both cancer cell lines, should be taken into account with regard to new therapeutic approaches in anticancer therapy.

  3. Linalool Exhibits Cytotoxic Effects by Activating Antitumor Immunity

    Directory of Open Access Journals (Sweden)

    Mei-Yin Chang

    2014-05-01

    Full Text Available According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC50 values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC50 values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors.

  4. Linalool exhibits cytotoxic effects by activating antitumor immunity.

    Science.gov (United States)

    Chang, Mei-Yin; Shen, Yi-Ling

    2014-05-22

    According to recent studies, the Plantaginaceae, which are traditional Chinese herbal remedies, have potential for use in viral infection treatment and cancer therapy. Linalool and p-coumaric acid are two of the biologically active compounds that can be isolated from the Plantaginaceae. This study mainly focused on investigating the bioactivity of linalool as well as the bioactivity of p-coumaric acid in terms of their cytotoxic effects on cancer cells. Whether the mechanisms of such effects are generated through apoptosis and immunoregulatory activity were also investigated. By using WST-1 analysis, it was shown that linalool and p-coumaric acid have good inhibitory effects against breast, colorectal and liver cancer cells. The IC50 values of linalool for those cancer cell types were 224 μM, 222 μM, and 290 μM, respectively, and the IC50 values of p-coumaric acid were 693 μM, 215 μM and 87 μM, respectively. Cell cycle analysis also confirmed that linalool and p-coumaric acid can lead to apoptosis. By using flow cytometry, it was determined that treatment with linalool rather than p-coumaric acid significantly increased the sub-G1 phase and that there were more cells concentrated in the G1 phase. Furthermore, by using cytokine array analysis, we found that linalool can stimulate IFN-γ, IL-13, IL-2, IL-21, IL-21R, IL-4, IL-6sR and TNF-α secretion. This demonstrated that in addition to the bidirectional regulation capabilities found in linalool, it also induces Th1 cellular immune response in T-47D cells. These results showed that linalool holds great potential for use in cancer therapy, and we believe that it could provide an alternative way to take action against tumors.

  5. In vitro and in vivo antitumor activity of Scutellaria barbate extract on murine liver cancer.

    Science.gov (United States)

    Dai, Zhi-Jun; Gao, Jie; Li, Zong-Fang; Ji, Zong-Zheng; Kang, Hua-Feng; Guan, Hai-Tao; Diao, Yan; Wang, Bao-Feng; Wang, Xi-Jing

    2011-05-27

    In the present study, we investigated the in vitro and in vivo antitumor effects of crude extract of Scutellaria Barbate (CE-SB) on mouse hepatoma H22 cells. The MTT assay was used to determine the growth inhibition of H22 cells in vitro. The in vivo therapeutic effects of CE-SB were determined using H22 tumor bearing mice. Besides, the body weight, tumor weight, thymus index and spleen index of H22 bearing mice were also measured. The tumor inhibitory rate (IR) was calculated according to the mean weight of tumor (MWT). The phagocytotic function of macrophages was examined by observing peritoneal macrophages phagocytize chicken RBC. The results showed that CE-SB could inhibit the growth of hepatoma H22 Cells in vitro and in vivo. Furthermore, CE-SB could improve immune function of H22 tumor bearing mice. Together these results indicate that CE-SB has antitumor activity and seems to be safe and effective for the use of anti-tumor therapy.

  6. Antitumor activity of extract and isolated compounds from Drechslera rostrata and Eurotium tonophilum

    Directory of Open Access Journals (Sweden)

    Fatmah A.S. Alasmary

    2018-02-01

    Full Text Available Total extracts of Drechslera rostrata and Eurotium tonophilum in addition of two isolated compounds from their cultures [di-2-ethylhexyl phthalate (H1 and 1,8-Dihydroxy-3-methoxy-6-methyl-anthraquinone (H2] were tested for their antitumor activity using four human carcinoma cell lines. Antitumor activity was assessed by performing MTT assay to check the % cell viability. The % viability of HCT-116 (colon carcinoma, HeLa (cervical carcinoma, HEp-2 (larynx carcinoma and HepG-2 (hepatocellular carcinoma cells decreased after treatment with Drechslera rostrata and Eurotium tonophilum extracts, these effects were ranged from 059.0 ±  0.1 to 217.0  ±  0.3 µg/ml on all types of cancer cells. The best activity was recorded for Eurotium tonpholium extract (054.5 ± 0.3, 059.0 ± 0.5 and 059.0 ± 0.1 for HEp-2, Hela, and HepG-2 respectively. The isolated compounds (H1&H2 were found to be responsible about the activities because they recorded the lowest IC50 on tested cell lines with range of 9.5–20.3 μg/ml. Vinblastine sulphate was used as a reference standard and showed in vitro anticancer activity. This study demonstrated that all extracts and isolated compounds have antitumor activity against HCT-116, HeLa, HEp-2 and HepG-2 cells.

  7. Antitumor activity of C-methyl-beta-D-ribofuranosyladenine nucleoside ribonucleotide reductase inhibitors.

    Science.gov (United States)

    Franchetti, Palmarisa; Cappellacci, Loredana; Pasqualini, Michela; Petrelli, Riccardo; Vita, Patrizia; Jayaram, Hiremagalur N; Horvath, Zsuzsanna; Szekeres, Thomas; Grifantini, Mario

    2005-07-28

    A series of adenosine derivatives substituted at the 1'-, 2'-, or 3'-position of the ribose ring with a methyl group was synthesized and evaluated for antitumor activity. From this study 3'-C-methyladenosine (3'-Me-Ado) emerged as the most active compound, showing activity against human myelogenous leukemia K562, multidrug resistant human leukemia K562IU, human promyelocytic leukemia HL-60, human colon carcinoma HT-29, and human breast carcinoma MCF-7 cell lines with IC(50) values ranging from 11 to 38 muM. Structure-activity relationship studies showed that the structure of 3'-Me-Ado is crucial for the activity. Substitution of a hydrogen atom of the N(6)-amino group with a small alkyl or cycloalkyl group, the introduction of a chlorine atom in the 2-position of the purine ring, or the moving of the methyl group from the 3'-position to other ribose positions brought about a decrease or loss of antitumor activity. The antiproliferative activity of 3'-Me-Ado appears to be related to its ability to deplete both intracellular purine and pyrimidine deoxynucleotides through ribonucleotide reductase inhibition.

  8. Influence of low dose ionizing radiation on amplification and antitumor activity of LAK/TIL cells

    International Nuclear Information System (INIS)

    Liu Wei; Hou Dianjun; Qiao Jianwei; Shang Ximei; Li Jieqing

    2000-01-01

    Objective: To study the influence of low dose ionization on amplification and antitumor activity of LAK/TIL cells. Methods: TIL cells isolated from Lewis lung cancer tissues and LAK cells from spleen of tumor-bearing mouse were irradiated with different low doses of X-rays and were cultured after irradiation. Results: Low dose ionizing radiation improved the amplification volume of LAK/TIL cells, decreased the cell death ratio in amplification process, and increased the toxicity of LAK/TIL cells, Conclusions: Low dose ionizing radiation can result in amplification of biologically activated lymphocytes, and decreases the death ratio of the cells in amplification process

  9. In Vitro and In Vivo Antitumor Activity of [Pt(O,O'-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma.

    Science.gov (United States)

    Muscella, Antonella; Vetrugno, Carla; Cossa, Luca Giulio; Antonaci, Giovanna; De Nuccio, Francesco; De Pascali, Sandra Angelica; Fanizzi, Francesco Paolo; Marsigliante, Santo

    2016-01-01

    Malignant pleural mesothelioma (MPM) is an aggressive malignancy highly resistant to chemotherapy. There is an urgent need for effective therapy inasmuch as resistance, intrinsic and acquired, to conventional therapies is common. Among Pt(II) antitumor drugs, [Pt(O,O'-acac)(γ-acac)(DMS)] (Ptac2S) has recently attracted considerable attention due to its strong in vitro and in vivo antiproliferative activity and reduced toxicity. The purpose of this study was to examine the efficacy of Ptac2S treatment in MPM. We employed the ZL55 human mesothelioma cell line in vitro and in a murine xenograft model in vivo, to test the antitumor activity of Ptac2S. Cytotoxicity assays and Western blottings of different apoptosis and survival proteins were thus performed. Ptac2S increases MPM cell death in vitro and in vivo compared with cisplatin. Ptac2S was more efficacious than cisplatin also in inducing apoptosis characterized by: (a) mitochondria depolarization, (b) increase of bax expression and its cytosol-to-mitochondria translocation and decrease of Bcl-2 expression, (c) activation of caspase-7 and -9. Ptac2S activated full-length PKC-δ and generated a PKC-δ fragment. Full-length PKC-δ translocated to the nucleus and membrane, whilst PKC-δ fragment concentrated to mitochondria. Ptac2S was also responsible for the PKC-ε activation that provoked phosphorylation of p38. Both PKC-δ and PKC-ε inhibition (by PKC-siRNA) reduced the apoptotic death of ZL55 cells. Altogether, our results confirm that Ptac2S is a promising therapeutic agent for malignant mesothelioma, providing a solid starting point for its validation as a suitable candidate for further pharmacological testing.

  10. Metformin increases antitumor activity of MEK inhibitors through GLI1 downregulation in LKB1 positive human NSCLC cancer cells.

    Science.gov (United States)

    Della Corte, Carminia Maria; Ciaramella, Vincenza; Di Mauro, Concetta; Castellone, Maria Domenica; Papaccio, Federica; Fasano, Morena; Sasso, Ferdinando Carlo; Martinelli, Erika; Troiani, Teresa; De Vita, Ferdinando; Orditura, Michele; Bianco, Roberto; Ciardiello, Fortunato; Morgillo, Floriana

    2016-01-26

    Metformin, widely used as antidiabetic drug, showed antitumoral effects expecially in combination with chemotherapy. Our group recently has demonstrated that metformin and gefitinib are synergistic in LKB1-wild-type NSCLC cells. In these models, metformin as single agent induced an activation and phosphorylation of mitogen-activated-protein-kinase (MAPK) through an increased C-RAF/B-RAF heterodimerization. Since single agent metformin enhances proliferating signals through the RAS/RAF/MAPK pathway, and several MEK inhibitors (MEK-I) demonstrated clinical efficacy in combination with other agents in NSCLC, we tested the effects of metformin plus MEK-I (selumetinib or pimasertib) on proliferation, invasiveness, migration abilities in vitro and in vivo in LKB1 positive NSCLC models harboring KRAS wild type and mutated gene. The combination of metformin with MEK-I showed a strong anti-proliferative and proapoptotic effect in Calu-3, H1299, H358 and H1975 human NSCLC cell lines, independently from the KRAS mutational status. The combination reduced the metastatic behaviour of NSCLC cells, via a downregulation of GLI1 trascritional activity, thus affecting the transition from an epithelial to a mesenchymal phenotype. Metformin and MEK-Is combinations also decreased the production and activity of MMP-2 and MMP-9 by reducing the NF-jB (p65) binding to MMP-2 and MMP-9 promoters. Metformin potentiates the antitumor activity of MEK-Is in human LKB1-wild-type NSCLC cell lines, independently from the KRAS mutational status, through GLI1 downregulation and by reducing the NF-jB (p65)-mediated transcription of MMP-2 and MMP-9.

  11. Antioxidant Activity, Antitumor Effect, and Antiaging Property of Proanthocyanidins Extracted from Kunlun Chrysanthemum Flowers

    Directory of Open Access Journals (Sweden)

    Siqun Jing

    2015-01-01

    Full Text Available The objective of the present study was to evaluate the antioxidant activity, antitumor effect, and antiaging property of proanthocyanidins from Kunlun Chrysanthemum flowers (PKCF grown in Xinjiang. In vitro antioxidant experiments results showed that the total antioxidant activity and the scavenging capacity of hydroxyl radicals (•OH and 1,1-diphenyl-2-picrylhydrazyl (DPPH• radicals increased in a concentration-dependent manner and were stronger than those of vitamin C. To investigate the antioxidant activity of PKCF in vivo, we used serum, liver, and kidney from mouse for the measurement of superoxide dismutase (SOD, malondialdehyde (MDA, and total antioxidant capacity (T-AOC. Results indicated that PKCF had antioxidative effect in vivo which significantly improved the activity of SOD and T-AOC and decreased MDA content. To investigate the antitumor activity of PKCF, we used H22 cells, HeLa cells, and Eca-109 cells with Vero cells as control. Inhibition ratio and IC50 values were measured by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay; PKCF showed great inhibitory activity on H22 cells and HeLa cells. We also used fruit flies as a model for analyzing the anti-aging property of PKCF. Results showed that PKCF has antiaging effect on Drosophila. Results of the present study demonstrated that PKCF could be a promising agent that may find applications in health care, medicine, and cosmetics.

  12. Antioxidant and antitumor activities of selenium- and zinc-enriched oyster mushroom in mice.

    Science.gov (United States)

    Yan, Huimin; Chang, Hui

    2012-12-01

    Selenium and zinc are well-known essential trace elements with potent biological functions. However, the possible health benefits of the combined administration of dietary selenium and zinc have not been studied extensively. In this study, we prepared selenium- and zinc-enriched mushrooms (SZMs) containing increased levels of selenium and zinc. The effects of SZMs on antioxidant and antitumor activities were evaluated. Mice were fed with either a control diet or a diet supplemented with SZMs or sodium selenite and zinc sulfate for 6 weeks. Antioxidant capacity was investigated by measuring the activities of antioxidant enzymes and the levels of lipid peroxide products. Results showed that treatment with SZMs significantly increased the activities of glutathione peroxidase (GPx) and superoxide dismutase and decreased the levels of malondialdehyde and lipofuscin. Furthermore, using a mouse model of lung tumors, we found that SZMs significantly decreased the number of tumor nodes with an increase in the activity of GPx. SZMs had a greater effect on the increase in both antioxidant and antitumor activities than did sodium selenite and zinc sulfate. These findings suggest that SZMs may be effective for improving antioxidant capacity and preventing tumors.

  13. Models for anti-tumor activity of bisphosphonates using refined topochemical descriptors

    Science.gov (United States)

    Goyal, Rakesh K.; Singh, G.; Madan, A. K.

    2011-10-01

    An in silico approach comprising of decision tree (DT), random forest (RF) and moving average analysis (MAA) was successfully employed for development of models for prediction of anti-tumor activity of bisphosphonates. A dataset consisting of 65 analogues of both nitrogen-containing and non-nitrogen-containing bisphosphonates was selected for the present study. Four refinements of eccentric distance sum topochemical index termed as augmented eccentric distance sum topochemical indices 1-4 ( {ξ_{{1c}}^{{ADS}},ξ_{{2c}}^{{ADS}},ξ_{{3c}}^{{ADS}},ξ_{{4c}}^{{ADS}}} ) have been proposed so as to significantly augment discriminating power. Proposed topological indices (TIs) along with the exiting TIs (>1,400) were subsequently utilized for development of models for prediction of anti-tumor activity of bisphosphonates. A total of 43 descriptors of diverse nature, from a large pool of molecular descriptors, calculated through E-Dragon software (version 1.0) and an in-house computer program were selected for development of suitable models by employing DT, RF and MAA. DT identified two TIs as most important and classified the analogues of the dataset with an accuracy of 97% in training set and 90.7% in tenfold cross-validated set. Random forest correctly classified the analogues with an accuracy of 89.2%. Four independent models developed through MAA predicted the activity of analogues of the dataset with an accuracy of 87.6% to 89%. The statistical significance of proposed models was assessed through intercorrelation analysis, specificity, sensitivity and Matthew's correlation coefficient. The proposed models offer a vast potential for providing lead structures for development of potent anti-tumor agents for treatment of cancer that has spread to the bone.

  14. Evaluation of in vivo antitumor activity of cleistanthin B in Swiss albino mice

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    Vipul R. Thummar

    2016-10-01

    Full Text Available To evaluate the in vivo antitumor activity of cleistanthin B in Ehrlich's ascites carcinoma (EAC and Dalton's ascites lymphoma (DAL cell lines induced malignant ascites mouse models and DAL cell line induced solid tumor mouse model. All animals were injected with 2 × 106 EAC/DAL cells i.p./s.c. to induce malignant ascites and solid tumor and treated with 5-fluorouracil (5-FU 20 mg/kg or cleistanthin B for 10 days. Cleistanthin B was given at three doses viz. 25, 50 and 100 mg/kg. The percentage increase in life span and the overall survival in malignant ascites animals and the tumor volume in solid tumor animals were measured. The haematological parameters were assessed in all animals before and 2 weeks after the treatment. Cleistanthin B 50 mg/kg and 5-FU significantly prolonged the life span (>25% of malignant ascites tumor bearing animals. The overall survival was significantly improved by both. Only cleistanthin B 50 mg/kg significantly reduced the elevated WBC counts in EAC tumor bearing animals. Both 5-FU and cleistanthin B 50 mg/kg reversed the malignancy induced increase in neutrophils and platelet counts and decrease in lymphocyte counts but not to the normal range. Only 5-FU significantly reduced the solid tumor volume. None of the three doses of cleistanthin B was effective against the solid tumor. Cleistanthin B has antitumor activity against EAC and DAL tumor mice but it is not as effective as 5-FU. At 50 mg/kg dose cleistanthin B exerts significant antitumor activity compared to 25 and 100 mg/kg dose. Its effect on WBC count is higher and advantageous when compared to 5-FU. But cleistanthin B in the doses used is not effective against solid tumor.

  15. Antitumor activity of biflorin, an o-naphthoquinone isolated from Capraria biflora.

    Science.gov (United States)

    Vasconcellos, Marne Carvalho de; Bezerra, Daniel Pereira; Fonseca, Aluísio Marques; Pereira, Márcio Roberto Pinho; Lemos, Telma Leda Gomes; Pessoa, Otília Deusdênia Loiola; Pessoa, Cláudia; Moraes, Manoel Odorico de; Alves, Ana Paula Negreiros Nunes; Costa-Lotufo, Letícia Veras

    2007-08-01

    Pharmacological studies with an aqueous extract obtained from leaves of Capraria biflora showed potent cytotoxic, analgesic, antimicrobial and anti-inflammatory activities. It has been demonstrated that biflorin possesses an in vitro cytotoxic activity against tumor cells. The in vivo antitumor activity of biflorin was evaluated on two mouse models, sarcoma 180 and Ehrlich carcinoma. Biflorin was active against both tumors with a very similar profile. In addition, biflorin was also able to increase the response elicited by 5-FU in mice inoculated with both tumors. The results showed a decrease in Ki67 staining in tumor cells from treated-animals when compared with non-treated groups, which suggests an inhibition of tumor proliferation rate. Histopathological analysis from kidneys and liver showed that biflorin possessed weak and reversible toxic effects. It was also demonstrated that biflorin acts as an immunoadjuvant agent, rising the production of ovalbumin-specific antibodies and inducing a discreet increase of the white pulp and nest of megakaryocytic in spleen of treated mice, which can be related to its antitumor properties.

  16. [Isolation and identification of proteins with anti-tumor and fibrinolysogen kinase activities from Eisenia foetida].

    Science.gov (United States)

    Zhao, Rui; Ji, Jian-Guo; Tong, Yuan-Peng; Chen, Qian; Pu, Hai; Ru, Bing-Gen

    2002-09-01

    Proteins from Eisenia foetida possess many biological activities. A group of proteins precipitated by ethanol were isolated and purified by Sephadex G-75 and HiPrep 16/60 DEAE columns, then identified by one- or two- dimensional electrophoresis and mass spectrometry. 2D gel experiments displayed that the pI of proteins from Eisenia foetida were mainly from 3.0 to 4.0. Anti-tumor and kinase activities were determined by in vitro experiments. The enthanol fraction D2(8) showed both of the activities. These ethanol-precipitated proteins were identified further by native polyacrylamide electrophoresis, the protein spots were cut off from gels and digested by trypsin, the peptide mass fingerprints (PMFs) were determined by mass spectrometry. PMF, molecular weight, amino acid composition and N-terminus of 6 proteins were characterized, and band 9 was identified as D2(8). The results suggested that there exist proteins in Eisenia foetida possessed both anti-tumor and fibrinolysogen kinase activities. These methods can be used for identification of the natural bioactive proteins.

  17. The Antitumor Activity of the Novel Compound Jesridonin on Human Esophageal Carcinoma Cells.

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    Cong Wang

    Full Text Available Jesridonin, a small molecule obtained through the structural modification of Oridonin, has extensive antitumor activity. In this study, we evaluated both its in vitro activity in the cancer cell line EC109 and its in vivo effect on tumor xenografts in nude mice. Apoptosis induced by Jesridonin was determined using an MTT assay, Annexin-V FITC assay and Hoechest 33258 staining. Apoptosis via mitochondrial and death receptor pathways were confirmed by detecting the regulation of MDM2, p53, and Bcl-2 family members and by activation of caspase-3/-8/-9. In addition, vena caudalis injection of Jesridonin showed significant inhibition of tumor growth in the xenograft model, and Jesridonin-induced cell apoptosis in tumor tissues was determined using TUNEL. Biochemical serum analysis of alkaline phosphatase (ALP, alanine transaminase (ALT, aspartate transaminase (AST, gamma-glutamyl transferase (GGT, total protein (TP and albumin (ALB indicated no obvious effects on liver function. Histopathological examination of the liver, kidney, lung, heart and spleen revealed no signs of JD-induced toxicity. Taken together, these results demonstrated that Jesridonin exhibits antitumor activity in human esophageal carcinomas EC109 cells both in vitro and in vivo and demonstrated no adverse effects on major organs in nude mice. These studies provide support for new drug development.

  18. L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity.

    Science.gov (United States)

    Geiger, Roger; Rieckmann, Jan C; Wolf, Tobias; Basso, Camilla; Feng, Yuehan; Fuhrer, Tobias; Kogadeeva, Maria; Picotti, Paola; Meissner, Felix; Mann, Matthias; Zamboni, Nicola; Sallusto, Federica; Lanzavecchia, Antonio

    2016-10-20

    Metabolic activity is intimately linked to T cell fate and function. Using high-resolution mass spectrometry, we generated dynamic metabolome and proteome profiles of human primary naive T cells following activation. We discovered critical changes in the arginine metabolism that led to a drop in intracellular L-arginine concentration. Elevating L-arginine levels induced global metabolic changes including a shift from glycolysis to oxidative phosphorylation in activated T cells and promoted the generation of central memory-like cells endowed with higher survival capacity and, in a mouse model, anti-tumor activity. Proteome-wide probing of structural alterations, validated by the analysis of knockout T cell clones, identified three transcriptional regulators (BAZ1B, PSIP1, and TSN) that sensed L-arginine levels and promoted T cell survival. Thus, intracellular L-arginine concentrations directly impact the metabolic fitness and survival capacity of T cells that are crucial for anti-tumor responses. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  19. Antitumor activity of anti-C-ERC/mesothelin monoclonal antibody in vivo.

    Science.gov (United States)

    Inami, Koichi; Abe, Masaaki; Takeda, Kazuyoshi; Hagiwara, Yoshiaki; Maeda, Masahiro; Segawa, Tatsuya; Suyama, Masafumi; Watanabe, Sumio; Hino, Okio

    2010-04-01

    Mesothelioma is an aggressive cancer often caused by chronic asbestos exposure, and its prognosis is very poor despite the therapies currently used. Due to the long latency period between asbestos exposure and tumor development, the worldwide incidence will increase substantially in the next decades. Thus, novel effective therapies are warranted to improve the prognosis. The ERC/mesothelin gene (MSLN) is expressed in wide variety of human cancers, including mesotheliomas, and encodes a precursor protein cleaved by proteases to generate C-ERC/mesothelin and N-ERC/mesothelin. In this study, we investigated the antitumor activity of C-ERC/mesothelin-specific mouse monoclonal antibody, 22A31, against tumors derived from a human mesothelioma cell line, ACC-MESO-4, in a xenograft experimental model using female BALB/c athymic nude mice. Treatment with 22A31 did not inhibit cell proliferation of ACC-MESO-4 in vitro; however, therapeutic treatment with 22A31 drastically inhibited tumor growth in vivo. 22A31 induced antibody-dependent cell-mediated cytotoxicity by natural killer (NK) cells, but not macrophages, in vitro. Consistently, the F(ab')(2) fragment of 22A31 did not inhibit tumor growth in vivo, nor did it induce antibody-dependent cell mediated cytotoxicity (ADCC) in vitro. Moreover, NK cell depletion diminished the antitumor effect of 22A31. Thus, 22A31 induced NK cell-mediated ADCC and exerted antitumor activity in vivo. 22A31 could have potential as a therapeutic tool to treat C-ERC/mesothelin-expressing cancers including mesothelioma.

  20. Antitumor activity and antioxidant status of Caesalpinia bonducella against Ehrlich ascites carcinoma in Swiss albino mice.

    Science.gov (United States)

    Gupta, Malaya; Mazumder, Upal Kanti; Kumar, Ramanathan Sambath; Sivakumar, Thangavel; Vamsi, Madgula Lakshmi Mohan

    2004-02-01

    The methanol extract of Caesalpinia bonducella FLEMING (Caesalpiniaceae) leaves (MECB) were evaluated for antitumor activity against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. The extract was administered at the doses of 50, 100, and 200 mg/kg body weight per day for 14 days after 24 h of tumor inoculation. After the last dose and 18 h fasting, the mice were sacrificed. The present study deals with the effect of MECB on the growth of transplantable murine tumor, life span of EAC-bearing hosts, hematological profile, and biochemical parameters such as lipid peroxidation (LPO), glutathione content (GSH), superoxide dismutase (SOD), and catalase (CAT) activities. MECB caused significant (P<0.01) decrease in tumor volume, packed cell volume, and viable cell count; and it prolonged the life span of EAC-tumor bearing mice. Hematological profile converted to more or less normal levels in extract-treated mice. MECB significantly (P<0.05) decreased the levels of lipid peroxidation and significantly (P<0.05) increased the levels of GSH, SOD, and CAT. The MECB was found to be devoid of conspicuous short-term toxicity in the mice when administered daily (i.p.) for 14 days at the doses of 50, 100, 200, and 300 mg/kg. The treated mice showed conspicuous toxic symptoms only at 300 mg/kg. The results indicate that MECB exhibited significant antitumor and antioxidant activity in EAC-bearing mice.

  1. Antitumor and immune regulation activities of the extracts of some Chinese marine invertebrates

    Science.gov (United States)

    Zhang, Lixin; Fan, Xiao; Han, Lijun

    2005-03-01

    Extracts of 21 marine invertebrates belonging to Coelenterata, Mollusca, Annelida, Bryozoa, Echiura, Arthropoda, Echinodermata and Urochordata were screened for the studies on their antitumor and immune regulation activities. Antitumor activity was determined by MTT method and immune regulation activity was studied using T- and B-lymphocytes in mice spleen in vitro. It was found that the n-butanol part of Asterina pectinifera, the acetic ether part of Tubuaria marina, 95% ethanol extract of Acanthochiton rubrolineatus have a high inhibition rate of 96.7%, 63.9% and 50.5% respectively on tumor cell line HL-60 at the concentration of 0.063 mg/ml. The inhibition rate of the acetic ether part of Tubuaria marina on the tumor cell line A-549 is 65.4% at concentration of 0.063 mg/mL. The 95% ethanol extract of Meretrix meretrix has so outstanding promoting effect on T-lymphocytes that their multiplication increases 25% when the sample concentration is only 1 μg/ml. On B-lymphocytes, the 95% extract of Rapana venosa, at concentration of 100 μg/ml, has a promotion percentage of 60%. On the other hand, under the condition of no cytotoxic effect, the 95% ethanol extracts of Acanthochiton rubrolineatus and Cellana toreum can reach 92% inhibition rate on T lymphocyte at concentration of 100 μg/ml, while the inhibition rate on B lymphocyte of the 95% extract of Acanthochiton rubrolineatus reaches 92% at the same concentration.

  2. Antitumoral Activity of Snake Venom Proteins: New Trends in Cancer Therapy

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    Leonardo A. Calderon

    2014-01-01

    Full Text Available For more than half a century, cytotoxic agents have been investigated as a possible treatment for cancer. Research on animal venoms has revealed their high toxicity on tissues and cell cultures, both normal and tumoral. Snake venoms show the highest cytotoxic potential, since ophidian accidents cause a large amount of tissue damage, suggesting a promising utilization of these venoms or their components as antitumoral agents. Over the last few years, we have studied the effects of snake venoms and their isolated enzymes on tumor cell cultures. Some in vivo assays showed antineoplastic activity against induced tumors in mice. In human beings, both the crude venom and isolated enzymes revealed antitumor activities in preliminary assays, with measurable clinical responses in the advanced treatment phase. These enzymes include metalloproteases (MP, disintegrins, L-amino acid oxidases (LAAOs, C-type lectins, and phospholipases A2 (PLA2s. Their mechanisms of action include direct toxic action (PLA2s, free radical generation (LAAOs, apoptosis induction (PLA2s, MP, and LAAOs, and antiangiogenesis (disintegrins and lectins. Higher cytotoxic and cytostatic activities upon tumor cells than normal cells suggest the possibility for clinical applications. Further studies should be conducted to ensure the efficacy and safety of different snake venom compounds for cancer drug development.

  3. Calcium pterin as an antitumor agent.

    Science.gov (United States)

    Moheno, Phillip B B

    2004-03-01

    A series of in vivo studies are reported that provide evidence for an immunologically mediated mechanism for the antitumor response from a calcium pterin (CaPterin) suspension. Strong antitumor efficacy was demonstrated in fully immunocompetent female C3H/HeN-MTV+ mice (retired breeders) presenting spontaneous mammary gland adenocarcinomas. Comparison of results obtained by testing CaPterin in either nude or SCID mice (severely compromised immunodeficient) implanted with MDA-MB-231 human cancer cells showed a significant antitumor response in the nudes and no response in the SCIDs. This comparison argues for B-cell immunological involvement in the mechanism of CaPterin antitumor activity since nude mice possess B-cell capability while SCID mice do not. This comparison also indicates that there is no measurable direct cancer cell toxicity from the CaPterin. Results showing no CaPterin antitumor efficacy against EMT6 tumor cells implanted in Balb/c mice also suggest an antitumor mechanism involving B-cells, since transforming growth factor beta (TGF-beta), produced by EMT6 cells, is known to cause B-cell apoptosis. Taken together, these results, along with those of other researchers, indicate that CaPterin's antitumor mechanism involves antibody-dependent cellular cytotoxicity (ADCC) mediated, for example, by natural killer (NK) cells, interlukin-2, and CaPterin.

  4. Activity of Strongly Magnetized Neutron Stars

    Science.gov (United States)

    Beloborodov, Andrei

    This proposal is the continuation of a previous 3-year project that focused on modeling the nonthermal emission from magnetars and pulsars and testing the models against new observations, in particular by NuSTAR. The proposed project develops in two directions: (1) First-principle simulations of the magnetospheric electron-positron discharge using our code APERTURE (based on the particle-in-cell method), which is specifically designed for this purpose. Its performance is demonstrated by the first application to rotation-powered pulsars, and it can significantly advance our understanding of the magnetospheric activity of magnetars and pulsars. Our simulations involve a detailed implementation of radiative processes, tracking the emission and propagation of gammarays and production of electron-positron pairs. The results will provide new theoretical foundation for interpreting emission from the twisted magnetospheres of neutron stars. They will clarify, in particular, the radiative mechanism of magnetar bursts and persistent emission. (2) Investigation of magnetic field evolution inside neutron stars, which is ultimately responsible for driving the magnetospheric activity of magnetars and their surface heating. Our recent results suggest two novel phenomena in the solid crust of an active magnetar: thermoplastic waves and Hall-mediated avalanches. We propose to investigate scenarios for the global magnetic field evolution in the core and the crust, and its observables including (a) twisting of the external magnetosphere and the resulting nonthermal activity, (b) subsurface heating, and (c) sudden changes of the rotation rate. We will use our models and the rich accumulated data to disentangle the key dynamic processes inside magnetars. This analysis can constrain the magnetic fields hidden inside magnetars, the state of their core matter and its possible superfluidity.

  5. Long-Chain Acetylenic Ketones from the Micronesian Sponge Haliclona sp. Importance of the 1-yn-3-ol Group for Antitumor Activity

    Directory of Open Access Journals (Sweden)

    Guang-Xiong Zhou

    2003-11-01

    Full Text Available Abstract: Two new long-chain C33 polyacetylenic compounds, halicynones A and B were isolated from the marine sponge Haliclona sp. along with known analogs. The known compound pellynol A possessing a 1-yn-3-ol terminus, exhibited strong antitumor activity against the human colon tumor cell line HCT-116 (IC50 0.026 μg/mL, however, the corresponding 1-yn-3-one, halicynone A, was inactive, which suggests an important role for the terminal 1-yn-3-ol functional group in mediating cytotoxic activity.

  6. Chemical composition and antitumor activity of different wild varieties of Moroccan thyme

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    Abdeslam Jaafari

    Full Text Available Many species of Thyme have been widely used in Moroccan folk medicine as anti-inflammatory, antioxidant and antinociceptive agents. This study was designed to examine the chemical composition and the in vitro antitumor activity of the essential oils and various extracts of thyme species collected in different regions of Morocco. The essential oil, obtained by hydrodistillation, and the various extracts, obtained by Soxhlet extraction, using solvents of varying polarity, were analysed by gas chromatography coupled to mass spectrometry (GC-MS. Both major and trace components were analysed. Overall, the major constituents in the chemical composition of Moroccan thyme populations were carvacrol, thymol, borneol and p-cymene. The rate of these components can hit respectively to 85%, 42%, 59%, and 23%. Furthermore, the essential oils as well as two pure products (carvacrol and thymol were tested for their antitumoral activity against P815 mastocytoma cell line. While all these products showed a dose dependent cytotoxic effect, the carvacrol was the most cytotoxic one compared to the others. Interestingly, when these products were tested against the normal human peripheral blood mononuclear cells, they show a proliferative effect instead of a cytotoxic one.

  7. Synthesis, antitumor activity, and cytotoxicity of 4-substituted 1-benzyl-5-diphenylstibano-1H-1,2,3-triazoles.

    Science.gov (United States)

    Yamada, Mizuki; Takahashi, Tsutomu; Hasegawa, Mai; Matsumura, Mio; Ono, Kanna; Fujimoto, Ryota; Kitamura, Yuki; Murata, Yuki; Kakusawa, Naoki; Tanaka, Motohiro; Obata, Tohru; Fujiwara, Yasuyuki; Yasuike, Shuji

    2018-01-15

    Trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) were synthesized by the Cu-catalyzed azide-alkyne cycloaddition of various ethynylstibanes (1) with benzylazide (2) in the presence of CuBr (5 mol%) under aerobic conditions. The reaction of 5-stibanotriazoles with HCl afforded C5-unsubstituted 1,2,3-triazoles (4a-f). The antitumor activity of trisubstituted 5-organostibano-1H-1,2,3-triazoles (3a-f) and their 5-unsubstituted 1,2,3-triazoles (4a-f) were evaluated in several tumor cell lines. All 5-stibanotriazoles (3a-f) exerted an excellent antitumor activity. On the contrary, 5-unsubstituted 1,2,3-triazoles (4a-f) without a diphenylantimony group in the molecule exhibited very low antitumor activity compared with 5-stibanotriazoles (3a-f). In compounds of both the series, the substituted 4-butyl group appeared to decrease antitumor activity. However, results suggested that organometal (antimony) in the molecule was required for greater antitumor activity. In addition, all 5-stibanotriazoles (3a-f), but not all 5-unsubstituted 1,2,3-triazoles (4a-f), exhibited cytotoxicity in normal vascular endothelial cells derived from bovine aorta. Among the compounds (3b-e) that exhibited excellent antitumor activity, those with 4-methylphenyl (3b) and 1-cyclohexenyl (3e) showed relatively low cytotoxicity to vascular endothelial cells. Together, these results suggest that trisubstituted 5-organostibano-1H-1,2,3-triazoles, including compounds 3b and 3e, may serve as potential anticancer therapeutic drugs in the future. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Synthesis, characterization, antitumoral and osteogenic activities of quercetin vanadyl(IV) complexes.

    Science.gov (United States)

    Ferrer, Evelina G; Salinas, María V; Correa, María J; Naso, Luciana; Barrio, Daniel A; Etcheverry, Susana B; Lezama, Luis; Rojo, Teófilo; Williams, Patricia A M

    2006-09-01

    The development of new vanadium derivatives with organic ligands, which improve the beneficial actions (insulin-mimetic, antitumoral) and decrease the toxic effects, is of great interest. A good candidate for the generation of a new vanadium compound is the flavonoid quercetin because of its own anticarcinogenic effect. The complex [VO(Quer)(2)EtOH]( n ) (QuerVO) has been synthesized and characterized by means of different spectroscopic techniques (UV-vis, Fourier transform IR, electron paramagnetic resonance) and its magnetic and stability properties. The inhibitory effect on bovine alkaline phosphatase (ALP) activity has been tested for the free ligand, the complex as well as for the vanadyl(IV) (comparative purposes). The biological activity of the complex on the proliferation of two osteoblast-like cells in culture, a normal one (MC3T3E1) and a tumoral one (UMR106), has been compared with that of the vanadyl(IV) cation and quercetin. The differentiation osteoblast markers ALP specific activity and collagen synthesis have been also tested. In addition, the effect of QuerVO on the activation of the extracellular regulated kinase (ERK) pathway is reported. The bone antitumoral effect of quercetin alone was established with the cell proliferation assays (it inhibits the proliferation of the tumoral cells and does not exert any effect on the normal osteoblasts). Moreover, the complex exerts osteogenic effects since it stimulates the type I collagen production and is a weak inhibitory agent upon ALP activity. Finally, QuerVO stimulated the ERK phosphorylation in a dose-response manner and this activation seems to be involved as one of the possible mechanisms for the biological effects of the complex.

  9. Antitumor and antibacterial activity of a crude methanol leaf extract of Vitex negundo L.

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    Islam Soriful

    2013-01-01

    Full Text Available In this study we evaluated a methanol leaf extract of Vitex negundo L. (Verbenaceae for antitumor and antibacterial activities using the potato disc bioassay and the agar disc diffusion method, respectively. Taking ≤20% tumor inhibition as significant, we found significant crown gall inhibition (24-48.39% with 1 and 10 mg/ml extracts while 0.1 mg/ml of the extract was ineffective (14.67% to 18.28%. Maximal tumor inhibition was observed with 10 mg/ml extract against Agrobacterium tumefaciens strain AtSl0105 (48.39%, followed by AtTa0112 (45.9% and AtAc0114 (44%. The methanol leaf extract showed growth inhibitory potency against all of the studied bacteria (Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Salmonella typhi. The minimum inhibitory concentrations ranged from 0.312 mg/ml to 1.25 mg/ml. The least MIC value was recorded against S. aureus and P. aeruginosa. The presented findings indicate that the methanol leaf extract could be considered as a source of novel antitumor and antibacterial compounds.

  10. Ultrasonic-assisted extraction, structure and antitumor activity of polysaccharide from Polygonum multiflorum.

    Science.gov (United States)

    Zhu, Weili; Xue, Xiaoping; Zhang, Zhanjun

    2016-10-01

    Polygonum multiflorum is a popular Chinese herbal medicine with various pharmacological functions. In this study, the ultrasonic-assisted extraction condition, structural characterization and antitumor activity of a polysaccharide from roots of P. multiflorum were investigated. The ultrasonic-assisted extraction condition was optimized by single-factor experiments and response surface methodology. Results showed that the maximum extraction yield (5.49%) was obtained at ultrasonic power 158W, extraction temperature 62°C, extraction time 80min and ratio of water to material 20mL/g. The obtained crude polysaccharides were further purified to afford a neutral and an acidic fraction. The structure of the main neutral polysaccharide (named PPS with molecular weight of 3.26×10(5)Da) was characterized as a linear (1→6)-α-d-glucan by gas chromatography, Fourier transform-infrared spectroscopy, methylation analysis, 1D and 2D nuclear magnetic resonance. At the concentration of 400μg/mL, the inhibitory ratios of PPS on HepG-2 and BGC-823 cells were 53.35% and 38.58%, respectively. Results suggested this polysaccharide could be a potential natural antitumor agent. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Antibody complementarity-determining regions (CDRs can display differential antimicrobial, antiviral and antitumor activities.

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    Luciano Polonelli

    Full Text Available BACKGROUND: Complementarity-determining regions (CDRs are immunoglobulin (Ig hypervariable domains that determine specific antibody (Ab binding. We have shown that synthetic CDR-related peptides and many decapeptides spanning the variable region of a recombinant yeast killer toxin-like antiidiotypic Ab are candidacidal in vitro. An alanine-substituted decapeptide from the variable region of this Ab displayed increased cytotoxicity in vitro and/or therapeutic effects in vivo against various bacteria, fungi, protozoa and viruses. The possibility that isolated CDRs, represented by short synthetic peptides, may display antimicrobial, antiviral and antitumor activities irrespective of Ab specificity for a given antigen is addressed here. METHODOLOGY/PRINCIPAL FINDINGS: CDR-based synthetic peptides of murine and human monoclonal Abs directed to: a a protein epitope of Candida albicans cell wall stress mannoprotein; b a synthetic peptide containing well-characterized B-cell and T-cell epitopes; c a carbohydrate blood group A substance, showed differential inhibitory activities in vitro, ex vivo and/or in vivo against C. albicans, HIV-1 and B16F10-Nex2 melanoma cells, conceivably involving different mechanisms of action. Antitumor activities involved peptide-induced caspase-dependent apoptosis. Engineered peptides, obtained by alanine substitution of Ig CDR sequences, and used as surrogates of natural point mutations, showed further differential increased/unaltered/decreased antimicrobial, antiviral and/or antitumor activities. The inhibitory effects observed were largely independent of the specificity of the native Ab and involved chiefly germline encoded CDR1 and CDR2 of light and heavy chains. CONCLUSIONS/SIGNIFICANCE: The high frequency of bioactive peptides based on CDRs suggests that Ig molecules are sources of an unlimited number of sequences potentially active against infectious agents and tumor cells. The easy production and low cost of small

  12. Preclinical antitumor activity of the orally available heat shock protein 90 inhibitor NVP-BEP800.

    Science.gov (United States)

    Massey, Andrew J; Schoepfer, Joseph; Brough, Paul A; Brueggen, Josef; Chène, Patrick; Drysdale, Martin J; Pfaar, Ulrike; Radimerski, Thomas; Ruetz, Stephan; Schweitzer, Alain; Wood, Mike; Garcia-Echeverria, Carlos; Jensen, Michael Rugaard

    2010-04-01

    Heat shock protein 90 (Hsp90) is a ubiquitously expressed molecular chaperone with ATPase activity involved in the conformational maturation and stability of key signaling molecules involved in cell proliferation, survival, and transformation. Through its ability to modulate multiple pathways involved in oncogenesis, Hsp90 has generated considerable interest as a therapeutic target. NVP-BEP800 is a novel, fully synthetic, orally bioavailable inhibitor that binds to the NH(2)-terminal ATP-binding pocket of Hsp90. NVP-BEP800 showed activity against a panel of human tumor cell lines and primary human xenografts in vitro at nanomolar concentrations. In A375 melanoma and BT-474 breast cancer cell lines, NVP-BEP800 induced client protein degradation (including ErbB2, B-Raf(V600E), Raf-1, and Akt) and Hsp70 induction. Oral administration of NVP-BEP800 was well tolerated and induced robust antitumor responses in tumor xenograft models, including regression in the BT-474 breast cancer model. In these tumor models, NVP-BEP800 modulated Hsp90 client proteins and downstream signaling pathways at doses causing antitumor activity. NVP-BEP800 showed in vivo activity in a variety of dosing regimens covering daily to weekly schedules, potentially providing a high degree of flexibility in dose and schedule within the clinical setting. Overall, given the mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, NVP-BEP800 is an exciting new oral Hsp90 inhibitor warranting further development. Mol Cancer Ther; 9(4); 906-19. (c)2010 AACR.

  13. Physicochemical properties, immunomodulation and antitumor activities of polysaccharide from Pavlova viridis.

    Science.gov (United States)

    Sun, Liqin; Chu, Jinling; Sun, Zhongliang; Chen, Lihong

    2016-01-01

    Polysaccharides synthesized by microalgae can be used as the functional ingredients of food or drugs. Here, we investigated the physicochemical properties and bioactivities of the polysaccharide from microalgae Pavlova viridis, and indicated the structure-activity relationship. The polysaccharides (PPS0) were degraded with H2O2-vitamin C assisted by ultrasonic waves. The functional group content, monosaccharide composition, and average molecular weight (avg-MW) were detected by chemical or chromatographic method. The immunomodulatory activities were evaluated in vitro by detecting nitric oxide (NO) emission, neutral red uptake and macrophage proliferation. Antitumor activities of degraded fragments were detected using S180-tumor-bearing mouse model by intragastric administration. Degraded polysaccharides PPS1 and PPS2 were obtained at avg-MW of 386.96 and 54.99 kDa. The sulfate group content of polysaccharide was 16%, and the uronic acid content was 5.88 and 8.48%. PPS mainly consisted of fructose, glucose and mannose. All the degraded PPSs could increase phagocytosis and proliferation of macrophages, and stimulated NO emission in a dose-dependently way. PPS2 in Low-MW fragments had the strongest immunoenhancing activities. Different doses of PPS all could inhibit the growth of implanted S180 tumor. At dose of 200 mg/kg/day, the tumor inhibition rate of PPS2 was 57.06%, about 23.6% less than that of CTX-treated group. Different-MW PPS significantly increased lymphocyte proliferation. At 200 mg/L, the proliferation index of PPS2 was 1.37, 2.03 times higher than that of CTX-treated group. The polysaccharides of Pavlova viridis had potential antitumor activities by improving immune response. Moreover, the bioactivities depend on their molecular weight. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells.

    Science.gov (United States)

    Kwak, Tae Won; Kim, Do Hyung; Jeong, Young-Il; Kang, Dae Hwan

    2015-09-26

    The aim of this study is to evaluate the anticancer activity of vorinostat-incorporated nanoparticles (vorinostat-NPs) against HuCC-T1 human cholangiocarcinoma cells. Vorinostat-NPs were fabricated by a nanoprecipitation method using poly(DL-lactide-co-glycolide)/poly(ethylene glycol) copolymer. Vorinostat-NPs exhibited spherical shapes with sizes Vorinostat-NPs have anticancer activity similar to that of vorinostat in vitro. Vorinostat-NPs as well as vorinostat itself increased acetylation of histone-H3. Furthermore, vorinostat-NPs have similar effectiveness in the suppression or expression of histone deacetylase, mutant type p53, p21, and PARP/cleaved caspase-3. However, vorinostat-NPs showed improved antitumor activity against HuCC-T1 cancer cell-bearing mice compared to vorinostat, whereas empty nanoparticles had no effect on tumor growth. Furthermore, vorinostat-NPs increased the expression of acetylated histone H3 in tumor tissue and suppressed histone deacetylase (HDAC) expression in vivo. The improved antitumor activity of vorinostat-NPs can be explained by molecular imaging studies using near-infrared (NIR) dye-incorporated nanoparticles, i.e. NIR-dye-incorporated nanoparticles were intensively accumulated in the tumor region rather than normal one. Our results demonstrate that vorinostat and vorinostat-NPs exert anticancer activity against HuCC-T1 cholangiocarcinoma cells by specific inhibition of HDAC expression. Thus, we suggest that vorinostat-NPs are a promising candidate for anticancer chemotherapy in cholangiocarcinoma. Graphical abstract Local delivery strategy of vorinostat-NPs against cholangiocarcinomas.

  15. Inecalcitol, an analog of 1,25D₃, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system

    Science.gov (United States)

    Ma, Yingyu; Yu, Wei-Dong; Hidalgo, Alejandro A.; Luo, Wei; Delansorne, Remi; Johnson, Candace S.; Trump, Donald L.

    2013-01-01

    Epidemiological data suggest an important role of vitamin D signaling in cancer development and progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D₃ (1,25D₃) has broad spectrum antitumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D₃, inecalcitol [19-nor-14-epi-23-yne-1,25-(OH)₂D₃; TX522], was developed to have superagonistic antitumor activities but low hypercalcemia potential. We examined the antitumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. In vitro, compared with 1,25D₃, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose-dependent manner with an IC₅₀ value 30 times lower than that of 1,25D₃. Both inecalcitol and 1,25D₃ induced a comparable level of G₀/G₁ cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D₃. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared with 1,25D₃. In vivo, inecalcitol inhibits SCC tumor growth in a dose-dependent fashion. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. While in vitro inecalcitol demonstrates apparent enhanced VDR binding and antiproliferative effects compared to 1,25D₃, in vivo these advantages disappear; at doses of inecalcitol that have equivalent antitumor effects, similar hypercalcemia is seen. This may be explained by the pharmacokinetics of 1,25D₃ vs. inecalcitol and attributed to the much shorter serum half-life of inecalcitol.We show that inecalcitol has potent antitumor activity in the SCC model system, and this is associated with a

  16. Chemical features of Ganoderma polysaccharides with antioxidant, antitumor and antimicrobial activities.

    Science.gov (United States)

    Ferreira, Isabel C F R; Heleno, Sandrina A; Reis, Filipa S; Stojkovic, Dejan; Queiroz, Maria João R P; Vasconcelos, M Helena; Sokovic, Marina

    2015-06-01

    Ganoderma genus comprises one of the most commonly studied species worldwide, Ganoderma lucidum. However, other Ganoderma species have been also reported as important sources of bioactive compounds. Polysaccharides are important contributors to the medicinal properties reported for Ganoderma species, as demonstrated by the numerous publications, including reviews, on this matter. Yet, what are the chemical features of Ganoderma polysaccharides that have bioactivity? In the present manuscript, the chemical features of Ganoderma polysaccharides with reported antioxidant, antitumor and antimicrobial activities (the most studied worldwide) are analyzed in detail. The composition of sugars (homo- versus hetero-glucans and other polysaccharides), type of glycosidic linkages, branching patterns, and linkage to proteins are discussed. Methods for extraction, isolation and identification are evaluated and, finally, the bioactivity of polysaccharidic extracts and purified compounds are discussed. The integration of data allows deduction of structure-activity relationships and gives clues to the chemical aspects involved in Ganoderma bioactivity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Production, Structural Elucidation, and In Vitro Antitumor Activity of Trehalose Lipid Biosurfactant from Nocardia farcinica Strain.

    Science.gov (United States)

    Christova, Nelly; Lang, Siegmund; Wray, Victor; Kaloyanov, Kaloyan; Konstantinov, Spiro; Stoineva, Ivanka

    2015-04-01

    The objective of this study was to isolate and identify the chemical structure of a biosurfactant produced by Nocardia farcinica strain BN26 isolated from soil, and evaluate its in vitro antitumor activity on a panel of human cancer cell lines. Strain BN26 was found to produce glycolipid biosurfactant on n-hexadecane as the sole carbon source. The biosurfactant was purified using medium-pressure liquid chromatography and characterized as trehalose lipid tetraester (THL) by nuclear magnetic resonance spectroscopy and mass spectrometry. Subsequently, the cytotoxic effects of THL on cancer cell lines BV-173, KE-37 (SKW-3), HL-60, HL-60/DOX, and JMSU-1 were evaluated by MTT assay. It was shown that THL exerted concentration-dependent antiproliferative activity against the human tumor cell lines and mediated cell death by the induction of partial oligonucleosomal DNA fragmentation. These findings suggest that THL could be of potential to apply in biomedicine as a therapeutic agent.

  18. Clinical development of reovirus for cancer therapy: An oncolytic virus with immune-mediated antitumor activity.

    Science.gov (United States)

    Gong, Jun; Sachdev, Esha; Mita, Alain C; Mita, Monica M

    2016-03-26

    Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.

  19. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

    Directory of Open Access Journals (Sweden)

    Estelle Daudigeos-Dubus

    Full Text Available The multikinase inhibitor regorafenib (BAY 73-4506 exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L. In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.

  20. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

    Science.gov (United States)

    Daudigeos-Dubus, Estelle; Le Dret, Ludivine; Lanvers-Kaminsky, Claudia; Bawa, Olivia; Opolon, Paule; Vievard, Albane; Villa, Irène; Pagès, Mélanie; Bosq, Jacques; Vassal, Gilles; Zopf, Dieter; Geoerger, Birgit

    2015-01-01

    The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.

  1. Saffron and natural carotenoids: Biochemical activities and anti-tumor effects.

    Science.gov (United States)

    Bolhassani, Azam; Khavari, Afshin; Bathaie, S Zahra

    2014-01-01

    Saffron, a spice derived from the flower of Crocus sativus, is rich in carotenoids. Two main natural carotenoids of saffron, crocin and crocetin, are responsible for its color. Preclinical studies have shown that dietary intake of some carotenoids have potent anti-tumor effects both in vitro and in vivo, suggesting their potential preventive and/or therapeutic roles in several tissues. The reports represent that the use of carotenoids without the potential for conversion to vitamin A may provide further protection and avoid toxicity. The mechanisms underlying cancer chemo-preventive activities of carotenoids include modulation of carcinogen metabolism, regulation of cell growth and cell cycle progression, inhibition of cell proliferation, anti-oxidant activity, immune modulation, enhancement of cell differentiation, stimulation of cell-to-cell gap junction communication, apoptosis and retinoid-dependent signaling. Taken together, different hypotheses for the antitumor actions of saffron and its components have been proposed such as a) the inhibitory effect on cellular DNA and RNA synthesis, but not on protein synthesis; b) the inhibitory effect on free radical chain reactions; c) the metabolic conversion of naturally occurring carotenoids to retinoids; d) the interaction of carotenoids with topoisomerase II, an enzyme involved in cellular DNA-protein interaction. Furthermore, the immunomodulatory activity of saffron was studied on driving toward Th1 and Th2 limbs of the immune system. In this mini-review, we briefly describe biochemical and immunological activities and chemo-preventive properties of saffron and natural carotenoids as an anticancer drug. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

    Science.gov (United States)

    Chen, Meihua; Xiang, Rong; Wen, Yuan; Xu, Guangchao; Wang, Chunting; Luo, Shuntao; Yin, Tao; Wei, Xiawei; Shao, Bin; Liu, Ning; Guo, Fuchun; Li, Meng; Zhang, Shuang; Li, Minmin; Ren, Kexing; Wang, Yongsheng; Wei, Yuquan

    2015-09-23

    Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.

  3. Novel neutralizing hedgehog antibody MEDI-5304 exhibits antitumor activity by inhibiting paracrine hedgehog signaling.

    Science.gov (United States)

    Michaud, Neil R; Wang, Youzhen; McEachern, Kristen A; Jordan, Jerold J; Mazzola, Anne Marie; Hernandez, Axel; Jalla, Sanjoo; Chesebrough, Jon W; Hynes, Mark J; Belmonte, Matthew A; Wang, Lidong; Kang, Jaspal S; Jovanovic, Jelena; Laing, Naomi; Jenkins, David W; Hurt, Elaine; Liang, Meina; Frantz, Christopher; Hollingsworth, Robert E; Simeone, Diane M; Blakey, David C; Bedian, Vahe

    2014-02-01

    The hedgehog pathway has been implicated in the tumorigenesis, tumor progression, and metastasis of numerous human cancers. We generated the first fully human hedgehog antibody MEDI-5304 and characterized its antitumor activity and preclinical toxicology. MEDI-5304 bound sonic hedgehog (SHH) and Indian hedgehog (IHH) with low picomolar affinity and neutralized SHH and IHH activity in cellular mGLI1 reporter assays. The antibody inhibited transcription of hedgehog target genes and osteoblast differentiation of C3H10T1/2 cells. We evaluated the activity of MEDI-5304 in vivo in model systems that allowed us to evaluate two primary hypotheses of hedgehog function in human cancer, paracrine signaling between tumor and stromal cells and cancer stem cell (CSC) self-renewal. MEDI-5304 displayed robust pharmacodynamic effects in stromal cells that translated to antitumor efficacy as a single agent in an HT-29/MEF coimplantation model of paracrine hedgehog signaling. MEDI-5304 also improved responses to carboplatin in the HT-29/MEF model. The antibody, however, had no effect as a single agent or in combination with gemcitabine on the CSC frequency or growth of several primary pancreatic cancer explant models. These findings support the conclusion that hedgehog contributes to tumor biology via paracrine tumor-stromal signaling but not via CSC maintenance or propagation. Finally, the only safety study finding associated with MEDI-5304 was ondontodysplasia in rats. Thus, MEDI-5304 represents a potent dual hedgehog inhibitor suitable for continued development to evaluate efficacy and safety in human patients with tumors harboring elevated levels of SHH or IHH.

  4. Structure and Antitumor and Immunomodulatory Activities of a Water-Soluble Polysaccharide from Dimocarpus longan Pulp

    Directory of Open Access Journals (Sweden)

    Fa-Yan Meng

    2014-03-01

    Full Text Available A new water-soluble polysaccharide (longan polysaccharide 1 (LP1 was extracted and successfully purified from Dimocarpus longan pulp via diethylaminoethyl (DEAE-cellulose anion-exchange and Sephacryl S-300 HR gel chromatography. The chemical structure was determined using Infrared (IR, gas chromatography (GC and nuclear magnetic resonance (NMR analysis. The results indicated that the molecular weight of the sample was 1.1 × 105 Da. Monosaccharide composition analysis revealed that LP1 was composed of Glc, GalA, Ara and Gal in a molar ratio of 5.39:1.04:0.74:0.21. Structural analysis indicated that LP1 consisted of a backbone of →4-α-d-Glcp-(1→4-α-d-GalpA-(1→4-α-d-Glcp-(1→4-β-d-Glcp-(1→ units with poly saccharide side chains composed of →2-β-d-Fruf-(1→2-l-sorbose-(1→ attached to the O-6 position of the α-d-Glcp residues. In vitro experiments indicated that LP1 had significantly high antitumor activity against SKOV3 and HO8910 tumor cells, with inhibition percentages of 40% and 50%, respectively. In addition, LP1 significantly stimulated the production of the cytokine interferon-γ (IFN-γ, increased the activity of murine macrophages and enhanced B- and T-lymphocyte proliferation. The results of this study demonstrate that LP1 has potential applications as a natural antitumor agent with immunomodulatory activity.

  5. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    Energy Technology Data Exchange (ETDEWEB)

    Massi, Paola [Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan (Italy); Valenti, Marta; Solinas, Marta; Parolaro, Daniela, E-mail: daniela.parolaro@uninsubria.it [Department of Structural and Functional Biology, Section of Pharmacology, Center of Neuroscience, University of Insubria, Via A. da Giussano 10, 20152 Busto Arsizio, Varese (Italy)

    2010-05-26

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells.

  6. Research on Characteristics, Antioxidant and Antitumor Activities of Dihydroquercetin and Its Complexes

    Directory of Open Access Journals (Sweden)

    Yan Zhang

    2017-12-01

    Full Text Available Dihydroquercetin is a kind of dihydroflavonol compounds with antioxidant, antitumor, antivirus and radioresistance activities. This study attempted to produce the dihydroquercetin complexes with lecithin and β-cyclodextrin, and research their characteristics and bioactivities via ultraviolet spectrum (UV, infrared spectroscopy (IR, scanning electron microscope (SEM, differential scanning calorimetry (DSC, X-ray diffraction spectrum (XRD, and MTT assay. Results showed that the complexes with lecithin and β-cyclodextrin could improve the solubility and dissolution rate, and remove the characteristic endothermic peak of dihydroquercetin. IR spectra proved their interaction, and results of SEM and XRD showed the amorphous characteristics of the dihydroquercetin compounds. These results indicated that dihydroquercetin was combined by lecithin or β-cyclodextrin with better physical and chemical properties, which would effectively improve the application value in the food and drug industries.

  7. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    International Nuclear Information System (INIS)

    Massi, Paola; Valenti, Marta; Solinas, Marta; Parolaro, Daniela

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells

  8. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer.

    Science.gov (United States)

    Schmieder, Roberta; Hoffmann, Jens; Becker, Michael; Bhargava, Ajay; Müller, Tina; Kahmann, Nicole; Ellinghaus, Peter; Adams, Robert; Rosenthal, André; Thierauch, Karl-Heinz; Scholz, Arne; Wilhelm, Scott M; Zopf, Dieter

    2014-09-15

    Regorafenib, a novel multikinase inhibitor, has recently demonstrated overall survival benefits in metastatic colorectal cancer (CRC) patients. Our study aimed to gain further insight into the molecular mechanisms of regorafenib and to assess its potential in combination therapy. Regorafenib was tested alone and in combination with irinotecan in patient-derived (PD) CRC models and a murine CRC liver metastasis model. Mechanism of action was investigated using in vitro functional assays, immunohistochemistry and correlation with CRC-related oncogenes. Regorafenib demonstrated significant inhibition of growth-factor-mediated vascular endothelial growth factor receptor (VEGFR) 2 and VEGFR3 autophosphorylation, and intracellular VEGFR3 signaling in human umbilical vascular endothelial cells (HuVECs) and lymphatic endothelial cells (LECs), and also blocked migration of LECs. Furthermore, regorafenib inhibited proliferation in 19 of 25 human CRC cell lines and markedly slowed tumor growth in five of seven PD xenograft models. Combination of regorafenib with irinotecan significantly delayed tumor growth after extended treatment in four xenograft models. Reduced CD31 staining indicates that the antiangiogenic effects of regorafenib contribute to its antitumor activity. Finally, regorafenib significantly delayed disease progression in a murine CRC liver metastasis model by inhibiting the growth of established liver metastases and preventing the formation of new metastases in other organs. In addition, our results suggest that regorafenib displays antimetastatic activity, which may contribute to its efficacy in patients with metastatic CRC. Combination of regorafenib and irinotecan demonstrated an increased antitumor effect and could provide a future treatment option for CRC patients. © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

  9. Antitumor activity of histamine and clozapine in a mouse experimental model of human melanoma.

    Science.gov (United States)

    Massari, Noelia A; Medina, Vanina A; Cricco, Graciela P; Martinel Lamas, Diego J; Sambuco, Lorena; Pagotto, Romina; Ventura, Clara; Ciraolo, Pablo J; Pignataro, Omar; Bergoc, Rosa M; Rivera, Elena S

    2013-12-01

    Functional presence of histamine H4 receptor (H4R) was demonstrated in human melanoma cell lines and biopsies. The purposes of this work were to investigate signal transduction pathways and biological responses triggered by the activation of H4R in human primary (WM35) and metastatic (M1/15) melanoma cell lines and to evaluate the in vivo antitumor activity of histamine (HA) and clozapine (CLZ) on human M1/15 melanoma xenografts. Clonogenic assay, incorporation of BrdU, cell cycle distribution, phosphorylation levels of ERK1/2 and cAMP production were evaluated in vitro. An experimental human melanoma model was developed into athymic nude mice. Tumor growth, survival and histochemical studies were performed in order to investigate the expression levels of H4R, HA, PCNA, mitotic index (MI), and angiogenesis. The results indicate that H4R agonists inhibited forskolin-induced cAMP levels only in M1/15 cells while increased phosphorylation levels of ERK1/2 and decreased proliferation in both cell types. In vivo studies show that HA and CLZ (1mgkg(-1), sc) significantly increased median survival and decreased tumor volume. These effects were associated to a reduction in MI, in the expression of proliferation marker and in intratumoral neovascularization. We conclude that HA and CLZ exhibit an antitumoral effect in vitro and in vivo on human melanoma, suggesting the therapeutic potential of these compounds for the treatment of malignant melanoma. Copyright © 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  10. Antitumor activity of theAilanthus altissimabark phytochemical ailanthone against breast cancer MCF-7 cells.

    Science.gov (United States)

    Wang, Ruxing; Lu, Yanjie; Li, Hong; Sun, Lixin; Yang, Ning; Zhao, Mingzhen; Zhang, Manli; Shi, Qingwen

    2018-04-01

    Ailanthone is isolated from the bark of Ailanthus altissima (Mill.) Swingle (Simaroubaceae). The mechanism that underlies the activity of ailanthone on MCF-7 cells was investigated by MTT assay. Breast cancer MCF-7 cells were treated with 0.5, 1.0, 2.0, 4.0 and 8.0 µg/ml ailanthone for 24, 48 and 72 h. The inhibition of proliferation induced by treatment with ailanthone was assessed by MTT assay. Apoptosis and cell cycle distribution in MCF-7 cells with the same doses of ailanthone for 48 h were determined by flow cytometry. Expression of apoptosis-associated genes and proteins were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, respectively. The results revealed that ailanthone inhibited MCF-7 cell proliferation. Flow cytometry assay demonstrated that ailanthone induced apoptosis and G 0 /G 1 cell cycle arrest in MCF-7 cells. Western blotting and RT-PCR assays demonstrated that upregulation of pro-apoptotic caspase-3 and Bcl-associated X, and downregulation of anti-apoptotic apoptosis regulator B-cell lymphoma-2 in MCF-7 cells may be associated with the induction of apoptosis and inhibition of proliferation. To the best of our knowledge, the present study is the first to investigate the antitumor activity of ailanthone from A. altissima on MCF-7 cells and to attempt to elucidate the underlying mechanism. The present study revealed the presence of ailanthone-mediated antitumor effects, indicating that ailanthone may be a novel phytomedicine with potential use in breast cancer therapy.

  11. Tuftsin: a hormone-like tetrapeptide with antimicrobial and antitumor activities

    International Nuclear Information System (INIS)

    Nishioka, K.; Amoscato, A.A.; Babcock, G.F.

    1981-01-01

    A specific fraction of immunoglobulin G binds to polymorphonuclear neutrophils and stimulates their phagocytic activity. This phagocytosis-stimulating activity resides solely in a small peptide termed tuftsin, of the sequence Thr-Lys-Pro-Arg, which has been isolated from the leukophilic immunoglobulin G fraction. The physiological significance of tuftsin has been demonstrated in splenectomized patients and patients with a congenital tuftsin abnormality, in whom the low levels of tuftsin in sera (measurable by radioimmunoassay) coincides with a high incidence of infection. Tuftsin has also been shown to enhance bactericidal activity in addition to phagocytosis. Its biological activities appear to be mediated via specific tuftsin receptors which have been found on macrophages, monocytes and granulocytes. In addition, tuftsin possesses chemotactic, migration-enhancing and mitogenic properties for leukocytes and has recently been shown to enhance their anti-tumor activity in vitro as well as in vivo. Other known activities of tuftsin include effects on the activity of the hexose monophosphate shunt, on the concentrations of intracellular cyclic nucleotides and on the efflux of Ca 2+ in leukocytes. Tuftsin has been chemically synthesized in various laboratories using different procedures and also is available commercially. The above features of tuftsin plus the expected low toxicity of this peptide make tuftsin a very attractive agent for immunotherapy against infection and cancer. However, a great deal of caution needs to be exercised when using tuftsin due to inhibitory contaminants found in certain commercial preparations

  12. Comparison of two self-assembled macromolecular prodrug micelles with different conjugate positions of SN38 for enhancing antitumor activity

    Directory of Open Access Journals (Sweden)

    Liu Y

    2015-03-01

    Full Text Available Yi Liu,1 Hongyu Piao,1 Ying Gao,1 Caihong Xu,2 Ye Tian,1 Lihong Wang,1 Jinwen Liu,1 Bo Tang,1 Meijuan Zou,1 Gang Cheng1 1Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, Liaoning Province, People’s Republic of China; 2Department of Food Science, Shenyang Normal University, Shenyang, Liaoning Province, People’s Republic of China Abstract: 7-Ethyl-10-hydroxycamptothecin (SN38, an active metabolite of irinotecan (CPT-11, is a remarkably potent antitumor agent. The clinical application of SN38 has been extremely restricted by its insolubility in water. In this study, we successfully synthesized two macromolecular prodrugs of SN38 with different conjugate positions (chitosan-(C10-OHSN38 and chitosan-(C20-OHSN38 to improve the water solubility and antitumor activity of SN38. These prodrugs can self-assemble into micelles in aqueous medium. The particle size, morphology, zeta potential, and in vitro drug release of SN38 and its derivatives, as well as their cytotoxicity, pharmacokinetics, and in vivo antitumor activity in a xenograft BALB/c mouse model were studied. In vitro, chitosan-(C10-OHSN38 (CS-(10sSN38 and chitosan-(C20-OHSN38 (CS-(20sSN38 were 13.3- and 25.9-fold more potent than CPT-11 in the murine colon adenocarcinoma cell line CT26, respectively. The area under the curve (AUC0–24 of SN38 after intravenously administering CS-(10sSN38 and CS-(20sSN38 to Sprague Dawley rats was greatly improved when compared with CPT-11 (both P<0.01. A larger AUC0–24 of CS-(20sSN38 was observed when compared to CS-(10sSN38 (P<0.05. Both of the novel self-assembled chitosan-SN38 prodrugs demonstrated superior anticancer activity to CPT-11 in the CT26 xenograft BALB/c mouse model. We have also investigated the differences between these macromolecular prodrug micelles with regards to enhancing the antitumor activity of SN38. CS-(20sSN38 exhibited better in vivo antitumor activity than CS-(10sSN38 at a dose of 2.5 mg/kg (P<0

  13. Effects of extraction methods on the yield, chemical structure and anti-tumor activity of polysaccharides from Cordyceps gunnii mycelia.

    Science.gov (United States)

    Zhu, Zhen-Yuan; Dong, Fengying; Liu, Xiaocui; Lv, Qian; YingYang; Liu, Fei; Chen, Ling; Wang, Tiantian; Wang, Zheng; Zhang, Yongmin

    2016-04-20

    This study was to investigate the effects of different extraction methods on the yield, chemical structure and antitumor activity of polysaccharides from Cordyceps gunnii (C. gunnii) mycelia. Five extraction methods were used to extract crude polysaccharides (CPS), which include room-temperature water extraction (RWE), hot-water extraction (HWE), microwave-assisted extraction (MAE), ultrasound-assisted extraction (UAE) and cellulase-assisted extraction (CAE). Then Sephadex G-100 was used for purification of CPS. As a result, the antitumor activities of CPS and PPS on S180 cells were evaluated. Five CPS and purified polysaccharides (PPS) were obtained. The yield of CPS by microwave-assisted extraction (CPSMAE) was the highest and its anti-tumor activity was the best and its macromolecular polysaccharide (3000-1000kDa) ratio was the largest. The PPS had the same monosaccharide composition, but their obvious difference was in the antitumor activity and the physicochemical characteristics, such as intrinsic viscosity, specific rotation, scanning electron microscopy and circular dichroism spectra. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Antibacterial and Antitumor Activity of Crude Methanolic Extracts from Various Macrofungi Species

    OpenAIRE

    POYRAZ, Burcu; GÜNEŞ, Hatice; TÜL, Bahar; SERMENLİ, Hayrünisa BAŞ

    2015-01-01

    Mushrooms are considered to be an important natural resource for the investigation of new compounds with antimicrobial, anti-tumor or immunomodulatory effects because of their secondary metabolites and degrading enzymes. In this study, antibacterial and antitumor potential of Cantharellus cibarius, Clitocybe geotropa, Gyromitra esculenta, Lactarius delicious, Melanoleuca exscissa, Ramaria flava, Sarcosphaera crassa, Morchella sp., Stereum hirsutum and Trametes versicolor mushrooms collected f...

  15. Metabolite profiling of ascidian Styela plicata using LC-MS with multivariate statistical analysis and their antitumor activity.

    Science.gov (United States)

    Palanisamy, Satheesh Kumar; Trisciuoglio, Daniela; Zwergel, Clemens; Del Bufalo, Donatella; Mai, Antonello

    2017-12-01

    To identify the metabolite distribution in ascidian, we have applied an integrated liquid chromatography- tandem mass spectrometry (LC-MS) metabolomics approach to explore and identify patterns in chemical diversity of invasive ascidian Styela plicata. A total of 71 metabolites were reported among these alkaloids, fatty acids and lipids are the most dominant chemical group. Multivariate statistical analysis, principal component analysis (PCA) showed a clear separation according to chemical diversity and taxonomic groups. PCA and partial least square discriminant analysis were applied to discriminate the chemical group of S. plicata crude compounds and classify the compounds with unknown biological activities. In this study, we reported for the first time that a partially purified methanol extract prepared from the ascidian S. plicata and Ascidia mentula possess antitumor activity against four tumor cell lines with different tumor histotype, such as HeLa (cervical carcinoma), HT29 (colon carcinoma), MCF-7 (breast carcinoma) and M14 (melanoma). S. plicata fraction SP-50 showed strong inhibition of cell proliferation and induced apoptosis in HeLa and HT29 cells, thus indicating S. plicata fraction SP-50 a potential lead compound for anticancer therapy. The molecular mechanism of action and chemotherapeutic potential of these ascidian unknown biomolecules need further research.

  16. A novel lipid-based nanomicelle of docetaxel: evaluation of antitumor activity and biodistribution

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    Ma M

    2012-07-01

    Full Text Available Mingshu Ma,1 Yanli Hao,1 Nan Liu,1 Zhe Yin,1 Lan Wang,1 Xingjie Liang,2 Xiaoning Zhang11Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing, China; 2National Center for Nanoscience and Technology, Beijing, ChinaPurpose: A lipid-based, nanomicelle-loaded docetaxel (M-DOC was designed and characterized. Optical imaging was employed to evaluate the pharmacokinetics and antitumor efficacy of docetaxel in vivo.Materials and methods: The M-DOC was prepared using the emulsion-diffusion method. Transmission electron microscopy and dynamic light scattering were used to assess the morphology and particle size of the M-DOC. Critical micelle concentrations, their stability under physiological conditions, and their encapsulation efficiency – as measured by high-performance liquid chromatography – were assessed. Pharmacological features were evaluated in two different animal models by comparing M-DOC treatments with docetaxel injections (I-DOC. Bioluminescence imaging was used to assess antitumor activity and docetaxel distribution in vivo, using nude mice injected with luciferase-expressing MDA-MB-231 human breast tumor cells. In addition, animals injected with B16 melanoma cells were used to measure survival time and docetaxel distribution.Results: The M-DOC was prepared as round, uniform spheres with an effective diameter of 20.8 nm. The critical micelle concentration of the original emulsion was 0.06%. Satisfactory encapsulation efficiency (87.6% ± 3.0% and 12-hour stability were achieved. Xenograft results demonstrated that the M-DOC was more effective in inhibiting tumor growth, without significantly changing body weight. Survival was prolonged by 12.6% in the M-DOC group. Tumor growth inhibitory rates in the M-DOC and I-DOC groups were 91.2% and 57.8% in volume and 71.8% and 44.9% in weight, respectively. Optical bioluminescence imaging of tumor growths yielded similar results. Area under the

  17. Structure Activity Relationships of N-linked and Diglycosylated Glucosamine-Based Antitumor Glycerolipids

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    Makanjuola Ogunsina

    2013-12-01

    Full Text Available 1-O-Hexadecyl-2-O-methyl-3-O-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (1 was previously reported to show potent in vitro antitumor activity on a range of cancer cell lines derived from breast, pancreas and prostate cancer. This compound was not toxic to mice and was inactive against breast tumor xenografts in mice. This inactivity was attributed to hydrolysis of the glycosidic linkage by glycosidases. Here three N-linked (glycosylamide analogs 2–4, one triazole-linked analog 5 of 1 as well as two diglycosylated analogs 6 and 7 with different stereochemistry at the C2-position of the glycerol moiety were synthesized and their antitumor activity against breast (JIMT-1, BT-474, MDA-MB-231, pancreas (MiaPaCa2 and prostrate (DU145, PC3 cancer cell lines was determined. The diglycosylated analogs 1-O-hexadecyl-2(R-, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (7 and the 1:1 diastereomeric mixture of 1-O-hexadecyl-2(R/S, 3-O-di-(2'-amino-2'-deoxy-β-D-glucopyranosyl-sn-glycerol (6 showed the most potent cytotoxic activity at CC50 values of 17.5 µM against PC3 cell lines. The replacement of the O-glycosidic linkage by a glycosylamide or a glycosyltriazole linkage showed little or no activity at highest concentration tested (30 µM, whereas the replacement of the glycerol moiety by triazole resulted in CC50 values in the range of 20 to 30 µM. In conclusion, the replacement of the O-glycosidic linkage by an N-glycosidic linkage or triazole-linkage resulted in about a two to three fold loss in activity, whereas the replacement of the methoxy group on the glycerol backbone by a second glucosamine moiety did not improve the activity. The stereochemistry at the C2-position of the glycero backbone has minimal effect on the anticancer activities of these diglycosylated analogs.

  18. Evaluation of antitumor activity and antioxidant status of Alternanthera brasiliana against Ehrlich ascites carcinoma in Swiss albino mice.

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    Samudrala, Pavan Kumar; Augustine, Bibin Baby; Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana; Lahkar, Mangala

    2015-01-01

    The main objective of the present study was to explore the antitumor activity of the ethyl acetate extract of the Alternanthera brasiliana (EAAB) and its antioxidant status against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. Based on the preliminary in vitro cytotoxicity studies, EAAB was selected for anti-tumor and antioxidant effects. Anticancer activity of EAAB was evaluated against EAC in Swiss albino mice at the doses of 200 and 400 mg/kg. EAAB was administered for 14 consecutive days after induction of cancer. After 24 h of the last dose and 18 h of fasting, half of the mice were sacrificed and rest were kept alive for assessing any increase in life span. The antitumor effect of EAAB was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological and biochemical parameters of EAC bearing host. Furthermore, the antioxidant and histopathological parameters were evaluated. EAAB treatment has shown significant decrease in tumor volume, viable cell count, tumor weight and elevated the life span of EAC tumor bearing mice in a dose dependent manner. In hematological profile count of RBC, hemoglobin, and WBC were found reverted to normal. EAAB also significantly decreased the levels of lipid peroxidation and significantly increased the levels of GSH, SOD and Catalase. From the above results it may be concluded that EAAB has potent dose dependent antitumor activity and is comparable to that of 5-flourouracil.

  19. Characterization and antitumor activity of camptothecin from endophytic fungusFusarium solaniisolated fromCamptotheca acuminate.

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    Ran, Xueqin; Zhang, Gen; Li, Sheng; Wang, Jiafu

    2017-06-01

    Camptothecin (CPT) is a potent drug against cancers, originally from plants. The endophytic fungi could produce the secondary metabolite same as the host and is used as medicine. The aim of this paper was to investigate an endophytic fungal CPT with anti-neoplastic activity. Endophytic fungi were isolated from Camptotheca acuminata in China. CPT from strain S-019 was characterized by TLC, HPLC and EI-MS analysis. Anti-tumor activity of fungal CPT was detected by MTT and fluorescent dye methods using Vero and PC-3 cells. A total of 94 endophytic fungi strains were isolated from tissues of C. acuminata and 16 fungi strains displayed cytotoxic activity on Vero or PC3 cells. Of which, the fungal strain S-019, classified as Fusarium solani , displayed impressive cytotoxic activity on cancer cells and was found to produce CPT by analysis of TLC, HPLC and EI-MS methods. Bioassay studies confirmed that the fungi CPT had potent cytotoxicity on Vero cells and induced apoptosis of Vero cells. The endophytic fungi from camptotheca trees are a reliable source for natural anticancer compounds. The endophytic fungi could produce CPT same as plant. The fungal CPT exhibited effective activity at inhibiting cell growth and inducing apoptosis on Vero cells.

  20. IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin

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    Zhi-Yong Wang

    2016-01-01

    Full Text Available Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.

  1. Selenylation of Polysaccharide from the Sweet Potato and Evaluation of Antioxidant, Antitumor, and Antidiabetic Activities.

    Science.gov (United States)

    Yuan, Bo; Yang, Xu-Qin; Kou, Meng; Lu, Chang-Yan; Wang, Yuan-Yuan; Peng, Jun; Chen, Ping; Jiang, Ji-Hong

    2017-01-25

    Interest in sweet potato as a functional food is growing. A polysaccharide (SWP) was isolated from the sweet potato tuber and elucidation of its structure as composed of rhamnose, glucose, and galactose undertaken. To improve its activity, selenylation of this novel polysaccharide (Se-SWP) was undertaken by using microwave synthesis. In vitro evaluation showed that the Se-SWP has excellent antioxidant activity on scavenging free radicals and reducing capacity. In vivo antitumor evaluation showed selenylation polysaccharide could effectively inhibit tumor growth (>50%) and adjust immune factor levels in the mice (IL-2, TNF-α, and VEGF). The antidiabetic potential of Se-SWP was tested in STZ-induced diabetic rats. The results indicated that the Se-SWP treatment significantly reduced the levels of malondialdehyde and other disadvantageous factors that were increased by the STZ treatment. Meanwhile, the Se-SWP treatment caused a significant increase in the activities of enzymatic antioxidants and the levels of nonenzymatic antioxidants in the organs of diabetic rats. All of the activity evaluations indicated that the selenylation method could improve the activity of sweet potato polysaccharide and its efficacy as a potential therapeutic, which will be the focus of further study.

  2. The role of bystander effects in the antitumor activity of the hypoxia-activated prodrug PR-104

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    Annika eFoehrenbacher

    2013-10-01

    Full Text Available Activation of prodrugs in tumors (e.g. by bioreduction in hypoxic zones has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such ‘bystander effects’ may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell and multicellular layers to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30% and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug

  3. The Role of Bystander Effects in the Antitumor Activity of the Hypoxia-Activated Prodrug PR-104

    Science.gov (United States)

    Foehrenbacher, Annika; Patel, Kashyap; Abbattista, Maria R.; Guise, Chris P.; Secomb, Timothy W.; Wilson, William R.; Hicks, Kevin O.

    2013-01-01

    Activation of prodrugs in tumors (e.g., by bioreduction in hypoxic zones) has the potential to generate active metabolites that can diffuse within the tumor microenvironment. Such “bystander effects” may offset spatial heterogeneity in prodrug activation but the relative importance of this effect is not understood. Here, we quantify the contribution of bystander effects to antitumor activity for the first time, by developing a spatially resolved pharmacokinetic/pharmacodynamic (SR-PK/PD) model for PR-104, a phosphate ester pre-prodrug that is converted systemically to the hypoxia-activated prodrug PR-104A. Using Green’s function methods we calculated concentrations of oxygen, PR-104A and its active metabolites, and resultant cell killing, at each point of a mapped three-dimensional tumor microregion. Model parameters were determined in vitro, using single cell suspensions to determine relationships between PR-104A metabolism and clonogenic cell killing, and multicellular layer (MCL) cultures to measure tissue diffusion coefficients. LC-MS/MS detection of active metabolites in the extracellular medium following exposure of anoxic single cell suspensions and MCLs to PR-104A confirmed that metabolites can diffuse out of cells and through a tissue-like environment. The SR-PK/PD model estimated that bystander effects contribute 30 and 50% of PR-104 activity in SiHa and HCT116 tumors, respectively. Testing the model by modulating PR-104A-activating reductases and hypoxia in tumor xenografts showed overall clonogenic killing broadly consistent with model predictions. Overall, our data suggest that bystander effects are important in PR-104 antitumor activity, although their reach may be limited by macroregional heterogeneity in hypoxia and reductase expression in tumors. The reported computational and experimental techniques are broadly applicable to all targeted anticancer prodrugs and could be used to identify strategies for rational prodrug optimization. PMID

  4. Evaluation of antitumor activity and in vivo antioxidant status of Anthocephalus cadamba on Ehrlich ascites carcinoma treated mice.

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    Dolai, Narayan; Karmakar, Indrajit; Suresh Kumar, R B; Kar, Biswakanth; Bala, Asis; Haldar, Pallab Kanti

    2012-08-01

    Anthocephalus cadamba (Roxb.) Miq. (Family: Rubiaceae) is commonly known as "Kadamba" in Sanskrit and Hindi in India. Various parts of this plant have been used as a folk medicine for the treatment of tumor, wound healing, inflammation and as a hypoglycemic agent. The purpose of this investigation was to evaluate the antitumor activity and antioxidant status of defatted methanol extract of A. cadamba (MEAC) on Ehrlich ascites carcinoma (EAC) treated mice. In vitro cytotoxicity assay has been evaluated by using the trypan blue method. The determination of in vivo antitumor activity was performed by using different EAC cells (2 × 10(6) cells, i.p.) inoculated mice groups (n=12). The groups were treated for 9 consecutive days with MEAC at the doses of 200 and 400 mg/kg b.w. respectively. After 24h of last dose and 18 h of fasting, half of the mice were sacrificed and the rest were kept alive for assessment of increase in life span. The antitumor potential of MEAC was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological parameters and biochemical estimations. Furthermore, antioxidant parameters were assayed by estimating liver and kidney tissue enzymes. MEAC showed direct cytotoxicity on EAC cell line in a dose dependant manner. MEAC exhibited significant (P<0.01) decrease in the tumor volume, viable cell count, tumor weight and elevated the life span of EAC tumor bearing mice. The hematological profile, biochemical estimations and tissue antioxidant assay were reverted to normal level in MEAC treated mice. Experimental results revealed that MEAC possesses potent antitumor and antioxidant properties. Further research is going on to find out the active principle(s) of MEAC for better understanding of mechanism of its antitumor and antioxidant activity. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  5. Chemical Characterization and Antitumor Activities of Polysaccharide Extracted from Ganoderma lucidum

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    Liang, Zengenni; Yi, Youjin; Guo, Yutong; Wang, Rencai; Hu, Qiulong; Xiong, Xingyao

    2014-01-01

    Ganoderma lucidum polysaccharide (GLP) is a biologically active substance reported to possess anti-tumor ability. Nonetheless, the mechanisms of GLP-stimulated apoptosis are still unclear. This study aims to determine the inhibitory and apoptosis-inducing effects of GLP on HCT-116 cells. We found that GLP reduced cell viability on HCT-116 cells in a time- and dose-dependent manner, which in turn, induced cell apoptosis. The observed apoptosis was characterized by morphological changes, DNA fragmentation, mitochondrial membrane potential decrease, S phase population increase, and caspase-3 and -9 activation. Furthermore, inhibition of c-Jun N-terminal kinase (JNK) by SP600125 led to a dramatic decrease of the GLP-induced apoptosis. Western blot analysis unveiled that GLP up-regulated the expression of Bax/Bcl-2, caspase-3 and poly (ADP-ribose) polymerase (PARP). These results demonstrate that apoptosis stimulated by GLP in human colorectal cancer cells is associated with activation of mitochondrial and mitogen-activated protein kinase (MAPK) pathways. PMID:24857920

  6. Chemical Characterization and Antitumor Activities of Polysaccharide Extracted from Ganoderma lucidum

    Directory of Open Access Journals (Sweden)

    Zengenni Liang

    2014-05-01

    Full Text Available Ganoderma lucidum polysaccharide (GLP is a biologically active substance reported to possess anti-tumor ability. Nonetheless, the mechanisms of GLP-stimulated apoptosis are still unclear. This study aims to determine the inhibitory and apoptosis-inducing effects of GLP on HCT-116 cells. We found that GLP reduced cell viability on HCT-116 cells in a time- and dose-dependent manner, which in turn, induced cell apoptosis. The observed apoptosis was characterized by morphological changes, DNA fragmentation, mitochondrial membrane potential decrease, S phase population increase, and caspase-3 and -9 activation. Furthermore, inhibition of c-Jun N-terminal kinase (JNK by SP600125 led to a dramatic decrease of the GLP-induced apoptosis. Western blot analysis unveiled that GLP up-regulated the expression of Bax/Bcl-2, caspase-3 and poly (ADP-ribose polymerase (PARP. These results demonstrate that apoptosis stimulated by GLP in human colorectal cancer cells is associated with activation of mitochondrial and mitogen-activated protein kinase (MAPK pathways.

  7. Synthesis of isoflavene-thiosemicarbazone hybrids and evaluation of their anti-tumor activity.

    Science.gov (United States)

    Yee, Eugene M H; Brandl, Miriam B; Black, David StC; Vittorio, Orazio; Kumar, Naresh

    2017-06-01

    Phenoxodiol is an isoflavene with potent anti-tumor activity. In this study, a series of novel mono- and di-substituted phenoxodiol-thiosemicarbazone hybrids were synthesized via the condensation reaction between phenoxodiol with thiosemicarbazides. The in vitro anti-proliferative activities of the hybrids were evaluated against the neuroblastoma SKN-BE(2)C, the triple negative breast cancer MDA-MB-231, and the glioblastoma U87 cancer cell lines. The mono-substituted hybrids exhibited potent anti-proliferative activity against all three cancer cell lines, while the di-substituted hybrids were less active. Selected mono-substituted hybrids were further investigated for their cytotoxicity against normal MRC-5 human lung fibroblast cells, which identified two hybrids with superior selectivity for cancer cells over normal cells as compared to phenoxodiol. This suggests that mono-substituted phenoxodiol-thiosemicarbazone hybrids have promising potential for further development as anti-cancer agents. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Poly(γ-glutamic acid)-coated lipoplexes loaded with Doxorubicin for enhancing the antitumor activity against liver tumors

    Science.gov (United States)

    Qi, Na; Tang, Bo; Liu, Guang; Liang, Xingsi

    2017-05-01

    The study was to develop poly-γ-glutamic acid (γ-PGA)-coated Doxorubicin (Dox) lipoplexes that enhance the antitumor activity against liver tumors. γ-PGA-coated lipoplexes were performed by electrostatistically attracting to the surface of cationic charge liposomes with anionic γ-PGA. With the increasing of γ-PGA concentration, the particle size of γ-PGA-coated Dox lipoplexes slightly increased, the zeta potential from positive shifted to negative, and the entrapment efficiency (EE) were no significant change. The release rate of γ-PGA-coated Dox lipoplexes slightly increased at acidic pH, the accelerated Dox release might be attributed to greater drug delivery to tumor cells, resulting in a higher antitumor activity. Especially, γ-PGA-coated Dox lipoplexes exhibited higher cellular uptake, significant in vitro cytotoxicity in HepG2 cells, and improved in vivo antitumor efficacy toward HepG2 hepatoma-xenografted nude models in comparison with Dox liposomes and free Dox solution. In addition, the analysis results via flow cytometry showed that γ-PGA-coated Dox lipoplexes induce S phase cell cycle arrest and significantly increased apoptosis rate of HepG2 cells. In conclusion, the presence of γ-PGA on the surface of Dox lipoplexes enhanced antitumor effects of liver tumors.

  9. Identification of a novel component leading to anti-tumor activity besides the major ingredient cordycepin in Cordyceps militaris extract.

    Science.gov (United States)

    Wada, Takeharu; Sumardika, I Wayan; Saito, Shingo; Ruma, I Made Winarsa; Kondo, Eisaku; Shibukawa, Masami; Sakaguchi, Masakiyo

    2017-09-01

    In accordance with our previous study that was carried out to identify novel anti-tumor ingredients, chromatographic separation in combination with an anti-tumor activity assay was used for analysis of Cordyceps militaris extract in this study. Various modes of chromatography including reversed-phase, cation-exchange and anion-exchange were used to separate components of Cordyceps militaris, which showed various chemical properties. Anti-tumor activity of each fraction was assessed by a Hoechst staining-based apoptosis assay using malignant melanoma MeWo cells. By these repeated approaches through chromatographic segregation and cell biological assay, we finally succeeded in identifying the target substance from a certain fraction that included neutral hydrophilic components using a pre-column and post-column chlorine adduct ionization LC-APCI-MS method. The target substance was a mono-carbohydrate, xylitol, that induced apoptotic cell death in MeWo cells but not in normal human OUMS-24 fibroblasts. This is the first study showing that Cordyceps militaris extract contains a large amount of xylitol. Thus, our results will contribute greatly to uncovering the mysterious multifunctional herbal drug Cordyceps militaris as an anti-tumor agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Coating Solid Lipid Nanoparticles with Hyaluronic Acid Enhances Antitumor Activity against Melanoma Stem-like Cells.

    Science.gov (United States)

    Shen, Hongxin; Shi, Sanjun; Zhang, Zhirong; Gong, Tao; Sun, Xun

    2015-01-01

    Successful anticancer chemotherapy requires targeting tumors efficiently and further potential to eliminate cancer stem cell (CSC) subpopulations. Since CD44 is present on many types of CSCs, and it binds specially to hyaluronic acid (HA), we tested whether coating solid lipid nanoparticles with hyaluronan (HA-SLNs)would allow targeted delivery of paclitaxel (PTX) to CD44-overexpressing B16F10 melanoma cells. First, we developed a model system based on melanoma stem-like cells for experiments in vitro and in mouse xenografts, and we showed that cells expressing high levels of CD44 (CD44(+)) displayed a strong CSC phenotype while cells expressing low levels of CD44 (CD44(-)) did not. This phenotype included sphere and colony formation, higher proportion of side population cells, expression of CSC-related markers (ALDH, CD133, Oct-4) and tumorigenicity in vivo. Next we showed that administering PTX-loaded HA-SLNs led to efficient intracellular delivery of PTX and induced substantial apoptosis in CD44(+) cells in vitro. In the B16F10-CD44(+) lung metastasis model, PTX-loaded HA-SLNs targeted the tumor-bearing lung tissues well and subsequently exhibited significant antitumor effects with a relative low dose of PTX, which provided significant survival benefit without evidence of adverse events. These findings suggest that the HA-SLNs targeting system shows promise for enhancing cancer therapy.

  11. Mechanism of the antitumoral activity of deferasirox, an iron chelation agent, on mantle cell lymphoma.

    Science.gov (United States)

    Vazana-Barad, Liat; Granot, Galit; Mor-Tzuntz, Rahav; Levi, Itai; Dreyling, Martin; Nathan, Ilana; Shpilberg, Ofer

    2013-04-01

    Mantle cell lymphoma (MCL) characterized by the t(11;14)(q13;q32) translocation, resulting in cyclin D1 overexpression, is one of the most challenging lymphomas to treat. Iron chelators, such as deferasirox, have previously been shown to exhibit anti-proliferative properties; however, their effect on MCL cells has never been investigated. We showed that deferasirox exhibited antitumoral activity against the MCL cell lines HBL-2, Granta-519 and Jeko-1, with 50% inhibitory concentration (IC(50)) values of 7.99 ± 2.46 μM, 8.93 ± 2.25 μM and 31.86 ± 7.26 μM, respectively. Deferasirox induced apoptosis mediated through caspase-3 activation and decreased cyclin D1 protein levels resulting from increased proteasomal degradation. We also demonstrated down-regulation of phosphor-RB (Ser780) expression, which resulted in increasing levels of the E2F/RB complex and G(1)/S arrest. Finally, we showed that deferasirox activity was dependent on its iron chelating ability. The present data indicate that deferasirox, by down-regulating cyclin D1 and inhibiting its related signals, may constitute a promising adjuvant therapeutic molecule in the strategy for MCL treatment.

  12. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations.

    Science.gov (United States)

    Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B; Hsu, David; Clary, Bryan M; Clay, Timothy M; Chen, Wei; Morse, Michael A; Lyerly, H Kim

    2011-06-15

    Wnt/β-catenin pathway activation caused by adenomatous polyposis coli (APC) mutations occurs in approximately 80% of sporadic colorectal cancers (CRC). The antihelminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined whether niclosamide could inhibit the Wnt/β-catenin pathway in human CRCs and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling, and exerted antiproliferative effects in human colon cancer cell lines and CRC cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar antiproliferative effects in these CRC model systems. In mice implanted with human CRC xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity, and led to tumor control. Our findings support clinical explorations to reposition niclosamide for the treatment of CRC.

  13. Antitumor activity of Portulaca oleracea L. polysaccharides against cervical carcinoma in vitro and in vivo.

    Science.gov (United States)

    Zhao, Rui; Gao, Xu; Cai, Yaping; Shao, Xingyue; Jia, Guiyan; Huang, Yulan; Qin, Xuegong; Wang, Jingwei; Zheng, Xiaoliang

    2013-07-25

    Portulaca oleracea L. has been used as folk medicine in different countries to treat different ailments in humans. P. oleracea L. polysaccharide (POL-P), extracted from P. oleracea L., is found to have bioactivities such as hypoglycemic and hypolipidemic activities, antioxidant and antitumor activities. In our study, a water-soluble polysaccharide (POL-P3b) was successfully purified from Galium verum L. by DEAE cellulose and Sephadex G-200 column chromatography. To evaluate the anticancer efficacy and associated mechanisms of POL-P3b on cervical cancer in vitro and in vivo, we showed that treatment of HeLa cell with POL-P3b inhibited cell proliferation. In addition, POL-P3b significantly inhibited tumor growth in U14-bearing mice. Further analysis indicated that POL-P3b possesses the activity of inhibiting cervical cancer cell growth in vitro and in vivo at a concentration- and time-dependent manner, and the mechanisms were associated with Sub-G1 phase cell cycle arrest, triggering DNA damage and inducing apoptosis. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Antitumor Activity of a 5-Hydroxy-1H-Pyrrol-2-(5H-One-Based Synthetic Small Molecule In Vitro and In Vivo.

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    Yunyun Geng

    Full Text Available Alternative chemo-reagents are in great demand because chemotherapy resistance is one of the major challenges in current cancer treatment. 5-hydoxy-1H-pyrrol-2-(5H-one is an important N-heterocyclic scaffold that is present in natural products and medicinal chemistry. However, its antitumor activity has not been systematically explored. In this study, we screened a panel of 5-hydoxy-1H-pyrrol-2-(5H-one derivatives and identified compound 1d as possessing strong anti-proliferative activity in multiple cancer cell lines. Cell cycle analysis revealed that 1d can induce S-phase cell cycle arrest and that HCT116 was sensitive to 1d-induced apoptosis. Further analysis indicated that 1d preferentially induced DNA damage and p53 activation in HCT116 cells and that 1d-induced apoptosis is partly dependent on p53. Furthermore, we showed that 1d significantly suppressed tumor growth in xenograft tumor models in vivo. Taken together, our results suggest that 5-hydoxy-1H-pyrrol-2-(5H-one derivatives bear potential antitumor activity and that 1d is an effective agent for cancer treatment.

  15. Antimicrobial and antitumor activity and diversity of endophytic fungi from traditional Chinese medicinal plant Cephalotaxus hainanensis Li.

    Science.gov (United States)

    Liu, Y-H; Hu, X-P; Li, W; Cao, X-Y; Yang, H-R; Lin, S-T; Xu, C-B; Liu, S-X; Li, C-F

    2016-05-13

    Endophytes from Cephalotaxus hainanensis Li, an important source of anti-leukemia drugs, have not been widely explored. In this study, 265 endophytic fungal isolates from C. hainanensis Li were screened for antimicrobial activities against tilapia, banana, rice, and rape and for antitumor activities against human leukemia cell lines (K562, NB4, and HL-60). Diversity was also analyzed. The results showed that 17.7% of the endophytic fungi had antimicrobial activities against at least three different test microbes, and activity against Fusarium oxysporum RKY102 was the highest at 15.8%. Cytotoxicity against at least one tumor cell line tested was observed in 18.5% of the endophytic fungi; with the highest value of 10.6% against K562. The endophytic fungal strains also showed relatively high activities against K562, NB4, and HL-60 while relatively fewer strains were cytotoxic against the human hepatic Hep-G2 and colon LoVo cancer cell lines. Thirty endophytic fungal strains showed both high antimicrobial and antitumor activities. Moreover, the analyses of the diversity of the 30 highly active strains showed they belonged to 20 species from 14 genera, and this is the first report of endophytic fungi Albonectria rigidiuscula, Colletotrichum magnisporum, and Nemania diffusa being isolated from Cephalotaxus plants. These findings suggest that natural antibacterial products for humans and tilapia; antifungal compounds for rice, rape, and banana; and antitumor compounds for leukemia therapy could be isolated from fungal strains derived from C. hainanensis Li.

  16. A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

    International Nuclear Information System (INIS)

    Jiménez-Medina, Eva; Garcia-Lora, Angel; Paco, Laura; Algarra, Ignacio; Collado, Antonia; Garrido, Federico

    2006-01-01

    Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented in vivo anti-tumoral activity in nude

  17. A new extract of the plant Calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation.

    Science.gov (United States)

    Jiménez-Medina, Eva; Garcia-Lora, Angel; Paco, Laura; Algarra, Ignacio; Collado, Antonia; Garrido, Federico

    2006-05-05

    Phytopharmacological studies of different Calendula extracts have shown anti-inflammatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE), a novel extract of the plant Calendula Officinalis (Asteraceae). An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL) proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation. The LACE extract presented in vivo anti-tumoral activity in

  18. Canine parvovirus NS1 protein exhibits anti-tumor activity in a mouse mammary tumor model.

    Science.gov (United States)

    Gupta, Shishir Kumar; Yadav, Pavan Kumar; Gandham, Ravi Kumar; Sahoo, A P; Harish, D R; Singh, Arvind Kumar; Tiwari, A K

    2016-02-02

    Many viral proteins have the ability to kill tumor cells specifically without harming the normal cells. These proteins, on ectopic expression, cause lysis or induction of apoptosis in the target tumor cells. Parvovirus NS1 is one of such proteins, which is known to kill high proliferating tumor cells. In the present study, we assessed the apoptosis inducing ability of canine parvovirus type 2 NS1 protein (CPV2.NS1) in vitro in 4T1 cells, and found it to cause significant cell death due to induction of apoptosis through intrinsic or mitochondrial pathway. Further, we also evaluated the oncolytic activity of CPV2.NS1 protein in a mouse mammary tumor model. The results suggested that CPV2.NS1 was able to inhibit the growth of 4T1 induced mouse mammary tumor as indicated by significantly reduced tumor volume, mitotic, AgNOR and PCNA indices. Further, inhibition of tumor growth was found to be because of induction of apoptosis in the tumor cells, which was evident by a significant increase in the number of TUNEL positive cells. Further, CPV2.NS1 was also able to stimulate the immune cells against the tumor antigens as indicated by the increased CD4+ and CD8+ counts in the blood of CVP2.NS1 treated mice. Further optimization of the delivery of NS1 protein and use of an adjuvant may further enhance its anti-tumor activity. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Intensive fibrosarcoma-binding capability of the reconstituted analog and its antitumor activity.

    Science.gov (United States)

    Xu, Jian; Du, Yue; Liu, Wen-Juan; Li, Liang; Li, Yi; Wang, Xiao-Fei; Yi, Hong-Fei; Shan, Chuan-Kun; Xia, Gui-Min; Liu, Xiu-Jun; Zhen, Yong-Su

    2018-11-01

    Fibrosarcomas are highly aggressive malignant tumors. It is urgently needed to explore targeted drugs and modalities for more effective therapy. Matrix metalloproteinases (MMPs) play important roles in tumor progression and metastasis, while several MMPs are highly expressed in fibrosarcomas. In addition, tissue inhibitor of metalloproteinase 2 (TIMP2) displays specific interaction with MMPs. Therefore, TIMP2 may play an active role in the development of fibrosarcoma-targeting agents. In the current study, a TIMP2-based recombinant protein LT and its enediyne-integrated analog LTE were prepared; furthermore, the fibrosarcoma-binding intensity and antitumor activity were investigated. As shown, intense and selective binding capability of the protein LT to human fibrosarcoma specimens was confirmed by tissue microarray. Moreover, LTE, the enediyne-integrated analog of LT, exerted highly potent cytotoxicity to fibrosarcoma HT1080 cells, induced apoptosis, and caused G2/M arrest. LTE at 0.1 nM markedly suppressed the migration and invasion of HT1080 cells. LTE at tolerated dose of 0.6 mg/kg inhibited the tumor growth of fibrosarcoma xenograft in athymic mice. The study provides evidence that the TIMP2-based reconstituted analog LTE may be useful as a targeted drug for fibrosarcome therapy.

  20. Construction of selenium nanoparticles/β-glucan composites for enhancement of the antitumor activity.

    Science.gov (United States)

    Jia, Xuewei; Liu, Qingye; Zou, Siwei; Xu, Xiaojuan; Zhang, Lina

    2015-03-06

    We report on a green procedure for the stabilization of selenium nanoparticles (SeNPs) by a naturally occurring β-glucan with triple helical conformation known as Lentinan (t-LNT) in water after denaturing into single chains (s-LNT) at 140 °C. The results demonstrated that the s-LNT can interact with SeNPs through Se-O-H interaction. Transmission electron microscopy (TEM), energy dispersive X-ray (EDX) spectra, UV/vis, X-ray diffraction (XRD) and dynamic light scattering (DLS) showed that s-LNT coated SeNPs to form a stable nano-composite Se/s-LNT, leading to good dispersion of SeNPs. Especially, the as-prepared Se/s-LNT composite in the solution could remain homogeneous and translucent for 30 days without any precipitates. Different size distribution of SeNPs was prepared by simply controlling the concentrations of selenite sodium and the corresponding reducing agent ascorbic acid. The size effect of SeNPs on anti-tumor activity was revealed that the SeNPs with more evenly particle size distribution show the higher anticancer activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Antitumor activity against murine lymphoma L5178Y model of proteins from cacao (Theobroma cacao L.) seeds in relation with in vitro antioxidant activity.

    Science.gov (United States)

    Preza, Ana M; Jaramillo, María E; Puebla, Ana M; Mateos, Juan C; Hernández, Rodolfo; Lugo, Eugenia

    2010-10-20

    Recently, proteins and peptides have become an added value to foodstuffs due to new knowledge about its structural analyses as related to antioxidant and anticancer activity. Our goal was to evaluate if protein fractions from cacao seeds show antitumor activity on lymphoma murine L5178Y model. The antioxidant activity of these fractions was also evaluated with the aim of finding a correlation with the antitumor activity. Differential extraction of proteins from unfermented and semi-fermented-dry cacao seeds was performed and characterized by SDS-PAGE and FPLC size-exclusion chromatography. Antitumor activity was evaluated against murine lymphoma L5178Y in BALB/c mice (6 × 104 cells i.p.), with a treatment oral dose of 25 mg/kg/day of each protein fraction, over a period of 15 days. Antioxidant activity was evaluated by the ABTS+ and ORAC-FL assays. Albumin, globulin and glutelin fractions from both cacao seed type were obtained by differential solubility extraction. Glutelins were the predominant fraction. In the albumin fraction, polypeptides of 42.3 and 8.5 kDa were found in native conditions, presumably in the form of two peptide chains of 21.5 kDa each one. The globulin fraction presented polypeptides of 86 and 57 kDa in unfermented cacao seed that produced the specific-cacao aroma precursors, and after fermentation the polypeptides were of 45 and 39 kDa. The glutelin fraction presented proteins >200 kDa and globulins components cacao seed, it was observed that the albumin fraction showed antitumoral activity, since it caused significant decreases (p cacao protein fractions with their identification, supporting the traditional use of the plant. The albumin fraction showed antitumor and free radical scavenging capacity, however both activities were not correlated. The protein fractions could be considered as source of potential antitumor peptides.

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

    Directory of Open Access Journals (Sweden)

    Zhao QQ

    2012-06-01

    was confirmed and the vector showed low cytotoxicity and strong targeting specificity to liver tumors in vitro. The in vivo study results showed that interleukin-12 delivered by the new gene vector CPT/DNA significantly enhanced the antitumor effect on ascites tumor-bearing imprinting control region mice as compared with polyethylenimine (25 kDa, CP, and other controls, which further demonstrate the targeting specificity of the new synthesized polymer.Conclusion: The synthesized CPT copolymer was proven to be an effective liver cancer-targeted vector for therapeutic gene delivery, which could be a potential candidate for targeted cancer gene therapy.Keywords: targeting, peptide, polyethylenimine, chitosan, antitumor

  3. Study on the Immunomodulation Effect of Isodon japonicus Extract via Splenocyte Function and NK Anti-Tumor Activity

    Directory of Open Access Journals (Sweden)

    Kyung-A Hwang

    2012-04-01

    Full Text Available Here we investigated the potential immune-enhancing activity of Isodon japonicus on murine splenocyte and natural-killer (NK cells in vitro. The ethanol extract of I. japonicus significantly enhanced the proliferation of splenocyte and induced the significant enhancement of NK cells’ activity against tumor cells (YAC-1. In addition, I. japonicus increased the production of interferon (IFN-γ and tumor necrosis factor (TNF-α, suggesting that the increase in NK cell cytotoxicity could be due to the enhancement of the NK cell production of both cytokines. Taken together, I. japonicus extract inhibited the growth of human leukemia cells (K562 by 74%. Our observation indicated that the anti-tumor effects of I. japonicus may be attributed to its ability to serve as a stimulant of NK anti-tumor activity. In addition, our results support the development of functional food studies on I. japonicus.

  4. Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses

    NARCIS (Netherlands)

    Dolen, Y.; Kreutz, M.; Gileadi, U.; Tel, J.; Vasaturo, A.; Dinther, E.A.W. van; Hout-Kuijer, M.A. van; Cerundolo, V.; Figdor, C.G.

    2016-01-01

    Antitumor immunity can be enhanced by the coordinated release and delivery of antigens and immune-stimulating agents to antigen-presenting cells via biodegradable vaccine carriers. So far, encapsulation of TLR ligands and tumor-associated antigens augmented cytotoxic T cell (CTLs) responses. Here,

  5. Dual PI3K/mTOR inhibitor BEZ235 exerts extensive antitumor activity in HER2-positive gastric cancer

    International Nuclear Information System (INIS)

    Zhu, Yan; Tian, Tiantian; Zou, Jianling; Wang, Qiwei; Li, Zhongwu; Li, Yanyan; Liu, Xijuan; Dong, Bin; Li, Na; Gao, Jing; Shen, Lin

    2015-01-01

    To investigate the in vitro and in vivo antitumor activity of dual PI3K/mTOR inhibitor BEZ235 (NVP-BEZ235) in HER2-positive gastric cancer. HER2-positive breast cancer cell line (BT474), HER2-positive (NCI-N87 and SNU216), and HER2-negative (MKN45) gastric cancer cell lines were used in this study. Cell viability, cell cycle, and HER2 downstream signaling pathways were analyzed using the MTS assay, flow cytometry, and western blotting, respectively. For the in vivo experiments, HER2-positive gastric cancer patient-derived xenografts were treated with BEZ235 to assess its antitumor activity. The sensitivity of trastuzumab in BT474 cells was higher than that for NCI-N87 and SNU216 cells, which may be partially attributed to continuously active HER2 downstream signaling pathway. BEZ235 inhibited the proliferation of NCI-N87 and SNU216 cells in vitro in a dose-dependent manner by inducing the cell cycle arrest at the G1 phase. BEZ235 demonstrated greater inhibitory effects than trastuzumab, a unique targeted drug, in both the in vitro and in vivo set of experiments. Additionally, our results indicate that BEZ235 displayed some synergism with trastuzumab. BEZ235 exhibited its antitumor activity in gastric cancer by inhibiting important HER2 downstream signaling pathways, as indicated by the inhibition of phosphorylated AKT and S6. The present study has demonstrated, for the first time, the antitumor activity of BEZ235 against HER2-positive gastric cancer in patient-derived xenografts, as well its synergistic interaction with trastuzumab. These important findings can be utilized to facilitate the design of future clinical trials. The online version of this article (doi:10.1186/s12885-015-1900-y) contains supplementary material, which is available to authorized users

  6. Antitumor activities of Juemingzi (Cassia tora L.) on Balb/c sarcoma 180-injected mice

    Science.gov (United States)

    CHEN, SHAOCHENG; LI, GUIJIE; ZHU, KAI; SUN, PENG; WANG, RUI; ZHAO, XIN

    2014-01-01

    The antitumor activity of Juemingzi (Cassia tora L.) was investigated in mice that were fed various concentrations of the compound. Although mice fed a low concentration (50 mg/kg b.w.) of Juemingzi exhibited a high tumor weight, the higher feeding concentrations (100 and 200 mg/kg b.w.) were associated with lower weight tumors. The growth rate of mouse splenocytes that were treated with 200 mg/kg b.w. Juemingzi was determined using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. This rate of proliferation was higher than that achieved with 100 and 50 mg/kg b.w. Juemingzi treatment by fetal bovine serum, lipopolysaccharide or concanavalin A. Compared with the lower concentrations of Juemingzi treatment, 200 mg/kg b.w. Juemingzi significantly (P<0.05) reduced aspartate aminotransferase, alanine transaminase and blood urea nitrogen levels. A high concentration of Juemingzi (200 mg/kg b.w.) significantly (P<0.05) increased the levels of tumor necrosis factor-α and interleukin-1β cytokines compared with those of the mice that were treated with 100 and 50 mg/kg b.w. Juemingzi. PMID:24348858

  7. Antitumor activities of Juemingzi (Cassia toraL.) on Balb/c sarcoma 180-injected mice.

    Science.gov (United States)

    Chen, Shaocheng; Li, Guijie; Zhu, Kai; Sun, Peng; Wang, Rui; Zhao, Xin

    2014-01-01

    The antitumor activity of Juemingzi ( Cassia tora L.) was investigated in mice that were fed various concentrations of the compound. Although mice fed a low concentration (50 mg/kg b.w.) of Juemingzi exhibited a high tumor weight, the higher feeding concentrations (100 and 200 mg/kg b.w.) were associated with lower weight tumors. The growth rate of mouse splenocytes that were treated with 200 mg/kg b.w. Juemingzi was determined using a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay. This rate of proliferation was higher than that achieved with 100 and 50 mg/kg b.w. Juemingzi treatment by fetal bovine serum, lipopolysaccharide or concanavalin A. Compared with the lower concentrations of Juemingzi treatment, 200 mg/kg b.w. Juemingzi significantly (P<0.05) reduced aspartate aminotransferase, alanine transaminase and blood urea nitrogen levels. A high concentration of Juemingzi (200 mg/kg b.w.) significantly (P<0.05) increased the levels of tumor necrosis factor-α and interleukin-1β cytokines compared with those of the mice that were treated with 100 and 50 mg/kg b.w. Juemingzi.

  8. A New 1D Chained Coordination Polymer: Synthesis, Crystal Structure, Antitumor Activity and Luminescent Property

    Directory of Open Access Journals (Sweden)

    Xi-Shi Tai

    2015-11-01

    Full Text Available A new 1D chained coordination polymer of Zn(II, {[Zn(L2(4,4′-bipy]·(H2O}n(1 (HL = N-acetyl-l-phenylalanine; 4,4′-bipy = 4,4′-bipyridine has been synthesized and characterized by elemental analysis, IR and X-ray single crystal diffraction analysis. Theresults show that each asymmetric unit of Zn(II complex belongs to monoclinic, space group P21 with a = 11.421(2 Å, b = 9.2213(17 Å, c = 15.188(3 Å,β = 106.112(3°, V = 1536.7(5 Å3, Z = 2, Dc = 1.444 g·cm−3, µ = 0.857 mm−1, F(000 = 696, and final R1 = 0.0439, ωR2 = 0.1013. The molecules form one-dimensional chained structure by its the bridging 4,4′-bipyridine ligands. The antitumor activities and luminescent properties of Zn(II coordination polymer have also been investigated.

  9. Characteristics and Antitumor Activity of Morchella esculenta Polysaccharide Extracted by Pulsed Electric Field

    Directory of Open Access Journals (Sweden)

    Chao Liu

    2016-06-01

    Full Text Available Polysaccharides from Morchella esculenta have been proven to be functional and helpful for humans. The purpose of this study was to investigate the chemical structure and anti-proliferating and antitumor activities of a Morchella esculenta polysaccharide (MEP extracted by pulsed electric field (PEF in submerged fermentation. The endo-polysaccharide was separated and purified by column chromatography and Gel permeation chromatography, and analyzed by gas chromatography. The MEP with an average molecular weight of 81,835 Da consisted of xylose, glucose, mannose, rhamnose and galactose at the ratio of 5.4:5.0:6.5:7.8:72.3. Structure of MEP was further analyzed by Fourier-transform infrared spectroscopy and 1H and 13C liquid-state nuclear magnetic resonance spectroscopy. Apoptosis tests proved that MEP could inhibit the proliferation and growth of human colon cancer HT-29 cells in a time- and dose-dependent manner within 48 h. This study provides more information on chemical structure of anti-proliferating polysaccharides isolated from Morchella esculenta.

  10. The effect of microneedles on the skin permeability and antitumor activity of topical 5-fluorouracil

    Directory of Open Access Journals (Sweden)

    Youssef W. Naguib

    2014-02-01

    Full Text Available Topical 5-fluorouracil (5-FU is approved for the treatment of superficial basal cell carcinoma and actinic keratosis. However, 5-FU suffers from poor skin permeation. Microneedles have been successfully applied to improve the skin permeability of small and large molecules, and even nanoparticles, by creating micron-sized pores in the stratum corneum layer of the skin. In this report, the feasibility of using microneedles to increase the skin permeability of 5-FU was tested. Using full thickness mouse skin mounted on Franz diffusion apparatus, it was shown that the flux of 5-FU through the skin was increased by up to 4.5-fold when the skin was pretreated with microneedles (500 μm in length, 50 μm in base diameter. In a mouse model with B16-F10 mouse melanoma cells implanted in the subcutaneous space, the antitumor activity of a commercially available 5-FU topical cream (5% was significantly enhanced when the cream was applied on a skin area that was pretreated with microneedles, as compared to when the cream was simply applied on a skin area, underneath which the tumor cells were implanted, and without pretreatment of the skin with microneedles. Fluorouracil is not approved for melanoma therapy, but the clinical efficacy of topical 5-FU against tumors such as basal cell carcinoma may be improved by integrating microneedle technology into the therapy.

  11. Anti-angiogenesis and anti-tumor activity of recombinant anginex

    International Nuclear Information System (INIS)

    Brandwijk, Ricardo J.M.G.E.; Dings, Ruud P.M.; Linden, Edith van der; Mayo, Kevin H.; Thijssen, Victor L.J.L.; Griffioen, Arjan W.

    2006-01-01

    Anginex, a synthetic 33-mer angiostatic peptide, specifically inhibits vascular endothelial cell proliferation and migration along with induction of apoptosis in endothelial cells. Here we report on the in vivo characterization of recombinant anginex and use of the artificial anginex gene for gene therapy approaches. Tumor growth of human MA148 ovarian carcinoma in athymic mice was inhibited by 80% when treated with recombinant anginex. Histological analysis of the tumors showed an approximate 2.5-fold reduction of microvessel density, suggesting that angiogenesis inhibition is the cause of the anti-tumor effect. Furthermore, there was a significant correlation between the gene expression patterns of 16 angiogenesis-related factors after treatment with both recombinant and synthetic anginex. To validate the applicability of the anginex gene for gene therapy, stable transfectants of murine B16F10 melanoma cells expressing recombinant anginex were made. Supernatants of these cells inhibited endothelial cell proliferation in vitro. Furthermore, after subcutaneous injection of these cells in C57BL/6 mice, an extensive delay in tumor growth was observed. These data show that the artificial anginex gene can be used to produce a recombinant protein with similar activity as its synthetic counterpart and that the gene can be applied in gene therapy approaches for cancer treatment

  12. Encapsulation of teniposide into albumin nanoparticles with greatly lowered toxicity and enhanced antitumor activity.

    Science.gov (United States)

    He, Xinyi; Xiang, Nanxi; Zhang, Jinjie; Zhou, Jing; Fu, Yao; Gong, Tao; Zhang, Zhirong

    2015-06-20

    Teniposide (VM-26) is a semisynthetic derivative of podophyllotoxin effective for the treatment of many types of tumors. However, the poor water solubility and adverse effects restrict its clinical use. Our study aimed to develop a novel phospholipid complex albumin nanoparticle (VM-E80-AN) to reduce the systemic toxicity and enhance antitumor activity of VM-26. Egg yolk lecithin E80 and human serum albumin (HSA) were used as the main excipients to replace Cremophor EL in the commercial formulation. The physicochemical properties of VM-E80-AN were characterized to optimize the formulation. Cell and animal studies were further carried out to estimate its tumor inhibition efficacy, biodistribution, and toxicity. Comparison between VM-26 solution and VM-E80-AN showed that VM-E80-AN significantly reduced the toxicity of VM-26 and enhanced the anticancer efficacy of the drug. Thus, VM-E80-AN represents a safe and promising formulation of teniposide for clinical application. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Anti-tumor activities of direct current (DC) therapy combined with fractionated radiation or chemotherapy

    International Nuclear Information System (INIS)

    Nakayama, Toshitake; Ito, Hisao; Hashimoto, Shozo

    1988-01-01

    Anti-tumor activities of direct current (DC) therapy combined with fractionated radiation or cyclophosphamide were studied in mice which were transplanted with murine fibrosarcoma (FSa) in the right thighs. Using TCD 50 assay, DC therapy, given in a single fraction, enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.3. Tumor control rates were more improved by the combination therapy with the smaller doses of radiation than the larger ones. When DC therapy was applied one time immediately after the first radiation of fractionated ones, the combination therapy still showed the enhanced effect. However, both of DC therapy and radiation were divided in three fractions and DC therapy was applied everytime after radiation, tumor growth retardation were not different between the combination therapy and radiation alone. This result suggests that there is a minimum amount of Coulombs to improve the effect of radiation alone. On the other hand, DC therapy combined with cyclophosphamide given in one fraction showed the same enhancement effect as those divided in three fractions. These results suggest that DC therapy combined with radiation or cyclophosphamide is effective to improve tumor control, but the mechanisms to enhance the effect of radiation or cyclophosphamide are different. (author)

  14. Antioxidant, antimicrobial, antitumor, and cytotoxic activities of an important medicinal plant (Euphorbia royleana from Pakistan

    Directory of Open Access Journals (Sweden)

    Aisha Ashraf

    2015-03-01

    Full Text Available The aim of present study was to evaluate antioxidant, antimicrobial, and antitumor activities of methanol, hexane, and aqueous extracts of fresh Euphorbia royleana. Total phenolic and flavonoid contents were estimated as gallic acid and querectin equivalents, respectively. Antioxidant activity was assessed by scavenging of free 2,2′- diphenyl-1-picrylhydrazyl radicals and reduction of ferric ions, and it was observed that inhibition values increase linearly with increase in concentration of extract. The results of ferric reducing antioxidant power assay showed that hexane extract has maximum ferric reducing power (12.70 ± 0.49 mg gallic acid equivalents/g of plant extract. Maximum phenolic (47.47 ± 0.71 μg gallic acid equivalents/mg of plant extract and flavonoid (63.68 ± 0.43 μg querectin equivalents/mg of plant extract contents were also found in the hexane extract. Furthermore, we examined antimicrobial activity of the three extracts (methanol, hexane, aqueous against a panel of microorganisms (Escherichia coli, Bacillus subtillis, Pasteurella multocida, Aspergillus niger, and Fusarium solani by disc-diffusion assay, and found the hexane extract to be the best antimicrobial agent. Hexane extract was also observed as to be most effective in a potato disc assay. As hexane extract showed potent activity in all the investigated assays, it was targeted for cytotoxic assessment. Maximum cytotoxicity (61.66% by hexane extract was found at 800 μg/mL. It is concluded that investigated extracts have potential for isolation of antioxidant and antimicrobial compounds for the pharmaceutical industry.

  15. In vivo antitumor activity of pegylated zinc protoporphyrin: targeted inhibition of heme oxygenase in solid tumor.

    Science.gov (United States)

    Fang, Jun; Sawa, Tomohiro; Akaike, Takaaki; Akuta, Teruo; Sahoo, Sanjeeb K; Khaled, Greish; Hamada, Akinobu; Maeda, Hiroshi

    2003-07-01

    High expression of the inducible isoform of heme oxygenase (HO-1) is now well known in solid tumors in humans and experimental animal models. We reported previously that HO-1 may be involved in tumor growth (Tanaka et al., Br. J. Cancer, 88: 902-909, 2003), in that inhibition of HO activity in tumors by using zinc protoporphyrin (ZnPP) significantly reduced tumor growth in a rat model. We demonstrate here that poly(ethylene glycol)-conjugated ZnPP (PEG-ZnPP), a water-soluble derivative of ZnPP, exhibited potent HO inhibitory activity and had an antitumor effect in vivo. In vitro studies with cultured SW480 cells, which express HO-1, showed that PEG-ZnPP induced oxidative stress, and consequently apoptotic death, of these cells. Pharmacokinetic analysis revealed that PEG-ZnPP-administered i.v. had a circulation time in blood that was 40 times longer than that for nonpegylated ZnPP. More important, PEG-ZnPP preferentially accumulated in solid tumor tissue in a murine model. In vivo treatment with PEG-ZnPP (equivalent to 1.5 or 5 mg of ZnPP/kg, i.v., injected daily for 6 days) remarkably suppressed the growth of Sarcoma 180 tumors implanted in the dorsal skin of ddY mice without any apparent side effects. In addition, this PEG-ZnPP treatment produced tumor-selective suppression of HO activity as well as induction of apoptosis. The major reason for tumor-selective targeting of PEG-ZnPP is attributed to the enhanced permeability and retention effect that is observed commonly in solid tumors for biocompatible macromolecular drugs. These findings suggest that tumor-targeted inhibition of HO activity could be achieved by using PEG-ZnPP, which induces apoptosis in solid tumors, probably through increased oxidative stress.

  16. Antitumor activity of sulfated hyaluronic acid fragments in pre-clinical models of bladder cancer

    Science.gov (United States)

    Jordan, Andre R.; Lokeshwar, Soum D.; Lopez, Luis E.; Hennig, Martin; Chipollini, Juan; Yates, Travis; Hupe, Marie C.; Merseburger, Axel S.; Shiedlin, Aviva; Cerwinka, Wolfgang H.; Liu, Kebin; Lokeshwar, Vinata B.

    2017-01-01

    Tumor cell-derived hyaluronidase HYAL-1 degrades hyaluronic acid (HA) into angiogenic fragments (AGF: 10-12 disaccharides). AGF support tumor growth and progression. Urine and tissue HAase/HYAL-1 levels are sensitive markers for high-grade bladder cancer (BCa) and its metastasis. In preclinical models of BCa, we evaluated whether o-sulfated AGF (sHA-F) inhibits HAase activity and has antitumor activity. At IC50 for HAase activity inhibition (5-20 μg/ml [0.4-1.7 μM]), sHA-F significantly inhibited proliferation, motility and invasion of HYAL-1 expressing BCa cells (253J-Lung, HT1376, UMUC-3), P<0.001. sHA-F did not affect the growth of HYAL-1 non-expressing BCa (5637, RT4, T24, TCCSUP) and normal urothelial (Urotsa, SV-HUC1) cells. sHA-F treatment induced apoptosis by death receptor pathway. sHA-F downregulated transcript and/or protein levels of HA receptors (CD44, RHAMM), p-AKT, β-catenin, pβ-Catenin(S552), Snail and Twist but increased levels of pβ-Catenin(T41/S45), pGSK-3α/β(S21/S9) and E-cadherin. sHA-F also inhibited CD44/Phosphoinositide 3-kinase (PI-3K) complex formation and PI-3K activity. AGF addition or myristoylated-AKT overexpression attenuated sHA-F effects. Contrarily, HYAL-1 expression sensitized RT4 cells to sHA-F treatment. In the 253J-L and HT1376 xenograft models, sHA-F treatment significantly inhibited tumor growth (P<0.001), plausibly by inhibiting angiogenesis and HA receptor-PI-3K/AKT signaling. This study delineates that sHA-F targets tumor-associated HA-HAase system and could be potentially useful in BCa treatment. PMID:27419371

  17. Aloin: a natural antitumor anthraquinone glycoside with iron chelating and non-atherogenic activities.

    Science.gov (United States)

    Esmat, Amr Y; Said, Mahmoud M; Khalil, Sally A

    2015-01-01

    The antitumor activity of aloin, the active anthraquinone of Aloe juice, against different murine and human tumors has been reported. In the present study, the impact of repeated aloin treatment at its maximum tolerated dose on serum levels of lipid profile, some elements, iron status and kidney function, compared with doxorubicin (a cardiotoxic anthracycline and inhibitor of erythropoiesis), was assessed. Rats were treated with a single dose of doxorubicin (30 mg/kg body weight, intraperitoneal) or aloin (50 mg/kg body weight, intramuscular) twice weekly over 2 weeks. Acute doxorubicin treatment elevated serum levels of triacylglycerols (59.90%), total cholesterol (42.29%), cholesteryl esters (54.75%), low density lipoprotein-cholesterol (230.16%), very low density lipoprotein-cholesterol (56.42%), urea (287.53%), and creatinine (85.38%), whereas serum high density lipoprotein-cholesterol, sodium, and calcium levels were reduced (44.61, 9.61, and 9.76%, respectively), as compared with controls. In contrast, aloin treatment showed insignificant changes in all the aforementioned parameters. Both doxorubicin and aloin induced erythropoiesis impairment demonstrated by a reduction in blood hemoglobin concentration. While aloin treatment elevated serum iron level (30.28%), doxorubicin treatment reduced serum levels of iron (51.47%) and percent transferrin saturation (55.21%), and in contrast, increased serum total iron binding capacity (34.85%). The chelating affinities of iron-aloin and -doxorubicin complexes, which contain bidentate iron-binding moieties, have been shown in the infrared spectra. The non-cardiotoxic effect of aloin treatment was due to its non-atherogenic and iron-chelating activities, which might also contribute in part to its anti-proliferative activity.

  18. Anti-tumor and immunomodulatory activities of an exopolysaccharide from Rhizopus nigricans on CT26 tumor-bearing mice.

    Science.gov (United States)

    Zhu, Lei; Cao, Jianfeng; Chen, Guochuang; Xu, Yanghui; Lu, Jingbo; Fang, Fang; Chen, Kaoshan

    2016-07-01

    This study was aimed to investigate the anti-tumor and immunomodulatory activities of an exopolysaccharide (EPS) from Rhizopus nigricans. Our results showed EPS could significantly inhibit the tumor growth and increase the immune organs index of CT26 tumor-bearing mice. EPS treatment increased the productions of interleukin-2 (IL-2) and tumor necrosis factor-α (TNF-α) levels in serum. The increase of percentage of CD8(+) cytotoxic T cells among total spleen T lymphocyte was also observed. Furthermore, EPS remarkably stimulate spleen lymphocytes proliferation in the absence or presence of mitogens. In addition, we found that EPS had synergistic effect with chemotherapy and improved immunosuppressive effect induced by 5-Fu. In summary, these findings indicated that the antitumor effects of EPS might be partly due to immune function activation and it might have potential to be used in the treatment for colorectal cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Nigella sativa modulates splenocyte proliferation, Th1/Th2 cytokine profile, macrophage function and NK anti-tumor activity.

    Science.gov (United States)

    Majdalawieh, Amin F; Hmaidan, Reem; Carr, Ronald I

    2010-09-15

    Nigella sativa, also known as blackseed, has long been used in traditional medicine for treating various conditions related to the respiratory and gastrointestinal systems as well as different types of cancers. In this study, the potential immunomodulatory effects of Nigella sativa are investigated in light of splenocyte proliferation, macrophage function, and NK anti-tumor activity using BLAB/c and C57/BL6 primary cells. Splenocyte proliferation was assessed by [(3)H]-thymidine incorporation. Griess assay was performed to evaluate NO production by macrophages. ELISA was performed to measure the level of cytokines secreted by splenocytes and macrophages. NK cytotoxic activity against YAC-1 tumor cells was examined by JAM assay. We demonstrate that the aqueous extract of Nigella sativa significantly enhances splenocyte proliferation in a dose-responsive manner. In addition, the aqueous extract of Nigella sativa favors the secretion of Th2, versus Th1, cytokines by splenocytes. The secretion of IL-6, TNFalpha, and NO; key pro-inflammatory mediators, by primary macrophages is significantly suppressed by the aqueous extract of Nigella sativa, indicating that Nigella sativa exerts anti-inflammatory effects in vitro. Finally, experimental evidence indicates that the aqueous extract of Nigella sativa significantly enhances NK cytotoxic activity against YAC-1 tumor cells, suggesting that the documented anti-tumor effects of Nigella sativa may be, at least in part, attributed to its ability to serve as a stimulant of NK anti-tumor activity. Our data present Nigella sativa as a traditionally used herb with potent immunomodulatory, anti-inflammatory, and anti-tumor effects. We anticipate that Nigella sativa ingredients may be employed as effective therapeutic agents in the regulation of diverse immune reactions implicated in various conditions and diseases such as cancer. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  20. CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation.

    Science.gov (United States)

    Deng, Jiehui; Wang, Eric S; Jenkins, Russell W; Li, Shuai; Dries, Ruben; Yates, Kathleen; Chhabra, Sandeep; Huang, Wei; Liu, Hongye; Aref, Amir R; Ivanova, Elena; Paweletz, Cloud P; Bowden, Michaela; Zhou, Chensheng W; Herter-Sprie, Grit S; Sorrentino, Jessica A; Bisi, John E; Lizotte, Patrick H; Merlino, Ashley A; Quinn, Max M; Bufe, Lauren E; Yang, Annan; Zhang, Yanxi; Zhang, Hua; Gao, Peng; Chen, Ting; Cavanaugh, Megan E; Rode, Amanda J; Haines, Eric; Roberts, Patrick J; Strum, Jay C; Richards, William G; Lorch, Jochen H; Parangi, Sareh; Gunda, Viswanath; Boland, Genevieve M; Bueno, Raphael; Palakurthi, Sangeetha; Freeman, Gordon J; Ritz, Jerome; Haining, W Nicholas; Sharpless, Norman E; Arthanari, Haribabu; Shapiro, Geoffrey I; Barbie, David A; Gray, Nathanael S; Wong, Kwok-Kin

    2018-02-01

    Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo , due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216-33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143 See related article by Jenkins et al., p. 196 This article is highlighted in the In This Issue feature, p. 127 . ©2017 American Association for Cancer Research.

  1. Identification of a novel potential antitumor activity of gossypol as an APE1/Ref-1 inhibitor

    Directory of Open Access Journals (Sweden)

    Qian CY

    2014-05-01

    Full Text Available Chengyuan Qian, Mengxia Li, Jiangdong Sui, Tao Ren, Zheng Li, Liang Zhang, Liwei Zhou, Yi Cheng, Dong WangCancer Center, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing, People's Republic of ChinaAbstract: The human apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (APE1/Ref-1, an essential multifunctional protein involved in the repair of oxidative deoxyribonucleic acid (DNA damage and transcriptional regulation, is often overexpressed in tumor tissues and cancer cells. Moreover, APE1/Ref-1 (APE1 overexpression has been linked to chemoresistance in human tumors. Thus, inhibiting APE1 function in cancer cells is considered a promising strategy to overcome resistance to therapeutic agents. Gossypol is a Bcl-2 homology 3 (BH3-mimetic agent and is able to bind to the BH3 domain of B-cell lymphoma 2 (Bcl-2 family members. Other studies demonstrated that Bcl-2 directly interacted with APE1 via its BH domains. Using apurinic/apyrimidinic (AP endonuclease assays, we found that gossypol inhibits the repair activity of APE1. Electrophoretic mobility shift assays and dual luciferase assays showed that gossypol could also inhibit the redox function of APE1. Using dual polarization interferometry technology, we show that gossypol can directly interact with APE1. Furthermore, addition of gossypol, in conjunction with APE1 overexpression, leads to cancer cell death. The addition of gossypol also enhances the cell killing effect of the laboratory alkylating agent methyl methanesulfonate and the clinical agent cisplatin (DDP. Administration of gossypol significantly inhibited the growth of xenografts. Furthermore, the combined treatment of gossypol and DDP resulted in a statistically higher antitumor activity compared with DDP alone in vivo. In conclusion, we have demonstrated that gossypol effectively inhibits the repair and redox activity of APE1 through a direct interaction.Keywords: cancer

  2. Potential antitumor agents. 37. Synthesis and antitumor activity of guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline.

    Science.gov (United States)

    Andreani, Aldo; Granaiola, Massimiliano; Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Lenaz, Giorgio; Fato, Romana; Bergamini, Christian; Farruggia, Giovanna

    2005-04-21

    This paper reports synthesis and antitumor activity of new guanylhydrazones from imidazo[2,1-b]thiazoles and from the new heterocyclic system thiazolo[2',3':2,3]imidazo[4,5-c]quinoline. The compounds were tested as potential antitumor agents at the National Cancer Institute. The effect of the guanylhydrazone of 2-chloro-6-(2,5-dimethoxy-4-nitrophenyl)imidazo[2,1-b]thiazole-5-carbaldehyde (41) was investigated, and it was found to be an inhibitor of Complex III of the mitochondrial respiratory chain and is able to induce apoptosis in the cell lines HT29 and HL60.

  3. Assessment of in vivo anti-tumor activity of human umbilical vein endothelial cell vaccines prepared by various antigen forms.

    Science.gov (United States)

    Zhou, Ling; Si, Chunfeng; Li, Defang; Lu, Meiyu; Zhong, Weilan; Xie, Zeping; Guo, Lin; Zhang, Shumin; Xu, Maolei

    2018-03-01

    Human umbilical vein endothelial cell (HUVEC) vaccine has been proved as an effective whole-cell vaccine, but the modest therapeutic anti-tumor efficiency limits its clinical use. Various antigen forms, including paraformaldehyde-fixed HUVEC, glutaraldehyde-fixed HUVEC, HUVEC lysate and live HUVEC, have been intensively used in HUVEC vaccine preparation, however, the most effective antigen form has not yet been identified. In the present study, these four commonly used antigen forms were used to prepare vaccines named Para-Fixed-EC, Glu-Fixed-EC, Lysate-EC, and Live-EC respectively, and the anti-tumor efficacy of these four vaccines was investigated. Results showed that Live-EC exhibited the most favorable anti-tumor growth and metastasis effects among the four vaccines in both H22 hepatocellular carcinoma and Lewis lung cancer models. High titer anti-HUVEC antibodies were detected in Live-EC immunized mice sera, and the immune sera of Live-EC group could significantly inhibit HUVEC proliferation and tube formation. Moreover, T cells isolated from Live-EC immunized mice exhibited strong cytotoxicity against HUVEC cells, with an increasing IFN-γ and decreasing Treg production in Live-EC immunized mice. Finally, CD31 immunohistochemical analysis of the excised tumors verified a significant reduction in vessel density after Live-EC vaccination, which was in accordance with the anti-tumor efficiency. Taken together, all the results proved that live HUVEC was the most effective antigen form to induce robust HUVEC specific antibody and CTL responses, which could lead to the significant inhibition of tumor growth and metastasis. We hope the present findings would provide a rationale for the further optimization of HUVEC vaccine. Copyright © 2017. Published by Elsevier B.V.

  4. In vivo study of the anti-inflammatory and antitumor activities of leaves from Plectranthus amboinicus (Lour.) Spreng (Lamiaceae).

    Science.gov (United States)

    Gurgel, Ana Pavla A Diniz; da Silva, Jackeline G; Grangeiro, Ana Ruth S; Oliveira, Danielli C; Lima, Cynthia M P; da Silva, Aldo C P; Oliveira, Rinalda A G; Souza, Ivone A

    2009-09-07

    Plectranthus amboinicus (Lour.) Spreng is a medicinal specie often used in Brazil, especially in Northeast Region, for the treatment of several diseases including inflammations and cancer. To evaluate the anti-inflammatory and antitumor activities of the hydroalcoholic extract from leaves of P. amboinicus in an attempt to determine whether the medicinal uses are supported by pharmacological effects. Anti-inflammatory activity was determined by carrageenan-induced paw edema method. The antitumor effect was evaluated in an in vivo experimental study, using the following tumors: Sarcoma-180 and Erlich ascite carcinoma. There were statistically significant decreases (p<.05) of edema paw in at the doses of 150, 250 and 350 mg/kg (i.p.) of the hydroalcoholic extract of P. amboinicus. Similarly, the administration of P. amboinicus at the doses of 100, 150, 250 and 350 mg/kg (i.p.) inhibited the growth of sarcoma-180 and Ehrlich ascite carcinoma tumors in mice. The results suggest that the hydroalcoholic extract of P. amboinicus possesses anti-inflammatory and antitumor activities, supporting the folk use of this medicinal specie.

  5. Antioxidant, antitumor activities and phyto chemical investigation of hedera nepalensis K. koch, an important medicinal plant from Pakistan

    International Nuclear Information System (INIS)

    Kanwal, S.; Ullah, N.; Ihsan-ul-Haq; Mirza, B.; Afzal, I.

    2011-01-01

    Hedera nepalensis is a ground-creeping evergreen woody plant growing mainly in the Himalayas and Kashmir. This plant is frequently used in folk medicines for the treatment of various ailments. The present research focused on the pharmacological evaluation and phyto chemical analysis of crude methanolic extract (CME) and three fractions, n-hexane (n-HF), ethyl acetate (EAF) and aqueous (AQF). The biological assays used for this study included DPPH free radical values scavenging assay, DNA protection assay and potato disc antitumor assay. Maximum antioxidant activities with IC/sub 50/ of 9.834 ppm and 14.22 ppm were shown by EAF and AQF, respectively. Crude methanolic extract (CME) and the fractions OH induced DNA damage assay, at all the concentrations tested. Both also exhibited significant DNA protection activity in EAF and AQF showed well-defined tumor inhibition in the potato disc antitumor assay, with the lowest IC/sub 50/ values shown by EAF and AQF (less than 1 ppm). Phyto chemical analysis showed the presence of flavonoids, steroids, tannins, terpenoids and cardiac glycosides in the crude extract and its fractions. The present study demonstrated that EAF and AQF of Hedera nepalensis have potent antioxidant and antitumor activity with the presence of effective phytochemicals. (author)

  6. Ferulic acid exerts antitumor activity and inhibits metastasis in breast cancer cells by regulating epithelial to mesenchymal transition.

    Science.gov (United States)

    Zhang, Xiang; Lin, Dan; Jiang, Rong; Li, Hongzhong; Wan, Jingyuan; Li, Hongyuan

    2016-07-01

    Metastasis, which frequently occurs in breast cancer, is the major cause of mortality; therefore, new treatment strategies are urgently needed. Ferulic acid, isolated from Ferula foetida, a perennial herb, has shown antineoplastic activity in various types of cancers, such as colon and lung cancer, and central nervous system tumors. However, its potential role in suppressing breast cancer metastasis has not been fully understood. In the present study, we evaluated the antitumor activity of ferulic acid in breast cancer cell line-based in vitro and in vivo models. We first showed that ferulic acid treatment resulted in decreased viability, increased apoptosis and suppression of metastatic potential in breast cancer cell line MDA-MB-231. Furthermore, it was demonstrated that the antitumor activity of ferulic acid and its role in suppressing metastasis were regulated by the reversal of epithelial-mesenchymal transition (EMT). Consistent with our findings in vitro, the antitumor potential of ferulic acid was also verified in an MDA-MB-231 xenograft mouse model where significantly decreased tumor volume, weight and increased apoptosis were observed. Taken together, these results indicate that ferulic acid may be used as an effective therapeutic agent against breast cancer.

  7. Sildenafil potentiates the antitumor activity of cisplatin by induction of apoptosis and inhibition of proliferation and angiogenesis

    Directory of Open Access Journals (Sweden)

    El-Naa MM

    2016-11-01

    Full Text Available Mona Mohamed El-Naa,1 Mohamed Othman,2,3 Sheren Younes4,5 1Faculty of Pharmacy, October University for Modern Sciences and Arts (MSA, 6 October City, Egypt; 2Preparatory Year College, University of Hail, Hail, Kingdom of Saudi Arabia; 3Faculty of Biotechnology, October University for Modern Science and Arts (MSA, 6 October City, Egypt; 4Pathology Department, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt; 5College of Medicine, Princess Nora Bint Abdulrahman University, Riyadh, Kingdom of Saudi ArabiaAbstract: Sildenafil is the first phosphodiesterase-5 inhibitor used for the treatment of erectile dysfunction. However, recent studies have been suggesting an antitumor effect of sildenafil. The current study assessed the aforementioned activity of sildenafil in vivo and in vitro in solid-tumor-bearing mice and in a human cell line MCF-7, respectively. Moreover, we investigated the impact of sildenafil on cisplatin antitumor activity. The solid tumor was induced by inoculation of Ehrlich ascites carcinoma cells in female mice. The tumor-bearing mice were assigned randomly to control (saline, sildenafil (sildenafil 5 mg/kg/d, PO daily for 15 days, cisplatin (cisplatin 7.5 mg/kg, IP once on the 12th day of Ehrlich ascites carcinoma inoculation, and combination therapy (cisplatin and sildenafil groups. The tumor volume was measured at the end of the treatment period along with the following parameters: angiogenin, vascular endothelial growth factor, tumor necrosis factor-α, Ki-67, caspase-3, DNA-flow cytometry analysis, and histopathological examination. The study results showed that sildenafil has significantly decreased the tumor volume by 30.4%, angiogenin and tumor necrosis factor-α contents, as well as vascular endothelial growth factor expression. Additionally, caspase-3 level significantly increased with sildenafil treatment, whereas Ki-67 expression failed to show any significant changes. Furthermore, the cell cycle

  8. Anti-tumor activity of exopolysaccharide from Rhizopus nigricans Ehrenb on S180 tumor-bearing mice.

    Science.gov (United States)

    Cao, Jianfeng; Hou, Dong; Lu, Jingbo; Zhu, Lei; Zhang, Pengying; Zhou, Nan; Chen, Kaoshan

    2016-04-15

    In this study, the effect of antitumor and immune activities of extracellular polysaccharides (EPS) from Rhizopus nigricans Ehrenb were investigated using S180 bearing mice. The results revealed that EPS in the concentration range 50-1000 μg/mL can inhibited S180 cell proliferation in a dose dependent manner. EPS at the highest dose of 1000 μg/mL showed significantly antitumor activity against S180 with inhibition rate of 47.53%. However, EPS significantly simulated spleen lymphocytes in the concentration of 500 μg/mL, and the increase proliferation ability showed a dose-dependent effect with EPS at the dose of 50-500 μg/mL. In comparison with the control groups, the weights of tumor were declined and the inhibition rates of tumor were remarkably decreased in the treated groups. Pretreatment with EPS at the dose of 75 mg/kg/day, the inhibition rate was decreased by 44.38% (Pcontrol group were very obvious. Meanwhile, the prophylactic administration of EPS could more efficiently inhibit the growth of S180 tumor than direct administration of EPS. EPS could prolong the survival period of S180 tumor bearing mice, and the doses 75 mg/kg/day of EPS and combined with cyclophosphamide (20 mg/kg/day) were 43.36% and 36.28% respectively compared to control groups (P<0.05). The results suggested EPS confirmed in vivo anti-tumor effects observed in vitro, and the mechanism of anti-tumor effect of EPS may be at least in part mediated by increased immune activity in host. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. The influence of physical activity in the anti-tumor immune response in experimental breast tumor.

    Science.gov (United States)

    Bianco, Thiago M; Abdalla, Douglas R; Desidério, Chamberttan S; Thys, Sofie; Simoens, Cindy; Bogers, John-Paul; Murta, Eddie F C; Michelin, Márcia A

    2017-10-01

    This study aimed to investigate the influence of physical activity in innate immunity to conduce to an effective antitumoral immune response analyzing the phenotype and activation status of infiltrating cells. We analysed the intracellular cytokines and the transcription factors of tumor infiltrating lymphocytes (TILS) and spleen leukocytes. The Nos2 gene expression was evaluated in spleen cells and futhermore the ROS production was measured and spleen cells; another cell evaluated was dendritic cells (TIDCs), their cytokines expression and membrane molecules; finally to understood the results obtained, we analysed the dendritic cells obtained from bone marrow. Were used female Balb/c mice divided into 4 groups: two controls without tumor, sedentary (GI) and trained (GII) and two groups with tumor, sedentary (GIII) or trained (GIV). The physical activity (PA) was realized acoording swimming protocol. Tumor was induced by injection of 4T1 cells. All experiments were performed in biological triplicate. After the experimental period, the tumor was removed and the cells were identified by flow cytometry with labeling to CD4, CD8, CD11c, CD11b, CD80, CD86 and Ia, and intracelular staining IL-10, IL-12, TNF-α, IFN-γ, IL-17, Tbet, GATA3, RORγt and FoxP3. The bone marrow of the animals was obtained to analyse the derivated DCs by flow cytometry and culture cells to obtain the supernatant to measure the cytokines. Our results demonstrated that the PA inhibit the tumoral growth although not to change the number of TILS, but reduced expression of GATA-3, ROR-γT, related with poor prognosis, and TNF-α intracellular; however occur one significantly reduction in TIDCS, but these cells expressed more co-stimulatory and presentation molecules. Furthermore, we observed that the induced PA stimulated the gene expression of Tbet and the production of inflammatory cytokines suggesting an increase of Th1 systemic response. The results evaluating the systemic influence in DCs

  10. Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer.

    Science.gov (United States)

    Huynh, Hung; Ong, Richard; Zopf, Dieter

    2015-10-29

    Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer. The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment. Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer.

  11. Targeting myeloid-derived suppressor cells augments antitumor activity against lung cancer

    Directory of Open Access Journals (Sweden)

    Srivastava MK

    2012-10-01

    Full Text Available Minu K Srivastava,1,2 Li Zhu,1,2 Marni Harris-White,2 Min Huang,1–3 Maie St John,1,3 Jay M Lee,1,3 Ravi Salgia,4 Robert B Cameron,1,3,5 Robert Strieter,6 Steven Dubinett,1–3 Sherven Sharma1–31Department of Medicine, UCLA Lung Cancer Research Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, 2Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 3Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Department of Medicine, University of Chicago, Chicago, IL, 5Department of Surgery, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, 6Department of Medicine, University of Virginia, Charlottesville, VA, USAAbstract: Lung cancer evades host immune surveillance by dysregulating inflammation. Tumors and their surrounding stromata produce growth factors, cytokines, and chemokines that recruit, expand, and/or activate myeloid-derived suppressor cells (MDSCs. MDSCs regulate immune responses and are frequently found in malignancy. In this review the authors discuss tumor-MDSC interactions that suppress host antitumor activities and the authors' recent findings regarding MDSC depletion that led to improved therapeutic vaccination responses against lung cancer. Despite the identification of a repertoire of tumor antigens, hurdles persist for immune-based anticancer therapies. It is likely that combined therapies that address the multiple immune deficits in cancer patients will be required for effective therapy. MDSCs play a major role in the suppression of T-cell activation and they sustain tumor growth, proliferation, and metastases. Regulation of MDSC recruitment, differentiation or expansion, and inhibition of the MDSC suppressive function with pharmacologic agents will be useful in the control of cancer growth and progression. Pharmacologic agents that regulate MDSCs may be more effective when combined with

  12. Pattern of antitumor activity of a novel camptothecin, ST1481, in a large panel of human tumor xenografts.

    Science.gov (United States)

    Pratesi, Graziella; De Cesare, Michelandrea; Carenini, Nives; Perego, Paola; Righetti, Sabina C; Cucco, Carla; Merlini, Lucio; Pisano, Claudio; Penco, Sergio; Carminati, Paolo; Vesci, Loredana; Zunino, Franco

    2002-12-01

    ST1481 is the lead compound of a novel series of 7-modified camptothecins, the 7-oxyimino methyl derivatives, characterized by potent topoisomerase I inhibition and cytotoxic activity. Based on its therapeutic efficacy in a human non-small cell lung carcinoma model and its favorable pharmacological profile, the novel analogue was selected for further preclinical development. We investigated the growth-inhibitory effects of ST1481 and topotecan, used as a reference compound, in a panel of human tumor cell lines of various tumor types (ovarian carcinoma, glioblastoma, osteosarcoma, and melanoma), including sublines with acquired resistance to cisplatin. We explored the antitumor efficacy in a large panel of human tumor xenografts, with particular reference to intrinsically resistant tumor types, using oral administration and an intermittent treatment schedule. ST1481 showed a potent antiproliferative activity with comparable effects in all tested cell lines. Only U-87-MG glioma cells were less sensitive, presumably as a consequence of the efficiency of the S-phase checkpoint. ST1481 produced a remarkable antitumor effect (tumor volume inhibition > 85%) in 16 of 18 examined models, with an appreciable rate of complete tumor regressions in 11 of 18 models (despite the nonoptimal intermittent treatment schedule). The most impressive antitumor effects were observed against lung carcinoma, melanoma, and osteosarcoma models, as documented by the high rate of complete responses (up to 100%). The efficacy of ST1481 was significantly superior to that of topotecan in 9 of 17 tumors. The novel drug was also markedly effective against slowly growing tumors (A549 lung carcinoma and HT29 colon carcinoma) when a daily protracted treatment was used to fully exploit the therapeutic potential of camptothecins. The unusual potency of ST1481 in a variety of tumor cell lines suggests the ability of the drug to overcome several resistance factors. The profile of antitumor efficacy further

  13. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level.

    Science.gov (United States)

    Zhao, Feng; He, En-Qi; Wang, Lu; Liu, Ke

    2008-01-01

    Andrographolide (1), a diterpenoid lactone isolated from a traditional herb (Andrographis paniculata), is known to possess potent anti-inflammatory activity. In this study, we investigated the anti-tumor effect of 1 on various cancer cell lines in vitro. It induced apoptosis of prostate cancer (PC-3) cells (the most sensitive cell line among the cell lines screened) via the activation of caspase 3, up-regulation of bax, and down-regulation of bcl-2. Furthermore, its inhibitory activity on the level of vascular endothelial growth factor was also verified by ELISA.

  14. Antitumor activity of acriflavine in lung adenocarcinoma cell line A549.

    Science.gov (United States)

    Lee, Chia-Jen; Yue, Chia-Herng; Lin, Yu-Jie; Lin, Yu-Yu; Kao, Shao-Hsuan; Liu, Jer-Yuh; Chen, Yieng-How

    2014-11-01

    Aim/Materials and Methods: In order to develop better drugs against non-small cell lung cancer (NSCLC), we screened a variety of compounds and treated the human lung adenocarcinoma cell line A549 with different drug concentrations. We then examined the cell viability using the MTT assay. Data show that a new candidate drug, acriflavine (ACF), suppresses the viability of A549 cells in a concentration- and time-dependent manner. Flow cytometry analysis revealed that ACF significantly caused cell growth arrest in the G2/M phase on A549 cells. Moreover, ACF decreased Bcl-2 expression and increased Bax expression. The content of cleaved poly(ADP-ribose)polymerase-1 (PARP-1) and caspase-3 are significantly increased. These findings suggest that ACF is cytotoxic against A549 cells and suppresses A549 cells growth through the caspase-3 activation pathway. In the in vivo test, nude mice bearing A549 cells xenografts by intravenous injection were randomly assigned into two groups: control and experimental group. Treatment was initiated 10 days after implantation and intraperitoneal injection of 0.9% normal saline or 2 mg/kg of ACF was continued daily for five weeks. ACF treatment significantly decreased tumor size and tumor spots on lung surface of tumor-bearing mice. ACF can inhibit cell growth in A549 cells. Our results may assist on the delineation of the mechanism(s) leading to NSCLC cell growth inhibition and provide a new antitumor strategy against NSCLC. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  15. Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo.

    Science.gov (United States)

    Tressler, R J; Garvin, L J; Slate, D L

    1994-05-15

    Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 microM to 3.9 microM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Molt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (non-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B-cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experimental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK-Hep-1, a human hepatic endothelioma, or Hep-3B, a liver adenocarcinoma, at any of the doses tested.

  16. Production of bioactive compounds with antitumor activity against sarcoma 180 by Pleurotus sajor-caju.

    Science.gov (United States)

    Assis, Ivaneliza Simionato; Chaves, Mariane Bonatti; Silveira, Marcia Luciane Lange; Gern, Regina Maria Miranda; Wisbeck, Elisabeth; Júnior, Agenor Furigo; Furlan, Sandra Aparecida

    2013-11-01

    This work studied the influence of culture medium composition and pH on exopolysaccharide (EPS) production by Pleurotus sajor-caju and validates the antitumor activity of the produced EPSs and of the mycelial biomass (intracellular polysaccharides [IPSs]) against Sarcoma 180 (S180) cells. The effect of the initial concentrations of (NH₄)₂SO₄, yeast extract and soy peptone on EPS production by P. sajor-caju was studied in shake flasks. A bioreactor was used to evaluate the pH values and the initial CaCO₃ and glucose concentrations. Extracts of EPSs (PE1) and IPSs obtained through two different separation processes (PM1 and PM2) were tested on mice inoculated with S180 cells. A medium containing 2.5, 1.0, and 1.0 g/L of (NH₄)₂SO₄, yeast extract and soy peptone, respectively, provided the highest EPS concentration (0.6 g/L). The use of pH 4.0, 1.0 g/L CaCO₃ and 20 g/L initial glucose concentration enhanced EPS productivity (3.84 g/L per hour). The PE1 extract promoted the highest reduction of S180 growth (86%), followed by the PM2 extract (80%); growth reduction was dose-independent for both substances. This work provides information about culture medium and conditions that enhanced the production of extracellular polysaccharides by P. sajor-caju. The results can contribute to the search for new bioactive products bringing novel aspects to the medical and pharmaceutical areas.

  17. Annonacin Exerts Antitumor Activity through Induction of Apoptosis and Extracellular Signal-regulated Kinase Inhibition.

    Science.gov (United States)

    Yap, Chee Voon; Subramaniam, Kavita S; Khor, Sik Wey; Chung, Ivy

    2017-01-01

    Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries. Annonacin, a natural pure compound extracted from the seeds of Annona muricata , is a potential alternative therapeutic agent to treat EC. To study the antitumor activity of annonacin and its mechanism of action in EC cells (ECCs). Viability of ECCs treated with annonacin for 72 h was determined using methyl thiazolyl tetrazolium assay. The induction of cell cycle arrest and apoptotic cell death was evaluated using propidium iodide and annexin V-PE/7-AAD assay, respectively. DNA strand breaks were visualized using transferase dUTP nick end labeling assay, and the effects of annonacin on survival signaling were determined using western blotting. Annonacin exhibited antiproliferative effects on EC cell lines (ECC-1 and HEC-1A) and primary cells (EC6-ept and EC14-ept) with EC 50 values ranging from 4.62 to 4.92 μg/ml. EC cells were shown arrested at G2/M phase after treated with 4 μg/ml of annonacin for 72 h. This led to a significant increase in apoptotic cell death (65.7%) in these cells when compared to vehicle-treated cells ( P cancer cells. Annonacin exerted antiproliferation effects on both endometrial cancer cell lines and primary cells via induction of apoptosis and inhibition of extracellular signal-regulated kinase. Our data represented that annonacin could be an alternative therapeutic treatment to combat endometrial cancer. Abbreviations Used: 7-AAD: 7-Amino-Actinomycin, ATP: Adenosine diphosphate, BSA: Bovine serum albumin, DNA: Deoxyribonucleic acid, EC: Endometrial cancer, ECC-1: Endometrial cancer cell-1, EC50: Half maximal effective concentration, Ept: Epithelial, FBS: Fetal bovine serum, HEC-1A: Human endometrial carcinoma-1A, MTT: Methyl thiazolyl tetrazolium, NaCl: Sodium chloride, NADH: Nicotinamide adenine dinucleotide, RPMI 1640: Roswell Park Memorial Institute Medium, SDS: Sodium dodecyl sulfate.

  18. A polysaccharide from Armillaria mellea exhibits strong in vitro anticancer activity via apoptosis-involved mechanisms.

    Science.gov (United States)

    Wu, Jun; Zhou, Jinxu; Lang, Yaoguo; Yao, Lei; Xu, Hai; Shi, Hubo; Xu, Shidong

    2012-11-01

    Armillaria mellea is a famous traditional Chinese medicinal and edible fungus. In this study, we purified a water-soluble polysaccharide (AMP) from the fruiting bodies of this fungus. AMP contained 94.8% carbohydrate, 2.3% uronic acid and 0.5% protein. Its molecular weight was determined as 4.6 × 10⁵ Da, as determined by high-performance gel-permeation chromatography (HPGPC). Gas chromatography (GC) analysis indicated that AMP was mainly composed of d-glucose. In vitro assay, AMP exhibited a potent tumor growth inhibitory effect on A549 cells, and induced cell cycle disruption in the G0/G1 phase, accompanied by an increment of apoptotic cells. Furthermore, AMP induced the disruption of mitochondrial membrane potential, thus leading to cytochrome c release from mitochondria and activation of caspase-3 and -9. Taken together, our results demonstrate that AMP possesses strong antitumor activities through the mitochondria dependent pathway and activation of caspase cascade through cytochrome c release. Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Synthesis and antitumor activity of a heterodinucleotide of BVDU and gemcitabine.

    Science.gov (United States)

    Cappellacci, L; Franchetti, P; Vita, P; Petrelli, R; Grifantini, M

    2008-05-01

    A heterodinucleotide comprising BVDU and Gemcitabine bound together by a 5',5'-pyrophospate bridge (BVDUp(2)dFdC) has been synthesized and evaluated as antitumor agent against AH13 rat sarcoma cells. BVDUp(2)dFdC showed a cytotoxicity similar to that of Gemcitabine.

  20. Woodfordin D and oenothein A, trimeric hydrolyzable tannins of macro-ring structure with antitumor activity.

    Science.gov (United States)

    Yoshida, T; Chou, T; Matsuda, M; Yasuhara, T; Yazaki, K; Hatano, T; Nitta, A; Okuda, T

    1991-05-01

    Two new antitumor trimeric hydrolyzable tannins, woodfordin D (5) and oenothein A (13), were isolated from the dried flowers of Woodfordia fruticosa, and their macrocyclic structures, which have a novel constituent unit (woodfordinoyl group) connecting the monomers, have been elucidated on the basis of spectral and chemical evidence. Oenothein A (13) was also isolated from the leaves of Oenothera biennis.

  1. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.

    Science.gov (United States)

    Li, Ning; Feng, Lin; Han, Hui-Qiong; Yuan, Jing; Qi, Xue-Kang; Lian, Yi-Fan; Kuang, Bo-Hua; Zhang, Yu-Chen; Deng, Cheng-Cheng; Zhang, Hao-Jiong; Yao, You-Yuan; Xu, Miao; He, Gui-Ping; Zhao, Bing-Chun; Gao, Ling; Feng, Qi-Sheng; Chen, Li-Zhen; Yang, Lu; Yang, Dajun; Zeng, Yi-Xin

    2016-10-10

    Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC. Copyright © 2016. Published by Elsevier Ireland Ltd.

  2. Preparation, Characterization, and In Vitro and Vivo Antitumor Activity of Oridonin-Conjugated Multiwalled Carbon Nanotubes Functionalized with Carboxylic Group

    Directory of Open Access Journals (Sweden)

    Chuanjin Wang

    2016-01-01

    Full Text Available Carbon nanotubes have shown great potential in tumor therapy. Oridonin (ORI is a poorly water-soluble diterpenoid compound (C20H28O6 used in the treatment of esophageal and hepatic carcinoma for decades. For the purpose of enhancing the antitumor potency and reducing cytotoxicity of ORI, multiwalled carbon nanotubes functionalized with carboxylic group (MWCNTs-COOH were used as ORI carrier. ORI was noncovalently encapsulated into (or onto the functionalized carbon nanotubes (MWCNTs-ORI. The obtained MWCNTs-ORI has been characterized. The ORI loading efficiency in MWCNTs-COOH carrier was studied to be about 82.6% (w/w. In vitro cytotoxicity assay on MWCNTs-ORI gave IC50 of 7.29±0.5 μg/mL and ORI-F gave IC50 of 14.5±1.4 μg/mL. The antitumor effect studies in vivo showed that MWCNTs-ORI improved antitumor activity of ORI in comparison with ORI-F. The tumor inhibition ratio for MWCNTs-ORI (1.68×10-2 g·Kg−1·d−1 was 86.4%, higher than that of ORI-F (1.68×10-2 g·Kg−1·d−1 which was 39.2%. This can greatly improve the pharmaceutical efficiency and reduce potential side effects.

  3. Synthesis, Characterization and in Vitro Antitumor Activity of Platinum(II Oxalato Complexes Involving 7-Azaindole Derivatives as Coligands

    Directory of Open Access Journals (Sweden)

    Pavel Štarha

    2014-07-01

    Full Text Available The platinum(II oxalato complexes [Pt(ox(naza2] (1–3 were synthesized and characterized by elemental analysis (C, H, N, multinuclear NMR spectroscopy (1H, 13C, 15N, 195Pt and electrospray ionization mass spectrometry (ESI-MS; naza = 4-chloro-7-azaindole (4Claza; 1, 3-bromo-7-azaindole (3Braza; 2 or 4-bromo-7-azaindole (4Braza; 3. The prepared substances were screened for their in vitro antitumor activity on the osteosarcoma (HOS and breast adenocarcinoma (MCF7 human cancer cell lines, where 2 showed moderate antitumor effect (IC50 = 27.5 μM, and 18.3 μM, respectively. The complex 2 was further tested on a panel of six others human cancer cell lines, including the malignant melanoma (G361, cervix carcinoma (HeLa, ovarian carcinoma (A2780, cisplatin-resistant ovarian carcinoma (A2780R, lung carcinoma (A549 and prostate adenocarcinoma (LNCaP. This substance was found to be moderate antitumor effective against G361 (IC50 = 17.3 μM, HeLa (IC50 = 31.8 μM and A2780 (IC50 = 19.2 μM cell lines. The complex 2 was also studied by NMR for its solution stability and by ESI-MS experiments for its ability to interact with biomolecules, such as cysteine, glutathione or guanosine 5'-monophosphate.

  4. Estimation of the potential antitumor activity of microencapsulated Lactobacillus acidophilus yogurt formulation in the attenuation of tumorigenesis in Apc(Min/+) mice.

    Science.gov (United States)

    Urbanska, Aleksandra Malgorzata; Bhathena, Jasmine; Martoni, Christopher; Prakash, Satya

    2009-02-01

    There is a strong correlation between orally administered probiotics and suppression of the low-grade inflammation that can lead to restoration of normal local immune functions. We studied the potential immunomodulatory and antitumorigenic properties of microencapsulated probiotic bacterial cells in a yogurt formulation in Min mice carrying a germline APC mutation. Daily oral administration of microencapsulated Lactobacillus acidophilus bacterial cells in the yogurt formulation mice resulted in significant suppression of colon tumor incidence, tumor multiplicity, and reduced tumor size. Results show that oral administration of microencapsulated L. acidophilus contributed to the stabilization of animal body weight and decreased the release of bile acids. Histopathological analyses revealed fewer adenomas in treated versus untreated animals. Furthermore, treated animals exhibited fewer gastrointestinal intra-epithelial neoplasias with a lower grade of dysplasia in detected tumors. Results suggest that oral administration of microencapsulated probiotic L. acidophilus exerts anti-tumorous activity, which consequently leads to reduced tumor outcome.

  5. Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety

    OpenAIRE

    Hong Chen; Bing-Bing Xu; Tao Sun; Zhan Zhou; Hui-Yuan Ya; Mu Yuan

    2017-01-01

    Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic...

  6. Antitumor activity of TY-011 against gastric cancer by inhibiting Aurora A, Aurora B and VEGFR2 kinases

    Directory of Open Access Journals (Sweden)

    Wang Liu

    2016-11-01

    Full Text Available Abstract Background Overexpression of Aurora A and B has been reported in a wide range of tumor types, including gastric cancer. Anti-angiogenesis has been considered as an important therapeutic modality in advanced gastric cancer. Here we identified a novel compound TY-011 with promising antitumor activity by targeting mitotic kinases (Aurora A and B and angiogenic receptor tyrosine kinase (VEGFR2. Methods HTRF® KinEASE™ assay was used to detect the effect of TY-011 against Aurora A, Aurora B and VEGFR2 activities. Docking simulation study was performed to predict the binding mode of TY-011 with Aurora A and B kinases. CCK-8 assay was used to test cell growth. Cell cycle and cell apoptosis was analyzed by flow cytometry. Gastric cancer cell xenograft mouse models were used for in vivo study. TUNEL kit was used to determine the apoptosis of tumor tissues. Immunohistochemistry analysis and HUVEC tube formation assay were performed to determine the anti-angiogenesis ability. Immunofluorescence and western blot were used to test protein expression. Results TY-011 was identified as a potential Aurora A and B inhibitor by HTRF® KinEASE™ assay. It effectively inhibited cellular Aurora A and B activities in a concentration-dependent manner. TY-011 occupied the ATP-binding site of both Aurora A and B kinases. TY-011 demonstrated prominent inhibitory effects on proliferation of gastric cancer cells. TY-011 treatment induced an obvious accumulation of cells at G2/M phase and a modest increase of cells with >4 N DNA content, which then underwent apoptosis. Meaningfully, orally administration of TY-011 demonstrated superior efficacy against the tumor growth in gastric cancer cell xenograft, with ~90% inhibition rate and 100% tumor regression at 9 mg/kg dose, and TY-011 did not affect the body weight of mice. Interestingly, we observed that TY-011 also antagonized tumor angiogenesis by targeting VEGFR2 kinase. Conclusions These results indicate that

  7. Cytotoxicity, radiosensitization, antitumor activity, and interaction with hyperthermia of a Co(III) mustard complex.

    Science.gov (United States)

    Teicher, B A; Abrams, M J; Rosbe, K W; Herman, T S

    1990-11-01

    A complex of Co(III) with a nitro group and a bis(2-chloroethyl)amine moiety was prepared in an effort to develop a new anticancer agent with radiosensitizing capabilities, direct antitumor activity, and the ability to interact positively with clinically relevant hyperthermia temperatures. The activity of this drug was compared to a similar Co(III) complex, nitro-bis(2,4-pentanedionato)(pyridine)cobalt(III) [Co(Py)], which bears a pyridine moiety mustard of bis(2-chloroethyl)amine and should have no alkylating abilities. In EMT6 cells nitro-bis(2,4- pentanedionato)(bis(2-chloroethyl)amine)cobalt(III) [Co(BCA)] was significantly more cytotoxic than Co(Py) and both drugs were more toxic toward normally oxygenated than hypoxic cells. Hyperthermia (42 degrees C, 1 h) increased the slope of the concentration-dependent survival curve for Co(BCA) but not for Co(Py) in normally oxygenated EMT6 cells. Co(BCA) was an effective radiosensitizer of hypoxic EMT6 cells in vitro, producing a dose-modifying factor of 2.40. In the human squamous cell line SCC-25 and the nitrogen mustard-resistant subline SCC-25/HN2 Co(BCA) was more cytotoxic than Co(Py), and the lethality of Co(BCA) was only minimally diminished in the SCC-25/HN2 line. In mice bearing the L1210 leukemia i.p., Co(BCA) had a broad range of therapeutically effective dosage and produced a greater than 60-day increase in life span at a dose 20-fold less than was lethally toxic. In addition, in the FSaIIC murine fibrosarcoma, Co(BCA) produced a tumor growth delay of 9.4 days at 75 mg/kg i.p. daily x 5, but Co(Py) produced a delay of only 2.9 days at 50 mg/kg daily x 5 and was lethally toxic above this dose. These results indicate that Co(BCA) has significant antineoplastic effects in vitro and in vivo and interacts positively with both radiation and mild hyperthermia. Its broad therapeutic dose range further suggests potential clinical utility.

  8. Statistical relationship of strong earthquakes with planetary geomagnetic field activity

    Science.gov (United States)

    Pogrebnikov, M. M.; Komarovski, N. I.; Kopytenko, Y. A.; Pushel, A. P.

    1984-12-01

    Earlier studies reported a significant decrease in the geomagnetic field before strong earthquakes. Possible relationships between earthquakes with magnitude greater than 7 (Soviet scale) and planetary terrestrial magnetic field activity as characterized by the K sub p index were investigated. A total of 100 cases of strong earthquakes on magnetically quiet days in 1965 to 1975 were studied. The K sub p indexes were studied for two days before and two days after the earthquakes. The dispersion curve shows a significant decrease one day before each event. The relationship of the planetary K sub p index with seismic activity indicates that the period of preparation for an earthquake and at the moment of the shock are reflected in the terrestrial magnetic field.

  9. A new class of radiation-activating antitumor prodrugs releasing 5-fluorodeoxyuridine: synthesis, reactivity and biological activity

    Energy Technology Data Exchange (ETDEWEB)

    Sakakibara, S.; Zhou, L.; Mori, M.; Hatta, H.; Nishimoto, S. [Department of Energy and Hydrocarbon Chemistry, Kyoto Univ., Kyoto (Japan); Shibamoto, Y. [Kyoto Univ., Institute for Frontier Medical Science, Kyoto (Japan)

    2000-03-01

    A number of 3-substituted 5-fluorodeoxyuridine (5-FdUrd) derivatives (1-6) were synthesized to evaluate their radiation reactivity and biological activity as a new class of prodrugs that can be radiation-activated to release 5-FdUrd. The compounds 2-6 bearing substituents with a 2-oxo group underwent radiolytic reduction to release 5-FdUrd in considerably high yields under anoxic conditions, while the compound 1 without 2-oxo substituent was inactive in releasing 5-FdUrd. The cytotoxicities of 2-6 toward P388 T cells of mouse leukemia were less than 5-FdUrd, as indicated by an MTT assay. The apparent cytotoxicities were significantly enhanced by X-irradiation under hypoxic conditions. A conclusion was that 2-6 have no antitumor effect in contrast to 5-FdUrd, but can potentiate the effect of cancer radiotherapy by releasing a cell-killing component 5-FdUrd. (author)

  10. Activating transcription factor 3 is crucial for antitumor activity and to strengthen the antiviral properties of Onconase.

    Science.gov (United States)

    Vert, Anna; Castro, Jessica; Ribó, Marc; Benito, Antoni; Vilanova, Maria

    2017-02-14

    Onconase is a ribonuclease that presents both antitumor and antiviral properties linked to its ribonucleolytic activity and represents a new class of RNA-damaging drugs. It has reached clinical trials for the treatment of several cancers and human papilloma virus warts. Onconase targets different RNAs in the cell cytosol but Onconase-treated cells present features that are different from a simple arrest of protein synthesis. We have used microarray-derived transcriptional profiling to identify Onconase-regulated genes in two ovarian cancer cell lines (NCI/ADR-RES and OVCAR-8). RT-qPCR analyses have confirmed the microarray findings. We have identified a network of up-regulated genes implicated in different signaling pathways that may explain the cytotoxic effects exerted by Onconase. Among these genes, activating transcription factor 3 (ATF3) plays a central role in the key events triggered by Onconase in treated cancer cells that finally lead to apoptosis. This mechanism, mediated by ATF3, is cell-type independent. Up-regulation of ATF3 may also explain the antiviral properties of this ribonuclease because this factor is involved in halting viral genome replication, keeping virus latency or preventing viral oncogenesis. Finally, Onconase-regulated genes are different from those affected by nuclear-directed ribonucleases.

  11. Anti-tumor promoting activity of bufadienolides from Kalanchoe pinnata and K. daigremontiana x tubiflora.

    Science.gov (United States)

    Supratman, U; Fujita, T; Akiyama, K; Hayashi, H; Murakami, A; Sakai, H; Koshimizu, K; Ohigashi, H

    2001-04-01

    Five bufadienolides (1-5) isolated from the leaves of Kalanchoe pinnata and K. daigremontiana x tubiflora (Crassulaceae) were examined for their inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells induced by the tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. All bufadienolides showed inhibitory activity, and bryophyllin A (1) exhibited the most marked inhibition (IC50 = 0.4 microM) among the tested compounds. Bryophyllin C (2), a reduction analogue of 1, and bersaldegenin-3-acetate (3) lacking the orthoacetate moiety were less active. These results strongly suggest that bufadienolides are potential cancer chemopreventive agents.

  12. Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety.

    Science.gov (United States)

    Chen, Hong; Xu, Bing-Bing; Sun, Tao; Zhou, Zhan; Ya, Hui-Yuan; Yuan, Mu

    2017-10-29

    Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145) cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC 50 ) cancer therapy.

  13. A new extract of the plant calendula officinalis produces a dual in vitro effect: cytotoxic anti-tumor activity and lymphocyte activation

    Directory of Open Access Journals (Sweden)

    Collado Antonia

    2006-05-01

    Full Text Available Abstract Background Phytopharmacological studies of different Calendula extracts have shown anti-inflamatory, anti-viral and anti-genotoxic properties of therapeutic interest. In this study, we evaluated the in vitro cytotoxic anti-tumor and immunomodulatory activities and in vivo anti-tumor effect of Laser Activated Calendula Extract (LACE, a novel extract of the plant Calendula Officinalis (Asteraceae. Methods An aqueous extract of Calendula Officinalis was obtained by a novel extraction method in order to measure its anti-tumor and immunomodulatory activities in vitro. Tumor cell lines derived from leukemias, melanomas, fibrosarcomas and cancers of breast, prostate, cervix, lung, pancreas and colorectal were used and tumor cell proliferation in vitro was measured by BrdU incorporation and viable cell count. Effect of LACE on human peripheral blood lymphocyte (PBL proliferation in vitro was also analyzed. Studies of cell cycle and apoptosis were performed in LACE-treated cells. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously human Ando-2 melanoma cells. Results The LACE extract showed a potent in vitro inhibition of tumor cell proliferation when tested on a wide variety of human and murine tumor cell lines. The inhibition ranged from 70 to 100%. Mechanisms of inhibition were identified as cell cycle arrest in G0/G1 phase and Caspase-3-induced apoptosis. Interestingly, the same extract showed an opposite effect when tested on PBLs and NKL cell line, in which in vitro induction of proliferation and activation of these cells was observed. The intraperitoneal injection or oral administration of LACE extract in nude mice inhibits in vivo tumor growth of Ando-2 melanoma cells and prolongs the survival day of the mice. Conclusion These results indicate that LACE aqueous extract has two complementary activities in vitro with potential anti-tumor therapeutic effect: cytotoxic tumor cell activity and lymphocyte activation

  14. Antitumor activity of polysaccharide from Laminaria japonica on mice bearing H22 liver cancer.

    Science.gov (United States)

    Zhu, Qingwen; Chen, Jianghua; Li, Qiong; Wang, Ting; Li, Haibo

    2016-11-01

    Water-soluble polysaccharide was extracted from Laminaria japonica, and its antitumor effect on mice bearing H22 liver cancer was investigated. The mice were inoculated with H22 hepatoma cells and randomly divided into four groups: three treatment groups that received 50, 100 and 150mg/kg L. japonica polysaccharide (LJP) intraperitoneal injection and one control group that received equal volume of physiological saline. Intraperitoneal injection of LJP increased serum interleukin-2 and tumour necrosis factor-α levels, as well as tumour inhibition rate of mice, but decreased serum vascular endothelial growth factor level. Therefore, LJP exerts antitumor effect and can be used as a therapeutic agent for cancer. Copyright © 2016 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2017-01-10

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

  16. Activation of Anti-tumor Immune Response by Ablation of HCC with Nanosecond Pulsed Electric Field.

    Science.gov (United States)

    Xu, Xiaobo; Chen, Yiling; Zhang, Ruiqing; Miao, Xudong; Chen, Xinhua

    2018-03-28

    Locoregional therapy is playing an increasingly important role in the non-surgical management of hepatocellular carcinoma (HCC). The novel technique of non-thermal electric ablation by nanosecond pulsed electric field has been recognized as a potential locoregional methodology for indicated HCC. This manuscript explores the most recent studies to indicate its unique anti-tumor immune response. The possible immune mechanism, termed as nano-pulse stimulation, was also analyzed.

  17. Antitumor Activity of Human Hydatid Cyst Fluid in a Murine Model of Colon Cancer

    Directory of Open Access Journals (Sweden)

    Edgardo Berriel

    2013-01-01

    Full Text Available This study evaluates the antitumor immune response induced by human hydatic cyst fluid (HCF in an animal model of colon carcinoma. We found that anti-HCF antibodies were able to identify cell surface and intracellular antigens in CT26 colon cancer cells. In prophylactic tumor challenge experiments, HCF vaccination was found to be protective against tumor formation for 40% of the mice (P=0.01. In the therapeutic setting, HCF vaccination induced tumor regression in 40% of vaccinated mice (P=0.05. This vaccination generated memory immune responses that protected surviving mice from tumor rechallenge, implicating the development of an adaptive immune response in this process. We performed a proteomic analysis of CT26 antigens recognized by anti-HCF antibodies to analyze the immune cross-reactivity between E. granulosus (HCF and CT26 colon cancer cells. We identified two proteins: mortalin and creatine kinase M-type. Interestingly, CT26 mortalin displays 60% homology with E. granulosus hsp70. In conclusion, our data demonstrate the capacity of HCF vaccination to induce antitumor immunity which protects from tumor growth in an animal model. This new antitumor strategy could open new horizons in the development of highly immunogenic anticancer vaccines.

  18. Genistein modulates the anti-tumor activity of cisplatin in MCF-7 breast and HT-29 colon cancer cells.

    Science.gov (United States)

    Hu, Xiao-Juan; Xie, Ming-Yong; Kluxen, Felix M; Diel, Patrick

    2014-03-01

    The function of genistein (GEN) on tumor prevention and tumor promotion is discussed controversially. A possible interference of GEN with chemotherapy has been only rarely addressed so far. In this study, effects of GEN on the anti-tumor activity of cisplatin (CIS) were investigated in the presence and absence of estradiol (10(-10) M) in MCF-7 breast and HT-29 colon cancer cells. Cells were treated with graded concentrations of GEN (10(-4)-10(-6) M), E2, CIS and combinations. Cell growth, proliferation and apoptosis were determined as well as the expression level of PCNA, Ki67 and BCL-2 family members. CIS and GEN 10(-4) M inhibited cell growth and induced apoptosis in MCF-7 and HT-29 cells in the presence and absence of E2. Co-treatment with CIS and 10(-4)M GEN resulted in additive effects. In concentrations of 10(-5) and 10(-6) M, GEN stimulated cell growth in MCF-7 cells. It promoted proliferation, inhibited apoptosis and counteracted the anti-tumor activity of CIS in MCF-7 and HT-29 cells. Particularly the ability of CIS to induce apoptosis was antagonized. In ER alpha-positive MCF-7 cells, but not in ER alpha-negative HT-29 cells, E2 was able to neutralize the anti-CIS effects of GEN. Our data provide evidence that GEN in the absence of E2, a situation which occurs in postmenopausal women, directly affects the anti-tumor activity of cytostatic drugs like CIS. The exact molecular mechanism has to be investigated in future studies.

  19. Structure, anti-Phytophthora and anti-tumor activities of a nortriterpenoid from the rhizome of Phlomis purpurea (Lamiaceae).

    Science.gov (United States)

    Mateus, Maria C; Neves, Dina; Dacunha, Bruno; Laczko, Endre; Maia, Cristiana; Teixeira, Rúben; Cravador, Alfredo

    2016-11-01

    To investigate bioactive compounds potentially involved in the biotic interactions exhibited by Phlomis purpurea (Lamiaceae) in rhizospheres infested with Phytophthora cinnamomi, the plant rhizome was chemically analysed. The nortriterpenoid (17S)-2α,3α,11α,23,24-pentahydroxy-19(18 → 17)-abeo-28-norolean-12-en-18-one, was isolated and its structure was elucidated by comprehensive spectroscopic analysis, chiefly using 2D NMR experiments, and X-ray analysis. It was shown to be exuded by roots and to exhibit anti-Phytophthora and antitumor activities. Copyright © 2016. Published by Elsevier Ltd.

  20. Antitumor activity of two derivatives from 2-acylamine-1, 4-naphthoquinone in mice bearing S180 tumor.

    Science.gov (United States)

    Bezerra, Daniel Pereira; Alves, Ana Paula Negreiros Nunes; de Alencar, Nylane Maria Nunes; Mesquita, Rodney de Oliveira; Lima, Michael Will; Pessoa, Cláudia; de Moraes, Manoel Odorico; Lopes, José Norberto Callegari; Lopes, Norberto Peporine; Costa-Lotufo, Letícia Veras

    2008-01-01

    Drugs containing a quinone moiety, such as anthracyclines, mitoxantrones and lapachol, show excellent anticancer activity. In this study, 2-butanoylamine-1,4-naphthoquinone (1) and 2-propanoylamine-1,4-naphthoquinone (2) derivatives from 2-amine-1 ,4-naphthoquinone were synthesized, and their antitumor activity in mice bearing Sarcoma 180 tumor were examined. In addition, hematology and biochemistry analyses, as well as, histopathological and morphological analyses were performed in order to evaluate the toxicological aspects of the naphthoquinones treatment. Both naphthoquinones showed potente antitumor activity. The inhibition rates were 33.48 and 42.35% for (1) and 37.65 and 55.24% for (2) at the dose of 25 and 50 mg/kg/day, respectively. In the histopathological analysis, the naphthoquinones showed only weak toxicity. Neither enzimatic activity of transaminases (aspartate aminotransferase-AST nor alanine aminotransferase-ALT), urea level nor hematological paramenter were significantly modified after naphthoquinones treatment. These data reinforce the anticancer potential of naphthoquinones derivatives.

  1. Synthesis and Antitumor Activity of Novel Arylpiperazine Derivatives Containing the Saccharin Moiety

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    Hong Chen

    2017-10-01

    Full Text Available Prostate cancer is a major public health problem worldwide. For the development of potential anti-prostate cancer agents, a series of novel arylpiperazine derivatives containing the saccharin moiety based on previous studies was designed, synthesized, and evaluated in prostate (PC-3, LNCaP, and DU145 cancer cell lines for their anticancer activities. The majority of the compounds exhibited excellent selective activity for the tested cancer cells. Compounds 4 and 12 exhibited strong cytotoxic activities against DU145 cells (half maximal inhibitory concentration (IC50 < 2 μM. The structure–activity relationship (SAR of these arylpiperazine derivatives was also discussed based on the obtained experimental data. This work provides a potential lead compound for anticancer agent development focusing on prostate cancer therapy.

  2. Antitumor activity of the Hsp90 inhibitor IPI-504 in HER2-positive trastuzumab-resistant breast cancer.

    Science.gov (United States)

    Scaltriti, Maurizio; Serra, Violeta; Normant, Emmanuel; Guzman, Marta; Rodriguez, Olga; Lim, Alice R; Slocum, Kelly L; West, Kip A; Rodriguez, Varenka; Prudkin, Ludmila; Jimenez, José; Aura, Claudia; Baselga, José

    2011-05-01

    Hsp90 facilitates the maturation and stability of numerous oncoproteins, including HER2. The aim of this study was to assess the antitumor activity of the Hsp90 inhibitor IPI-504 in trastuzumab-resistant, HER2-overexpressing breast cancer cells. Therapy with trastuzumab, IPI-504, and the combination of trastuzumab and IPI-504 was evaluated in trastuzumab-sensitive and trastuzumab-resistant cells. Inhibition of protein targets, cell proliferation, and tumor growth was assessed in vitro and in xenograft models. IPI-504 inhibited proliferation of both trastuzumab-sensitive and trastuzumab-resistant cells. Administration of IPI-504 markedly reduced total levels of HER2 and Akt, as well as phosphorylated Akt and mitogen-activated protein kinase (MAPK), to an equal extent in trastuzumab-sensitive and trastuzumab-resistant cells. IPI-504, used as single agent or in combination with trastuzumab, also inhibited in vivo the growth of both trastuzumab-sensitive and -resistant tumor xenografts. As a mechanism for the observed antitumor activity, IPI-504 resulted in a marked decrease in the levels of HER2, Akt, p-Akt, and p-MAPK in trastuzumab-resistant xenografts as early as 12 hours after a single dose of IPI-504. IPI-504-mediated Hsp90 inhibition may represent a novel therapeutic approach in trastuzumab refractory HER2-positive breast cancer.

  3. Tivantinib (ARQ-197) exhibits anti-tumor activity with down-regulation of FAK in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Xi, Wei-Hong [Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Nanchang University, Nanchang 330006 (China); Yang, Li-Yun [Department of Blood Transfusion, First Affiliated Hospital, Nanchang University, Nanchang 330006 (China); Cao, Zhong-Yi, E-mail: m18070383032@163.com [Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Nanchang University, Nanchang 330006 (China); Qian, Yong, E-mail: yfykqkqy@163.com [Department of Oral and Maxillofacial Surgery, First Affiliated Hospital, Nanchang University, Nanchang 330006 (China)

    2015-02-20

    Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide and the 5 years survival rate of the patients is about 60% in the USA, due to acquired chemotherapeutic resistance and metastasis of the disease. In this study, we found that tivantinib, a selective MET inhibitor, suppresses OCSS cell proliferation and colony formation, however, anti-tumor activities induced by tivantinib are independent of the inhibition of MET signaling pathway. In addition, tivantinib cause G2/M cell cycle arrest and caspases-dependent apoptosis in OSCC cell lines. We also found that tivantinib dose-dependently suppressed the activation and expression of FAK. In all, these data suggested that tivantinib may be developed as a chemotherapeutic agent to effectively treat certain cancers including OSCC. - Highlights: • Tivantinib suppresses OSCC cell growth independent of the inhibition of HGF/MET signaling pathway. • Tivantinib blocks cell cycle and induces caspases-mediated apoptosis. • Tivantinib elicits its anti-tumor activity with the inhibition of FAK signaling pathway.

  4. The vitamin-like dietary supplement para-aminobenzoic acid enhances the antitumor activity of ionizing radiation

    International Nuclear Information System (INIS)

    Xavier, Sandhya; MacDonald, Shannon; Roth, Jennifer; Caunt, Maresa; Akalu, Abebe; Morais, Danielle; Buckley, Michael T.; Liebes, Leonard; Formenti, Silvia C.; Brooks, Peter C.

    2006-01-01

    Purpose: To determine whether para-aminobenzoic acid (PABA) alters the sensitivity of tumor cells to ionizing radiation in vitro and in vivo. Methods and Materials: Cellular proliferation was assessed by WST-1 assays. The effects of PABA and radiation on tumor growth were examined with chick embryo and murine models. Real-time reverse transcriptase-polymerase chain reaction and Western blotting were used to quantify p21 CIP1 and CDC25A levels. Results: Para-aminobenzoic acid enhanced (by 50%) the growth inhibitory activity of radiation on B16F10 cells, whereas it had no effect on melanocytes. Para-aminobenzoic acid enhanced (50-80%) the antitumor activity of radiation on B16F10 and 4T1 tumors in vivo. The combination of PABA and radiation therapy increased tumor apoptosis. Treatment of tumor cells with PABA increased expression of CDC25A and decreased levels of p21 CIP1 . Conclusions: Our findings suggest that PABA might represent a compound capable of enhancing the antitumor activity of ionizing radiation by a mechanism involving altered expression of proteins known to regulate cell cycle arrest

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

    Science.gov (United States)

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

    2017-01-01

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

  6. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

    Science.gov (United States)

    Su, Rui; Dong, Lei; Li, Chenying; Nachtergaele, Sigrid; Wunderlich, Mark; Qing, Ying; Deng, Xiaolan; Wang, Yungui; Weng, Xiaocheng; Hu, Chao; Yu, Mengxia; Skibbe, Jennifer; Dai, Qing; Zou, Dongling; Wu, Tong; Yu, Kangkang; Weng, Hengyou; Huang, Huilin; Ferchen, Kyle; Qin, Xi; Zhang, Bin; Qi, Jun; Sasaki, Atsuo T; Plas, David R; Bradner, James E; Wei, Minjie; Marcucci, Guido; Jiang, Xi; Mulloy, James C; Jin, Jie; He, Chuan; Chen, Jianjun

    2018-01-11

    R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N 6 -methyladenosine (m 6 A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m 6 A/MYC/CEBPA signaling. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Pyrvinium targets the unfolded protein response to hypoglycemia and its anti-tumor activity is enhanced by combination therapy.

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    De-Hua Yu

    Full Text Available We identified pyrvinium pamoate, an old anthelminthic medicine, which preferentially inhibits anchorage-independent growth of cancer cells over anchorage-dependent growth (approximately 10 fold. It was also reported by others to have anti-tumor activity in vivo and selective toxicity against cancer cells under glucose starvation in vitro, but with unknown mechanism. Here, we provide evidence that pyrvinium suppresses the transcriptional activation of GRP78 and GRP94 induced by glucose deprivation or 2-deoxyglucose (2DG, a glycolysis inhibitor, but not by tunicamycin or A23187. Other UPR pathways induced by glucose starvation, e.g. XBP-1, ATF4, were also found suppressed by pyrvinium. Constitutive expression of GRP78 via transgene partially protected cells from pyrvinium induced cell death under glucose starvation, suggesting that suppression of the UPR is involved in pyrvinium mediated cytotoxicity under glucose starvation. Xenograft experiments showed rather marginal overall anti-tumor activity for pyrvinium as a monotherapy. However, the combination of pyrvinium and Doxorubicin demonstrated significantly enhanced efficacy in vivo, supporting a mechanistic treatment concept based on tumor hypoglycemia and UPR.

  8. The in vitro antitumor activity of arene-ruthenium(II) curcuminoid complexes improves when decreasing curcumin polarity.

    Science.gov (United States)

    Caruso, Francesco; Pettinari, Riccardo; Rossi, Miriam; Monti, Elena; Gariboldi, Marzia Bruna; Marchetti, Fabio; Pettinari, Claudio; Caruso, Alessio; Ramani, Modukuri V; Subbaraju, Gottumukkala V

    2016-09-01

    The antitumor activity of ruthenium(II) arene (p-cymene, benzene, hexamethylbenzene) derivatives containing modified curcumin ligands (HCurcI=(1E,4Z,6E)-5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)hepta-1,4,6-trien-3-one and HCurcII=(1E,4Z,6E)-5-hydroxy-1,7-bis(4-methoxyphenyl)hepta-1,4,6-trien-3-one) is described. These have been characterized by IR, ESI-MS and NMR spectroscopy. The X-ray crystal structure of HCurcI has been determined and compared with its related Ru complex. Four complexes have been evaluated against five tumor cell lines, whose best activities [IC 50 (μM)] are: breast MCF7, 9.7; ovarian A2780, 9.4; glioblastoma U-87, 9.4; lung carcinoma A549, 13.7 and colon-rectal HCT116, 15.5; they are associated with apoptotic features. These activities are improved when compared to the already known corresponding curcumin complex, (p-cymene)Ru(curcuminato)Cl, about twice for the breast and ovarian cancer, 4.7 times stronger in the lung cancer and about 6.6 times stronger in the glioblastoma cell lines. In fact, the less active (p-cymene)Ru(curcuminato)Cl complex only shows similar activity to two novel complexes in the colon cancer cell line. Comparing antitumor activity between these novel complexes and their related curcuminoids, improvement of antiproliferative activity is seen for a complex containing CurcII in A2780, A549 and U87 cell lines, whose IC 50 are halved. Therefore, after replacing OH curcumin groups with OCH 3 , the obtained species HCurcI and its Ru complexes have increased antitumor activity compared to curcumin and its related complex. In contrast, HCurcII is less cytotoxic than curcumin but its related complex [(p-cymene)Ru(CurcII)Cl] is twice as active as HCurcII in 3 cell lines. Results from these novel arene-Ru curcuminoid species suggest that their increased cytotoxicity on tumor cells correlate with increase of curcuminoid lipophilicity. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Effects of the antitumor agents from various natural sources on drug-metabolizing system, phagocytic activity and complement system in sarcoma 180-bearing mice.

    Science.gov (United States)

    Ito, H

    1986-03-01

    Correlation between antitumor activity and effects on some biological properties, such as phagocytic activity of the reticuloendothelial system, the third component of complement (C3) activation, hepatic drug-metabolizing activities and pentobarbital-induced narcosis, of antitumor agents from various natural sources such as B B (Broncasma Berna), GU-P (Grifora umbellata polysaccharide), OK-432, PS-K (Polysaccharide Kureha), and RA-P (Rumex acetosa polysaccharide) were studied with female ICR mice implanted with Sarcoma 180 solid tumor. All of these agents depressed aniline hydroxylase and aminopyrine demethylase activities, prolonged the duration of pentobarbital-induced narcosis, and significantly enhanced the phagocytic activity and C3 activity. Especially, RA-P which has the strongest antitumor activity was the most effective in changing these activities. The biological activities of GU-P at a dose of 10 mg/kg reached the same level as that found with PS-K at a dose of 100 mg/kg. a possible mechanism of inhibition of Sarcoma 180 solid tumor growth by the treatment with the antitumor agents could be interpreted as due to the C3 activation, the stimulation of phagocytic activity and depression of the hepatic microsomal drug-metabolizing system in tumor-bearing mice.

  10. Antitumor activity of the selective cyclooxygenase-2 inhibitor, celecoxib, on breast cancer in Vitro and in Vivo

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    Dai Zhi-Jun

    2012-12-01

    Full Text Available Abstract Background Cyclooxygenase-2(COX-2 promotes carcinogenesis, tumor proliferation, angiogenesis, prevention of apoptosis, and immunosuppression. Meanwhile, COX-2 over-expression has been associated with tumor behavior and prognosis in several cancers. This study investigated the antitumor effects of the selective COX-2 inhibitor, Celecoxib, on breast cancer in vitro and in vivo. Methods Human breast cancer MCF-7 and MDA-MB-231 cells were cultured with different concentration (10, 20, 40 μmol/L of celecoxib after 0-96 hours in vitro. MTT assay was used to determine the growth inhibition of breast cancer cells in vitro. The expression of COX-2 on mRNA was measured by real-time quantitive PCR analysis. Flow cytometry was performed to analyze the cell cycle of MCF-7 cells. Levels of PGE2 were measured by ELISA method. The in vivo therapeutic effects of celecoxib were determined using rat breast cancer chemically induced by 7,12-dimethylben anthracene (DMBA. Results The inhibition of proliferation of both MCF-7 and MDA-MB-231 cells in vitro by celecoxib was observerd in time and dose dependent manner. Celecoxib effectively down-regulated the expression of COX-2. The cell cycle was arrested at G0/G1, and rate of cells in S phase was obviously decreased. Levels of PGE2 were inhibited by Celecoxib. The tumor incidence rate of the celecoxib group was lower than that of the control group. In addition, the tumor latency period of the celecoxib group was longer than that of the control group. Conclusions Celecoxib inhibited the proliferation of breast cancer cell lines in vitro, and prevented the occurrence of rat breast cancer chemically induced by DMBA. Therefore, celecoxib exhibits an antitumor activity and seems to be effective in anti-tumor therapy.

  11. Myxoma virus expressing a fusion protein of interleukin-15 (IL15 and IL15 receptor alpha has enhanced antitumor activity.

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    Vesna Tosic

    Full Text Available Myxoma virus, a rabbit poxvirus, can efficiently infect various types of mouse and human cancer cells. It is a strict rabbit-specific pathogen, and is thought to be safe as a therapeutic agent in all non-rabbit hosts tested including mice and humans. Interleukin-15 (IL15 is an immuno-modulatory cytokine with significant potential for stimulating anti-tumor T lymphocytes and NK cells. Co-expression of IL15 with the α subunit of IL15 receptor (IL15Rα greatly enhances IL15 stability and bioavailability. Therefore, we engineered a new recombinant myxoma virus (vMyx-IL15Rα-tdTr, which expresses an IL15Rα-IL15 fusion protein plus tdTomato red fluorescent reporter protein. Permissive rabbit kidney epithelial (RK-13 cells infected with vMyx-IL15Rα-tdTr expressed and secreted the IL15Rα-IL15 fusion protein. Functional activity was confirmed by demonstrating that the secreted fusion protein stimulated proliferation of cytokine-dependent CTLL-2 cells. Multi-step growth curves showed that murine melanoma (B16-F10 and B16.SIY cell lines were permissive to vMyx-IL15Rα-tdTr infection. In vivo experiments in RAG1-/- mice showed that subcutaneous B16-F10 tumors treated with vMyx-IL15Rα-tdTr exhibited attenuated tumor growth and a significant survival benefit for the treated group compared to the PBS control and the control viruses (vMyx-IL15-tdTr and vMyx-tdTr. Immunohistological analysis of the subcutaneous tumors showed dramatically increased infiltration of NK cells in vMyx-IL15Rα-tdTr treated tumors compared to the controls. In vivo experiments with immunocompetent C57BL/6 mice revealed a strong infiltrate of both NK cells and CD8+ T cells in response to vMyx-IL15Rα-tdTr, and prolonged survival. We conclude that delivery of IL15Rα-IL15 in a myxoma virus vector stimulates both innate and adaptive components of the immune system.

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

    Science.gov (United States)

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

    2015-07-01

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

  13. Enhanced Antitumoral Activity of Extracts Derived from Cultured Udotea flabellum (Chlorophyta

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    Rosa Moo-Puc

    2011-01-01

    Full Text Available Very few studies have been performed to evaluate the effect of culture conditions on the production or activity of active metabolites in algae. Previous studies suggest that the synthesis of bioactive compounds is strongly influenced by irradiance level. To investigate whether the antiproliferative activity of Udotea flabellum extracts is modified after cultivation, this green alga was cultured under four photon flux densities (PFD for 30 days. After 10, 20, and 30 days, algae were extracted with dichloromethane: methanol and screened for antiproliferative activity against four human cancer cell lines (laryngeal—Hep-2, cervix—HeLa, cervix squamous—SiHa and nasopharynx—KB by SRB assay. Lipid and phenol content were evaluated by standardized methods on algae organic extracts. After 10 days of cultivation, organic U. flabellum extracts showed a significant increase in antiproliferative activity on Hela and SiHa cells when compared to noncultured algae extracts. Extracts obtained after 10 and 20 days of culture were active on KB and Hep-2 cells. Total phenol and polyunsaturated fatty acid content in organic extracts changed with cultivation time but not by irradiance treatment. Extracts from U. flabellum obtained after 10 and 20 days of culture have been selected for fractionation and isolation of active compounds.

  14. Formulation optimization of Docetaxel loaded self-emulsifying drug delivery system to enhance bioavailability and anti-tumor activity.

    Science.gov (United States)

    Valicherla, Guru R; Dave, Kandarp M; Syed, Anees A; Riyazuddin, Mohammed; Gupta, Anand P; Singh, Akhilesh; Wahajuddin; Mitra, Kalyan; Datta, Dipak; Gayen, Jiaur R

    2016-05-31

    Poor bioavailability of Docetaxel (DCT) arising due to its low aqueous solubility and permeability limits its clinical utility. The aim of the present study was to develop DCT loaded self-emulsified drug delivery systems (D-SEDDS) and evaluate its potential ability to improve the oral bioavailability and therapeutic efficacy of DCT. D-SEDDS were characterized for their in vitro antitumor activity, in situ single pass intestinal perfusion (SPIP), bioavailability, chylomicron flow blocking study and bio-distribution profile. The D-SEDDS were prepared using Capryol 90, Vitamin E TPGS, Gelucire 44/14 and Transcutol HP with a ratio of 32.7/29.4/8.3/29.6 using D-Optimal Mixture Design. The solubility of DCT was improved upto 50 mg/mL. The oral bioavailability of the D-SEDDS in rats (21.84 ± 3.12%) was increased by 3.19 fold than orally administered Taxotere (6.85 ± 1.82%). The enhanced bioavailability was probably due to increase in solubility and permeability. In SPIP, effective permeability of D-SEDDS was significantly higher than Taxotere. D-SEDDS showed 25 fold more in vitro cytotoxic activity compared to free DCT. Chylomicron flow blocking study and tissue distribution demonstrated the intestinal lymphatic transport of D-SEDDS and higher retention in tumor than Taxotere. The data suggests that D-SEDDS showed desired stability, enhanced oral bioavailability and in vitro antitumor efficacy.

  15. [Antitumor activity of the plant remedy peptide extract PE-PM in a new mouse T-lymphoma/eukemia model].

    Science.gov (United States)

    Chaadaeva, A V; Tenkeeva, I I; Moiseeva, E V; Svirshchevskaia, E V; Demushkin, V P

    2009-01-01

    A new mouse ASF-LL model of adult T-lymphoma/leukemia (ATLL) in humans was characterized by cytological, histopathological, and flow cytometry analyses. Encouraging similarities of morphological, pathological, and clinical signs were found. These included characteristic flower appearance of leukemic cells, lymphadenopathy and hepatosplenomegaly, multiple growths in the skin, urogenital tissues, lungs and pituitary gland, CD4+CD25+ phenotype of the majority of tumor cells that were selectin-L positive, a rapid clinical course, and poor response to standard chemotherapy. Plant peptides obtained from the traditional Russian herbal medicine have gradually gained considerable attention as a new source of anticancer drugs. We have tested antitumor activity of a peptide extract PE-PM obtained from a mixture of Chelidonium majus L., Inula helenium L., Equisetum arvense L. and Inonotus obliquus in new mouse T-lymphoma/leukemia model ASF-LL. Distinct antitumor activity of two local injections of the peptide extract PE-PM was detected by tumor growth inhibition and survival improvement of 33% of recipients bearing intraperitoneal form of ASF-LL.

  16. Nanoparticle Delivery of Artesunate Enhances the Anti-tumor Efficiency by Activating Mitochondria-Mediated Cell Apoptosis

    Science.gov (United States)

    Liu, Rui; Yu, Xiwei; Su, Chang; Shi, Yijie; Zhao, Liang

    2017-06-01

    Artemisinin and its derivatives were considered to exert a broad spectrum of anti-cancer activities, and they induced significant anti-cancer effects in tumor cells. Artemisinin and its derivatives could be absorbed quickly, and they were widely distributed, selectively killing tumor cells. Since low concentrations of artesunate primarily depended on oncosis to induce cell death in tumor cells, its anti-tumor effects were undesirable and limited. To obtain better anti-tumor effects, in this study, we took advantage of a new nanotechnology to design novel artesunate-loaded bovine serum albumin nanoparticles to achieve the mitochondrial accumulation of artesunate and induce mitochondrial-mediated apoptosis. The results showed that when compared with free artesunate's reliance on oncotic death, artesunate-loaded bovine serum albumin nanoparticles showed higher cytotoxicity and their significant apoptotic effects were induced through the distribution of artesunate in the mitochondria. This finding indicated that artesunate-loaded bovine serum albumin nanoparticles damaged the mitochondrial integrity and activated mitochondrial-mediated cell apoptosis by upregulating apoptosis-related proteins and facilitating the rapid release of cytochrome C.

  17. Antitumor activity of Chlorella sorokiniana and Scenedesmus sp. microalgae native of Nuevo León State, México

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    Raul Reyna-Martinez

    2018-02-01

    Full Text Available Cancer cases result in 13% of all deaths worldwide. Unwanted side effects in patients under conventional treatments have led to the search for beneficial alternative therapies. Microalgae synthesize compounds with known in vitro and in vivo biological activity against different tumor cell lines. Therefore, native microalgae from the State of Nuevo Leon, Mexico may become a potential source of antitumor agents. The aim of the present study was to evaluate the in vitro cytotoxic effect of Nuevo Leon regional Chlorella sorokiniana (Chlorellales: Chlorellaceae and Scenedesmus sp. (Chlorococcales: Scenedesmaceae. Native microalgae crude organic extracts cytotoxicity against murine L5178Y-R lymphoma cell line and normal lymphocyte proliferation were evaluated using the MTT reduction colorimetric assay. Cell death pathway was analyzed by acridine orange and ethidium bromide staining, DNA degradation in 2% agarose gel electrophoresis and caspases activity. Results indicated significant (p < 0.05 61.89% ± 3.26% and 74.77% ± 1.84% tumor cytotoxicity by C. sorokiniana and Scenedesmus sp. methanol extracts, respectively, at 500 µg/mL, by the mechanism of apoptosis. This study contributes to Mexican microalgae biodiversity knowledge and their potential as antitumor agent sources.

  18. Enhanced photostability, radical scavenging and antitumor activity of indole-3-carbinol-loaded rose hip oil nanocapsules.

    Science.gov (United States)

    Gehrcke, Mailine; Giuliani, Laura Minussi; Ferreira, Luana Mota; Barbieri, Allanna Valentini; Sari, Marcel Henrique Marcondes; da Silveira, Elita Ferreira; Azambuja, Juliana Hofstatter; Nogueira, Cristina Wayne; Braganhol, Elizandra; Cruz, Letícia

    2017-05-01

    This study aimed to develop poly(ε-caprolactone) nanocapsules loaded with indole-3-cabinol (I3C) using rose hip oil (RHO) or medium chain triglycerides (MCT) as oil core. In vitro radical scavenging activity (DPPH method), hemolysis, and antitumor effects on breast (MCF-7) and glioma (C6) cells were conducted. Preformulation evaluations revealed that RHO is suitable to prepare the nanocapsules considering the log P determination and dissolution/swelling experiments of polymer films. The nanocapsules were prepared and presented adequate physicochemical characteristics as mean size around 250nm, polydispersity index values oil core (RHO or MCT) on these parameters. However, the photodegradation study demonstrated that RHO nanocapsules showed less degree of I3C degradation in comparison to MCT nanocapsules. The in vitro release profile showed that both nanocapsule suspensions demonstrated an initial burst effect followed by a prolonged I3C release. In addition, the formulations were considered hemocompatibles at 10μg/mL and showed an enhanced radical scavenging activity in comparison to free I3C. Moreover, nanocapsules prepared with RHO increased about two times the antitumor effect of I3C on MCF-7 and C6 cells without significant reduction of astrocyte cell viability. In conclusion, nanocapsule formulations developed in this study might be considered promising for cancer treatment. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Antitumor Activity of Chinese Propolis in Human Breast Cancer MCF-7 and MDA-MB-231 Cells

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    Hongzhuan Xuan

    2014-01-01

    Full Text Available Chinese propolis has been reported to possess various biological activities such as antitumor. In present study, anticancer activity of ethanol extract of Chinese propolis (EECP at 25, 50, 100, and 200 μg/mL was explored by testing the cytotoxicity in MCF-7 (human breast cancer ER(+ and MDA-MB-231 (human breast cancer ER(− cells. EECP revealed a dose- and time-dependent cytotoxic effect. Furthermore, annexin A7 (ANXA7, p53, nuclear factor-κB p65 (NF-κB p65, reactive oxygen species (ROS levels, and mitochondrial membrane potential were investigated. Our data indicated that treatment of EECP for 24 and 48 h induced both cells apoptosis obviously. Exposure to EECP significantly increased ANXA7 expression and ROS level, and NF-κB p65 level and mitochondrial membrane potential were depressed by EECP dramatically. The effects of EECP on p53 level were different in MCF-7 and MDA-MB-231 cells, which indicated that EECP exerted its antitumor effects in MCF-7 and MDA-MB-231 cells by inducing apoptosis, regulating the levels of ANXA7, p53, and NF-κB p65, upregulating intracellular ROS, and decreasing mitochondrial membrane potential. Interestingly, EECP had little or small cytotoxicity on normal human umbilical vein endothelial cells (HUVECs. These results suggest that EECP is a potential alternative agent on breast cancer treatment.

  20. Anti-tumor and anti-virus activity of polysaccharides extracted from Sipunculus nudus(SNP) on Hepg2.2.15.

    Science.gov (United States)

    Su, Jie; Jiang, Linlin; Wu, Jingna; Liu, Zhiyu; Wu, Yuping

    2016-06-01

    Many polysaccharides have biological activities and have been investigated for their antitumor effects. In this study, we investigated the anti-tumor activity and anti-virus activity of SNP-the water-soluble polysaccharides extracted from Sipunculus nudus on Hepg2.2.15. Flow cytometry analysis demonstrated that SNP induced dose-dependent cell apoptosis on Hepg2.2.15. Real-time PCR and Western Blot analysis showed that SNP down-regulated the synthesis of HBsAg, HBV-DNA and enhanced the expression of pro-apoptosis proteins TNF-α, caspase-3, and Bax, while decreasing the expression of the anti-apoptosis proteins survivin, Bcl-2, and VEGF. These results suggested that SNP suppressed cell viability of Hepg2.2.15 and that could be a novel anti-tumor and anti-HBV agent. Copyright © 2016. Published by Elsevier B.V.

  1. The preparation of three selenium-containing Cordyceps militaris polysaccharides: Characterization and anti-tumor activities.

    Science.gov (United States)

    Liu, Fei; Zhu, Zhen-Yuan; Sun, Xiaoli; Gao, Hui; Zhang, Yong-Min

    2017-06-01

    In the present work, three fractions of selenized Cordyceps militaris polysaccharides (SeCPS) named SeCPS- I, SeCPS- II and SeCPS- III were isolated and purified by ultra-filtration. Their selenium content were measured as 541.3, 863.7 and 623.3μg/g respectively by a graphite furnace atomic absorption spectroscopy. The monosaccharide comformation analysis showed that they were mainly consisted of D-Mannose, D-Glucose, and D-Galactose in mole ratios of 1:7.63:0.83, 1:1.34:0.31 and 1:3.77:0.41 respectively. Their structure characteristics were compared by IFR and NMR spectroscopy. Scanning electron microscopy (SEM) and Congo red (CR) spectrophotometric method were used to investigate their morphological characteristics and conformational transition. SeCPS-II showed the strongest anti-tumor effects judging from the result of in vitro anti-tumor assays against two tumor cell lines (hepatocellular carcinoma HepG-2 cells and lung adenocarcinom A549 cells). Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Synthesis and Anti-Tumor Activity of Novel Aminomethylated Derivatives of Isoliquiritigenin

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    Haoran Fu

    2014-10-01

    Full Text Available A series of new aminomethylated derivatives of isoliquiritigenin was synthesized. The structures of the compounds were confirmed by IR, MS, NMR, 13C-NMR and elemental analyses. Cytotoxic activities of these derivatives towards the human prostatic cell line PC-3, human mammary cancer cell line MCF-7 and human oophoroma cell line HO-8910 in vitro were tested. The IC50 values showed cytotoxic activities of some of these new derivatives were relatively strong. Furthermore, tumor growth inhibition in vivo of aminomethylated derivatives of isoliquiritigenin 15 was superior to that of isoliquritigenin and reached inhibition rates of 71.68%. The detailed synthesis, spectroscopic data, biological and pharmacologicalactivities of the synthesized compounds were provided.

  3. Improvement of anti-tumor activity of photodynamic therapy through inhibition of cytoprotective mechanism in tumor cells

    Science.gov (United States)

    Nowis, Dominika; Szokalska, Angelika; Makowski, Marcin; Winiarska, Magdalena; Golab, Jakub

    2009-06-01

    Photodynamic therapy (PDT) leads to oxidative damage of cellular macromolecules, including numerous proteins that undergo multiple modifications such as fragmentation, cross-linking and carbonylation that result in protein unfolding and aggregation. Several mechanisms are involved in the protective responses to PDT that include activation of transcription factors, heat shock proteins, antioxidant enzymes and antiapoptotic pathways. Identification of these cytoprotective mechanisms might result in the design of more effective combination strategies to improve the antitumor efficacy of PDT. By using various molecular biology approaches, including microarray-based technologies we have identified genes that are up-regulated following PDT. Subsequent experiments revealed that some of these gene products can become targets for the combined therapeutic regimens encompassing PDT and selective small-molecule inhibitors. These include superoxide dismutase (SOD-2), cyclooxygenase 2 (COX-2), heme oxygenase 1 (HO-1), and proteins engaged in signaling endoplasmatic reticulum (ER) stress and unfolded protein response (UPR). Since a major mechanism for elimination of carbonylated proteins is their degradation by proteasomes, we hypothesized that a combination of PDT with proteasome inhibitors might lead to accumulation of carbonylated proteins in ER, aggravated ER stress and potentiated cytotoxicity towards tumor cells. Indeed, we observed that incubation of tumor cells with three different proteasome inhibitors, including bortezomib, MG132 and PSI gave increased accumulation of carbonylated and ubiquitinated proteins in PDT-treated cells. Proteasome inhibitors effectively sensitized tumor cells to PDT-mediated cytotoxicity and augmented antitumor effects of PDT in vivo.

  4. Antitumor activity of a polysaccharide fraction from Laminaria japonica on U14 cervical carcinoma-bearing mice.

    Science.gov (United States)

    Zhai, Qingzhi; Li, Xiuli; Yang, Yizhuo; Yu, Ling; Yao, Yuanqing

    2014-01-01

    In the present study, we investigated the in vitro and in vivo antitumor effects of a sulfated polysaccharide fraction from the brown alga Laminaria japonica (LJSP) on cervical carcinoma. In vitro, the results showed that LJSP exhibited the highest cell growth inhibitory effect on cervical carcinoma U14 cells among five tumor cell lines. In vivo, the results showed that LJSP could not only inhibit the growth of the tumor but also enhance the spleen and thymus indexes, as well as the body weight of U14 tumor-bearing mice. Moreover, the white blood cell count of H22 tumor-bearing mice showed no change in the LJSP-treated groups and little toxicological effects were observed on hepatic function and renal function in LJSP-treated mice bearing U14 tumor cells. Besides, LJSP induced apoptosis of transplanted tumor tissues by increasing the ratio of Bax/Bcl-2. These data showed that LJSP exhibited prominent antitumor activities and low toxic effects; thus, it could be developed to a safe and effective anticancer agent.

  5. Preparation, characterization, and antitumor activity of paclitaxel-loaded folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes.

    Science.gov (United States)

    Niu, Ruifang; Zhao, Peiqi; Wang, Hanjie; Yu, Man; Cao, Shuzhen; Zhang, Fei; Chang, Jin

    2011-06-01

    Targeting therapy is a promising strategy for enhancing the therapeutic potential of chemotherapeutic agents. In this study, we report the construction of a multifunctional drug delivery system, termed folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes (FA-TATp-PLs), which is originally derived from octadecyl-quaternized lysine modified chitosan and cholesterol. Our data revealed that FA-TATp-PLs have a particle size of about 60 nm with a zeta potential of about 30 mV, a low burst release effect within the first day, a sustained release for the next 14 days in vitro as well as an instant cellular uptake by folate receptor-overexpressing KB human nasopharyngeal carcinoma cells. In vitro cytotoxicity of paclitaxel-loaded FA-TATp-PLs in KB cells was superior to that of Taxol(®). Furthermore, a comparable antitumor efficacy of paclitaxel-loaded FA-TATp-PLs and Taxol(®) was observed at the same doses in murine models bearing nasopharyngeal carcinoma. These results demonstrate that the paclitaxel formulation not only exhibits a higher antitumor activity but also significantly reduces the toxicity and improves the bioavailability as compared to that of free paclitaxel for the treatment of nasopharyngeal carcinoma. Taken together, our findings indicate that paclitaxel-loaded FA-TATp-PLs are a promising nano-sized drug formulation for future cancer therapy.

  6. 1,25D3 enhances antitumor activity of gemcitabine and cisplatin in human bladder cancer models

    Science.gov (United States)

    Ma, Yingyu; Yu, Wei-Dong; Trump, Donald L.; Johnson, Candace S.

    2010-01-01

    Background 1,25 dihydroxyvitamin D3 (1,25D3) potentiates the cytotoxic effects of several common chemotherapeutic agents. The combination of gemcitabine and cisplatin (GC) is a current standard chemotherapy regimen for bladder cancer. We investigated whether 1,25D3 could enhance the antitumor activity of GC in bladder cancer model systems. Methods Human bladder cancer T24 and UMUC3 cells were pretreated with 1,25D3 followed by GC. Apoptosis were assessed by annexin V staining. Caspase activation was examined by immunoblot analysis and substrate-based caspase activity assay. The cytotoxic effects were examined using MTT and in vitro clonogenic assay. p73 protein levels were assessed by immunoblot analysis. Knockdown of p73 was achieved by siRNA. The in vivo antitumor activity was assessed by in vivo excision clonogenic assay and tumor regrowth delay in the T24 xenograft model. Results 1,25D3 pretreatment enhanced GC-induced apoptosis and the activities of caspases- 8, 9 and 3 in T24 and UMUC3 cells. 1,25D3 synergistically reduced GC-suppressed surviving fraction in T24 cells. 1,25D3, gemcitabine, or cisplatin induced p73 accumulation, which was enhanced by GC or 1,25D3 and GC. p73 expression was lower in human primary bladder tumor tissue compared with adjacent normal tissue. Knockdown of p73 increased clonogenic capacity of T24 cells treated with 1,25D3, GC or 1,25D3 and GC. 1,25D3 and GC combination enhanced tumor regression compared with 1,25D3 or GC alone. Conclusions 1,25D3 potentiates GC-mediated growth inhibition in human bladder cancer models in vitro and in vivo, which involves p73 induction and apoptosis. PMID:20564622

  7. Facile synthesis and quantitative structure-activity relationship study of antitumor active 2-(4-oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles.

    Science.gov (United States)

    Hanna, Mona Maurice; George, Riham François

    2012-01-01

    2-(5-Arylidene-4-oxo-3-phenyl-thiazolidin-2-ylidene)-3-oxo-propionitriles 4a-j were prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a,b. The latter was obtained via electrophilic attack of phenylisothiocyanate on 3-oxo-propionitriles 1a,b followed by reaction with chloroacetyl chloride under basic condition. Additionally, 2-(5-heteroalicyclic methylene) analogues 5a-h were prepared via Mannich reaction of the appropriate secondary amines and formaldehyde with 4-thiazolidinones 3a,b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116 and breast T47D cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explain the observed antitumor properties.

  8. Exceptionally Potent Anti-Tumor Bystander Activity of an scFv:sTRAIL Fusion Protein with Specificity for EGP2 Toward Target Antigen-Negative Tumor Cells

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    Edwin Bremer

    2004-09-01

    Full Text Available Previously, we reported on the target cell-restricted fratricide apoptotic activity of scFvC54:sTRAIL, a fusion protein comprising human-soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL genetically linked to the antibody fragment scFvC54 specific for the cell surface target antigen EGP2. In the present study, we report that the selective binding of scFvC54:sTRAIL to EGP2-positive target cells conveys an exceptionally potent pro-apoptotic effect toward neighboring tumor cells that are devoid of EGP2 expression (bystander cells. The anti-tumor bystander activity of scFvC54:sTRAIL was detectable at target-tobystander cell ratios as low as 1:100. Treatment in the presence of EGP2-blocking or TRAIL-neutralizing antibody strongly inhibited apoptosis in both target and bystander tumor cells. In the absence of target cells, bystander cell apoptosis induction was abrogated. The bystander apoptosis activity of scFvC54:sTRAIL did not require internalization, enzymatic conversion, diffusion, or communication (gap junctional intracellular communication between target and bystander cells. Furthermore, scFvC54:sTRAIL showed no detectable signs of innocent bystander activity toward freshly isolated blood cells. Further development of this new principle is warranted for approaches where cancer cells can escape from antibody-based therapy due to partial loss of target antigen expression.

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

    Science.gov (United States)

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

    2014-11-01

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

  10. A novel polysaccharide from Ganoderma atrum exerts antitumor activity by activating mitochondria-mediated apoptotic pathway and boosting the immune system.

    Science.gov (United States)

    Zhang, Shenshen; Nie, Shaoping; Huang, Danfei; Feng, Yanling; Xie, Mingyong

    2014-02-19

    Ganoderma is a precious health-care edible medicinal fungus in China. A novel Ganoderma atrum polysaccharide (PSG-1) is the main bioactive component. We investigated the antitumor effect and molecular mechanisms of PSG-1. It exhibited no significant effect on cell proliferation directly. In contrast, administration of PSG-1 markedly suppressed tumor growth in CT26 tumor-bearing mice. It was observed that PSG-1 caused apoptosis in CT26 cells. Apoptosis was associated with loss of mitochondrial membrane potential, enhancement of mitochondrial cytochrome c release and intracellular ROS production, elevation of p53 and Bax expression, downregulation of Bcl-2, and the activation of caspase-9 and -3. Moreover, PSG-1 enhanced immune organ index and promoted lymphocyte proliferation as well as cytokine levels in serum. Taken together, our data indicate that PSG-1 has potential antitumor activity in vivo by inducing apoptosis via mitochondria-mediated apoptotic pathway and enhances host immune system function. Therefore, PSG-1 could be a safe and effective antitumor, bioactive agent or functional food.

  11. Synthesis and antitumor activity of 2-beta-D-ribofuranosyloxazole-4-carboxamide (oxazofurin).

    Science.gov (United States)

    Franchetti, P; Cristalli, G; Grifantini, M; Cappellacci, L; Vittori, S; Nocentini, G

    1990-10-01

    Condensation of 3,4,6-tri-O-benzoyl-2,5-anhydro-D-allonyl chloride (4) with ethyl 2-amino-2-cyanoacetate (5) provided 2-[(3',4',6'-tri-O-benzoyl-2',5'-anhydroallonyl)amino]-2-cyanoa cetate (6). Compound 6 was treated with hydrogen chloride gas to give ethyl 5-amino-2-(2',3',5'-tri-O-benzoyl-beta-D- ribofuranosyl)oxazole-4-carboxylate (8). Reductive dediazotization of blocked nucleoside 8 provided ethyl 2-(2',3',5'-tri-O- benzoyl-beta-D-ribofuranosyl)oxazole-4-carboxylate (10), which after deblocking with sodium methoxide and ammonolysis was converted to 2-beta-D-ribofuranosyl-oxazole-4-carboxamide (oxazofurin, 3), an analogue of the antitumor and antiviral C-nucleoside tiazofurin (1). Oxazofurin (3) was found to be cytotoxic toward B16 murine melanoma cells in culture but inactive against murine leukemia P388 and L1210.

  12. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    Science.gov (United States)

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

    2014-01-01

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

  13. A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma.

    Directory of Open Access Journals (Sweden)

    Sergio Arancibia

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

  14. Enhanced anti-tumor activity of a new curcumin-related compound against melanoma and neuroblastoma cells

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    Pastorino Fabio

    2010-06-01

    Full Text Available Abstract Background Sharing the common neuroectodermal origin, melanoma and neuroblastoma are tumors widely diffused among adult and children, respectively. Clinical prognosis of aggressive neuroectodermal cancers remains dismal, therefore the search for novel therapies against such tumors is warranted. Curcumin is a phytochemical compound widely studied for its antioxidant, anti-inflammatory and anti-cancer properties. Recently, we have synthesized and tested in vitro various curcumin-related compounds in order to select new anti-tumor agents displaying stronger and selective growth inhibition activity on neuroectodermal tumors. Results In this work, we have demonstrated that the new α,β-unsaturated ketone D6 was more effective in inhibiting tumor cells growth when compared to curcumin. Normal fibroblasts proliferation was not affected by this treatment. Clonogenic assay showed a significant dose-dependent reduction in both melanoma and neuroblastoma colony formation only after D6 treatment. TUNEL assay, Annexin-V staining, caspases activation and PARP cleavage unveiled the ability of D6 to cause tumor cell death by triggering apoptosis, similarly to curcumin, but with a stronger and quicker extent. These apoptotic features appear to be associated with loss of mitochondrial membrane potential and cytochrome c release. In vivo anti-tumor activity of curcumin and D6 was surveyed using sub-cutaneous melanoma and orthotopic neuroblastoma xenograft models. D6 treated mice exhibited significantly reduced tumor growth compared to both control and curcumin treated ones (Melanoma: D6 vs control: P and D6 vs curcumin P Neuroblastoma: D6 vs both control and curcumin: P . Conclusions Our data indicate D6 as a good candidate to develop new therapies against neural crest-derived tumors.

  15. Oleuropein potentiates anti-tumor activity of cisplatin against HepG2 through affecting proNGF/NGF balance.

    Science.gov (United States)

    Sherif, Iman O; Al-Gayyar, Mohammed M H

    2018-04-01

    Oleuropein is considered as a new chemotherapeutic agent in human hepatocellular carcinoma (HCC) while, its exact underlying molecular mechanism still not yet explored. In addition, cisplatin is a standard anticancer drug against solid tumors with toxic side effects. Therefore, we conducted this study to assess antitumor activity of oleuropein either alone or in combination with cisplatin against HepG2, human HCC cell lines, via targeting pro-NGF/NGF signaling pathway. HepG2 cells were treated with cisplatin (20, 50, 100 μM) and oleuropein (100, 200, 300 and 400 μM) as well as some of the cells were treated with 50 μM cisplatin and different concentrations of oleuropein. Gene expressions of nerve growth factor (NGF), matrix metalloproteinase-7 (MMP-7) and caspase-3 were evaluated by real time-PCR. In addition, protein levels of NGF and pro-form of NGF (pro-NGF) were measured by ELISA while, nitric oxide (NO) content was determined colorimetrically. Cisplatin treatment showed a significant elevation of NO content and pro-NGF protein level with a marked reduction of NGF protein level in addition to the upregulation of caspase-3 along with downregulation of MMP-7 gene expressions in a dose-dependent manner. However, the combination of 50 μM cisplatin and 200 μM oleuropein showed the most potent effect on the molecular level when compared with oleuropein or cisplatin alone. Our results showed for the first time that the anti-tumor activity of oleuropein against HCC could be attributed to influencing the pro-NGF/NGF balance via affecting MMP-7 activity without affecting the gene expression of NGF. Concurrent treatment with both oleuropein and cisplatin could lead to more effective chemotherapeutic combination against HCC. Copyright © 2018 Elsevier Inc. All rights reserved.

  16. Antitumor activity of platinum(II) complexes with histamine and radioiodinated histamine in a transplantable murine adenocarcinoma model

    Energy Technology Data Exchange (ETDEWEB)

    Garnuszek, Piotr [Department of Radiopharmaceuticals, National Medicines Institute, 00-725 Warsaw (Poland)], E-mail: pgarnuszek@il.waw.pl; Karczmarczyk, Urszula; Maurin, Michal [Department of Radiopharmaceuticals, National Medicines Institute, 00-725 Warsaw (Poland)

    2008-07-15

    Purpose: Antitumor activity of the dichloroplatinum(II)-histamine complexes labeled with I-125 or I-131 was investigated in a transplantable murine adenocarcinoma (MA) model. Methods: The tumor model was obtained in C3H/W female mice after subcutaneous inoculation of the tumor cells derived from the mice bearing a mammary tumor of spontaneous origin. Antitumor activities of the platinum-histamine complexes were investigated in three independent experiments, which differed in applied doses of preparations (PtCl{sub 2}Hist, PtCl{sub 2}[{sup 125}I]Hist, PtCl{sub 2}[{sup 131}I]Hist, PtCl{sub 2}Hist/PtCl{sub 2}[{sup 125}I]Hist and PtCl{sub 2}Hist/PtCl{sub 2}[{sup 131}I]Hist), treatment schedules as well as stages of the disease progress in the animals used. Experiment 1 included long-term, multidose treatment with low single doses (treatment duration 31-32 days; 8-10 doses of ca. 0.25{center_dot}MTD{sub Pt} each). Experiment 2 included short-term, multidose treatment with higher single doses (4xca. 0.5{center_dot}MTD{sub Pt} up to Day 13 of the treatment). Experiment 3 included long-term concomitant multidose treatment with higher single doses (9x0.9-0.4{center_dot}MTD{sub Pt} up to Day 33). Results: The long-term treatment with the platinum-histamine preparations revealed inhibiting activity on the tumor growth and size in comparison to control groups. The most intensive and significant antitumor effects were observed for the radioactive complexes. The tumor growth delay factors (GDFs) observed in Experiment 1 were 0.4, 0.7, and 1.2 for PtCl{sub 2}Hist, PtCl{sub 2}Hist/PtCl{sub 2}[{sup 131}I]Hist, and PtCl{sub 2}Hist/PtCl{sub 2}[{sup 125}I]Hist, respectively. Significant (P<.05) prolongations of median survivals (MS) were found in Experiment 2 following the treatment with higher single doses of PtCl{sub 2}Hist and PtCl{sub 2}His/PtCl{sub 2}[{sup 125}I]Hist (Ratio MS{sub tr}/MS{sub con} ca. 1.4). A slightly less potent activity was observed for PtCl{sub 2}Hist

  17. Antitumor activity of platinum(II) complexes with histamine and radioiodinated histamine in a transplantable murine adenocarcinoma model

    International Nuclear Information System (INIS)

    Garnuszek, Piotr; Karczmarczyk, Urszula; Maurin, Michal

    2008-01-01

    Purpose: Antitumor activity of the dichloroplatinum(II)-histamine complexes labeled with I-125 or I-131 was investigated in a transplantable murine adenocarcinoma (MA) model. Methods: The tumor model was obtained in C3H/W female mice after subcutaneous inoculation of the tumor cells derived from the mice bearing a mammary tumor of spontaneous origin. Antitumor activities of the platinum-histamine complexes were investigated in three independent experiments, which differed in applied doses of preparations (PtCl 2 Hist, PtCl 2 [ 125 I]Hist, PtCl 2 [ 131 I]Hist, PtCl 2 Hist/PtCl 2 [ 125 I]Hist and PtCl 2 Hist/PtCl 2 [ 131 I]Hist), treatment schedules as well as stages of the disease progress in the animals used. Experiment 1 included long-term, multidose treatment with low single doses (treatment duration 31-32 days; 8-10 doses of ca. 0.25·MTD Pt each). Experiment 2 included short-term, multidose treatment with higher single doses (4xca. 0.5·MTD Pt up to Day 13 of the treatment). Experiment 3 included long-term concomitant multidose treatment with higher single doses (9x0.9-0.4·MTD Pt up to Day 33). Results: The long-term treatment with the platinum-histamine preparations revealed inhibiting activity on the tumor growth and size in comparison to control groups. The most intensive and significant antitumor effects were observed for the radioactive complexes. The tumor growth delay factors (GDFs) observed in Experiment 1 were 0.4, 0.7, and 1.2 for PtCl 2 Hist, PtCl 2 Hist/PtCl 2 [ 131 I]Hist, and PtCl 2 Hist/PtCl 2 [ 125 I]Hist, respectively. Significant (P 2 Hist and PtCl 2 His/PtCl 2 [ 125 I]Hist (Ratio MS tr /MS con ca. 1.4). A slightly less potent activity was observed for PtCl 2 Hist/PtCl 2 [ 131 I]Hist, and no survival improvement was found for the groups treated mostly with the radiation (PtCl 2 [ 125 I]Hist and PtCl 2 [ 131 I]Hist). The intensive and long-term concomitant scheduling of the radioactive platinum-histamine complexes labeled with I-125 and I-131

  18. Antitumor activity of antisense oligonucleotide p45Skp2 in soft palate carcinoma cell squamous in vitro

    Directory of Open Access Journals (Sweden)

    Supriatno Supriatno

    2013-03-01

    Full Text Available Background: Human soft palate cancers are characterized by a high degree of local invasion and metastasis to the regional lymph nodes. Treatment options for this cancer are limited. However, a new strategy for refractory cancer, gene therapy is watched with keen interest. p45Skp2 gene as a tumor promoter gene is one of target of the oral cancer therapy. To inhibit the activity of p45Skp2 gene is carried-out the genetic engineering via antisense technique. Purpose: To examine the antitumor activity of p45Skp2 antisense (p45Skp2 AS gene therapy in human soft palate [Hamakawa-Inoue (HI] cancer cells. Methods: Pure laboratory experimental study with post test only control group design was conducted as a research design. To investigate the apoptosis induction of p45Skp2 AStransfected cell was evaluated by colorimetric caspase-3 assay and Flow cytometry. Furthermore, to detect the suppression of in vitro HI cell invasion and cell growth of p45Skp2 AS-treatment cell was examined by Boyden chamber kit and MTT assay, respectively. Results: The cell number of p45Skp2 AS-treated HI cell was significant decreased when compared with that of p45Skp2 sense (p45Skp2 S cells (p<0.05. p45Skp2 AS-treated cell induced apoptosis characterized by an increase in the early and late apoptosis, and activation of caspase-3 (p<0.05. Therefore, suppression of HI cell invasion and cell growth were markedly increased by p45Skp2 AS treatment (p<0.05. Conclusion: Antisense oligonucleotide p45Skp2 has a high antitumor activity in human soft palate cancer cell, targeting this molecule could represent a promising new therapeutics approach for this type of cancer.Latar belakang: Kanker palatum lunak mempunyai karakteristik invasi dan metastasis ke limfonodi regional yang tinggi. Pilihan perawatan kanker tersebut masih sangat terbatas. Walaupun demikian, strategi baru untuk penanganan kanker yaitu terapi gen menjadi pilihan utama. Gen p45Skp2 sebagai gen pemacu tumor merupakan salah

  19. Superior anti-tumor activity of the MDM2 antagonist idasanutlin and the Bcl-2 inhibitor venetoclax in p53 wild-type acute myeloid leukemia models

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    Christian Lehmann

    2016-06-01

    Full Text Available Abstract Background Venetoclax, a small molecule BH3 mimetic which inhibits the anti-apoptotic protein Bcl-2, and idasanutlin, a selective MDM2 antagonist, have both shown activity as single-agent treatments in pre-clinical and clinical studies in acute myeloid leukemia (AML. In this study, we deliver the rationale and molecular basis for the combination of idasanutlin and venetoclax for treatment of p53 wild-type AML. Methods The effect of idasanutlin and venetoclax combination on cell viability, apoptosis, and cell cycle progression was investigated in vitro using established AML cell lines. In vivo efficacy was demonstrated in subcutaneous and orthotopic xenograft models generated in female nude or non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice. Mode-of-action analyses were performed by means of cell cycle kinetic studies, RNA sequencing as well as western blotting experiments. Results Combination treatment with venetoclax and idasanutlin results in synergistic anti-tumor activity compared with the respective single-agent treatments in vitro, in p53 wild-type AML cell lines, and leads to strongly superior efficacy in vivo, in subcutaneous and orthotopic AML models. The inhibitory effects of idasanutlin were cell-cycle dependent, with cells arresting in G1 in consecutive cycles and the induction of apoptosis only evident after cells had gone through at least two cell cycles. Combination treatment with venetoclax removed this dependency, resulting in an acceleration of cell death kinetics. As expected, gene expression studies using RNA sequencing showed significant alterations to pathways associated with p53 signaling and cell cycle arrest (CCND1 pathway in response to idasanutlin treatment. Only few gene expression changes were observed for venetoclax treatment and combination treatment, indicating that their effects are mediated mainly at the post-transcriptional level. Protein expression studies demonstrated that

  20. Virosomes of hepatitis B virus envelope L proteins containing doxorubicin: synergistic enhancement of human liver-specific antitumor growth activity by radiotherapy.

    Science.gov (United States)

    Liu, Qiushi; Jung, Joohee; Somiya, Masaharu; Iijima, Masumi; Yoshimoto, Nobuo; Niimi, Tomoaki; Maturana, Andrés D; Shin, Seol Hwa; Jeong, Seong-Yun; Choi, Eun Kyung; Kuroda, Shun'ichi

    2015-01-01

    Bionanocapsules (BNCs) are hollow nanoparticles consisting of hepatitis B virus (HBV) envelope L proteins and have been shown to deliver drugs and genes specifically to human hepatic tissues by utilizing HBV-derived infection machinery. The complex of BNCs with liposomes (LPs), the BNC-LP complexes (a LP surrounded by BNCs in a rugged spherical form), could also become active targeting nanocarriers by the BNC function. In this study, under acidic conditions and high temperature, BNCs were found to fully fuse with LPs (smooth-surfaced spherical form), deploying L proteins with a membrane topology similar to that of BNCs (ie, virosomes displaying L proteins). Doxorubicin (DOX) was efficiently encapsulated via the remote loading method at 14.2%±1.0% of total lipid weight (mean ± SD, n=3), with a capsule size of 118.2±4.7 nm and a ζ-potential of -51.1±1.0 mV (mean ± SD, n=5). When mammalian cells were exposed to the virosomes, the virosomes showed strong cytotoxicity in human hepatic cells (target cells of BNCs), but not in human colon cancer cells (nontarget cells of BNCs), whereas LPs containing DOX and DOXOVES (structurally stabilized PEGylated LPs containing DOX) did not show strong cytotoxicity in either cell type. Furthermore, the virosomes preferentially delivered DOX to the nuclei of human hepatic cells. Xenograft mice harboring either target or nontarget cell-derived tumors were injected twice intravenously with the virosomes containing DOX at a low dose (2.3 mg/kg as DOX, 5 days interval). The growth of target cell-derived tumors was retarded effectively and specifically. Next, the combination of high dose (10.0 mg/kg as DOX, once) with tumor-specific radiotherapy (3 Gy, once after 2 hours) exhibited the most effective antitumor growth activity in mice harboring target cell-derived tumors. These results demonstrated that the HBV-based virosomes containing DOX could be an effective antitumor nanomedicine specific to human hepatic tissues, especially in

  1. Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer.

    Science.gov (United States)

    Song, Dongweon; Chaerkady, Raghothama; Tan, Aik Choon; García-García, Elena; Nalli, Anuradha; Suárez-Gauthier, Ana; López-Ríos, Fernando; Zhang, Xian Feng; Solomon, Anna; Tong, Jeffrey; Read, Margaret; Fritz, Christian; Jimeno, Antonio; Pandey, Akhilesh; Hidalgo, Manuel

    2008-10-01

    Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling.

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

    Energy Technology Data Exchange (ETDEWEB)

    Qi, Huan; Zuo, Dai-Ying; Bai, Zhao-Shi; Xu, Jing-Wen; Li, Zeng-Qiang [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang (China); Shen, Qi-Rong; Wang, Zhi-Wei [Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang (China); Zhang, Wei-Ge, E-mail: zhangweige2000@sina.com [Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang (China); Wu, Ying-Liang, E-mail: yingliang_1016@163.com [Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang (China)

    2014-12-12

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

  3. LB-1 Exerts Antitumor Activity in Pancreatic Cancer by Inhibiting HIF-1α and Stat3 Signaling.

    Science.gov (United States)

    Niu, Fei; Li, Yan; Lai, Fang-Fang; Ni, Lin; Ji, Ming; Jin, Jing; Yang, Han-Ze; Wang, Chao; Zhang, Dong-Ming; Chen, Xiao-Guang

    2015-09-01

    Hypoxia is widely present in pancreatic cancer and subsequently causes the overexpression of hypoxia-inducible factor-1α (HIF-1α) and signal transducer and activator of transcription-3 (Stat3). HIF-1α and Stat3 function cooperatively to regulate a number of downstream genes that are implicated in tumorigenesis. Thus, inhibition of HIF-1α and Stat3 is a potential therapeutic strategy for pancreatic cancer. In this study, we explored how LB-1, a novel triptolide (LA) derivative, exerted its antitumor effect through blockade of HIF-1α and Stat3 signaling. Our data showed that LB-1 was able to inhibit the proliferation and colony formation of Mia-PaCa2 and SW1990 cells. LB-1 suppressed HIF-1α protein accumulation by promoting its proteasome degradation and reducing transactivation. Moreover, the silence of HIF-1α by shRNA partially prevented the proliferation inhibition triggered by LB-1. As expected, LB-1 also decreased Stat3 protein accumulation and blocked the physical interactions between HIF-1α/p300/phosphor-Stat3 (p-Stat3) at the pharmacological concentration to reduce VEGF expression, thereby hypoxia-induced angiogenesis. In the Mia-PaCa2 nude xenograft model, therapeutic treatment with LB-1 significantly inhibited tumor growth and had minimal systemic toxicity compared to the mother drug LA. Furthermore, in accordance with in vitro results, HIF-1α activation and Stat3 expression in tumors were blocked by LB-1 through mTOR-dependent pathway. Taken together, these results illustrate that, as a potent inhibitor of HIF-1α and Stat3 signaling, LB-1 exhibits antitumor effect and could be potentially used to treat pancreatic cancer. © 2015 Wiley Periodicals, Inc.

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

    Science.gov (United States)

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

    2017-08-01

    Resveratrol (Rsv) is widely reported to possess anticarcinogenic properties in a plethora of cellular and animal models having limited toxicity toward normal cells. In the molecular level, Rsv can act as a suppressive agent for several impaired signaling pathways on cancer cells. However, Fukuhara and Miyata have shown a non-proteic reaction of Rsv, which can act as a prooxidant agent in the presence of copper (Cu), causing cellular oxidative stress accompanied of DNA damage. After this discovery, the complex Rsv-Cu was broadly explored as an antitumor mechanism in multiples tumor cell lines. The aim of the study is to explore the anticarcinogenic behavior of resveratrol-Cu(II) complex in MCF-7 cell line. Selectivity of Rsv binding to Cu ions was analyzed by HPLC and UV-VIS. The cells were enriched with concentrations of 10 and 50µM CuSO 4 solution and treated with 25µM of Rsv. Copper uptake after enrichment of cells, as its intracellular distribution in MCF-7 line, was scanned by ICP-MS and TEM-EDS. Cell death and intracellular ROS production were determined by flow cytometry. Different from the extracellular model, no relationship of synergy between Rsv-Cu(II) and reactive oxidative species (ROS) production was detected in vitro. ICP-MS revealed intracellular copper accumulation to both chosen concentrations (0.33±0.09 and 1.18±0.13ppb) but there is no promotion of cell death by Rsv-Cu(II) complex. In addition, significant attenuation of ROS production was detected when cells were exposed to CuSO 4 after Rsv treatment, falling from 7.54% of ROS production when treated only with Rsv to 3.07 and 2.72% with CuSO 4 . Based on these findings antitumor activity of resveratrol when in copper ions presence, is not mediated by Rsv-Cu complex formation in MCF-7 human cell line, suggesting that the antitumoral reaction is dependent of a cancer cellular model. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. Radiation-induced antitumor properties of vitamin B5 (pantothenic acid) and its effect on mitomycin C activity: experiments in vitro.

    Science.gov (United States)

    Schittl, Heike; Getoff, Nikola

    2007-01-01

    Vitamin B5 (pantothenic acid) shows a strongly pronounced antitumor effect under the influence of ionizing radiation. In the frame of experiments in vitro (model: Escherichia coli bacteria, AB1157) performed under the exact knowledge of concentration and kind of the free radicals acting in the various aqueous media (pH 7.4) the following was established: (i) vitamin B5 possesses a very intense antitumor property, (ii) it exerts a strong synergistic effect on mitomycin C (MMC), (iii) the oxidizing species (OH*, O2*-) appears to be most important in the initiation of the observed effect. The generated radiolytic products from vitamin B5 very likely also play an important role in this respect.

  6. Escin, a natural mixture of triterpene saponins, exhibits antitumor activity against hepatocellular carcinoma.

    Science.gov (United States)

    Zhou, Xue-ying; Fu, Feng-hua; Li, Zhen; Dong, Qiu-ju; He, Jie; Wang, Chang-hai

    2009-12-01

    Escin, a mixture of triterpene saponins extracted from Aesculus wilsonii Rehd., was used to analyze the antitumor effect in hepatocellular carcinoma in vivo and in vitro. At a dose of 2.8 mg/kg, escin had a rather high inhibition ratio (43.5 %) on mice H22 tumor growth in vivo. The results of the SRB cell viability assay showed that escin could induce significant concentration- and time-dependent inhibition of HepG (2) cell viability. Disruption of the G (1)/S phase of cell cycle progression accompanied by the induction of apoptosis were also observed in HepG (2) cells following escin treatment. The results of pulse-field gel electrophoresis and Western blot analysis show the induction of caspase-independent apoptosis by escin. This study provides evidence that escin induces cell cycle checkpoint arrest and caspase-independent cell death in HepG (2) cells, in support of its efficacious potential as a chemopreventive agent. Georg Thieme Verlag KG Stuttgart. New York.

  7. Optimal treatment scheduling of ionizing radiation and sunitinib improves the antitumor activity and allows dose reduction

    International Nuclear Information System (INIS)

    Kleibeuker, Esther A; Hooven, Matthijs A ten; Castricum, Kitty C; Honeywell, Richard; Griffioen, Arjan W; Verheul, Henk M; Slotman, Ben J; Thijssen, Victor L

    2015-01-01

    The combination of radiotherapy with sunitinib is clinically hampered by rare but severe side effects and varying results with respect to clinical benefit. We studied different scheduling regimes and dose reduction in sunitinib and radiotherapy in preclinical tumor models to improve potential outcome of this combination treatment strategy. The chicken chorioallantoic membrane (CAM) was used as an angiogenesis in vivo model and as a xenograft model with human tumor cells (HT29 colorectal adenocarcinoma, OE19 esophageal adenocarcinoma). Treatment consisted of ionizing radiation (IR) and sunitinib as single therapy or in combination, using different dose-scheduling regimes. Sunitinib potentiated the inhibitory effect of IR (4 Gy) on angiogenesis. In addition, IR (4 Gy) and sunitinib (4 days of 32.5 mg/kg per day) inhibited tumor growth. Ionizing radiation induced tumor cell apoptosis and reduced proliferation, whereas sunitinib decreased tumor angiogenesis and reduced tumor cell proliferation. When IR was applied before sunitinib, this almost completely inhibited tumor growth, whereas concurrent IR was less effective and IR after sunitinib had no additional effect on tumor growth. Moreover, optimal scheduling allowed a 50% dose reduction in sunitinib while maintaining comparable antitumor effects. This study shows that the therapeutic efficacy of combination therapy improves when proper dose-scheduling is applied. More importantly, optimal treatment regimes permit dose reductions in the angiogenesis inhibitor, which will likely reduce the side effects of combination therapy in the clinical setting. Our study provides important leads to optimize combination treatment in the clinical setting

  8. In Vitro Antitumor Activity of Aloperine on Human Thyroid Cancer Cells through Caspase-Dependent Apoptosis

    Directory of Open Access Journals (Sweden)

    Ying-Ray Lee

    2018-01-01

    Full Text Available The global incidence of thyroid cancer, one of the most common endocrine malignancies, is especially high among women. Although most patients with thyroid cancers exhibit a good prognosis with standard treatment, there are no effective therapies for patients with anaplastic thyroid cancers or cancers that have reached an advanced or recurrent level. Therefore, it is important to develop highly effective compounds for treating such patients. Aloperine, a natural compound isolated from Sophora alopecuroides, has been reported to possess antioxidant, anti-inflammatory, anti-neuronal injury, anti-renal injury, antitumor, anti-allergic, and antiviral properties. In this study, we show that aloperine can inhibit cell growth in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers. Moreover, it could suppress in vitro tumorigenesis and promote cellular apoptosis. Further analysis demonstrated the involvement of caspase-dependent apoptosis, including intrinsic and/or extrinsic pathways, in aloperine-induced cellular apoptosis. However, cell cycle regulation was not detected with aloperine treatment. This study suggests the potential therapeutic use of aloperine in human anaplastic thyroid cancers and multidrug-resistant papillary thyroid cancers.

  9. In vitro and in vivo antitumor activity of a novel porphyrin-based photosensitizer for photodynamic therapy.

    Science.gov (United States)

    Chen, Jing-Jing; Hong, Ge; Gao, Li-Jing; Liu, Tian-Jun; Cao, Wen-Jun

    2015-09-01

    Photodynamic therapy (PDT) is a promising treatment in cancer therapy, based on the use of a photosensitizer activated by visible light in the presence of oxygen. Nowadays significant research efforts have been focused on finding a new photosensitizer. In the present paper, the antitumor effects of a novel porphyrin-based photosensitizer, {Carboxymethyl-[2-(carboxymethyl-{[4-(10,15,20-triphenylporphyrin-5-yl)-phenylcarbamoyl]-methyl}-amino)-ethyl]-amino}-acetic acid (ATPP-EDTA) on two types of human malignant tumor cells in vitro and a gastric cancer model in nude mice, were evaluated. The PDT efficacy with ATPP-EDTA in vitro was assessed by MTT assay. The intracellular accumulation was detected with fluorescence spectrometer, and the intracellular distribution was determined by laser scanning confocal microscopy. The mode of cell death was investigated by Hoechst 33342 staining and flow cytometer. BGC823-derived xenograft tumor model was established to explore the in vivo antitumor effects of ATPP-EDTA. ATPP-EDTA exhibited intense phototoxicity on both cell lines in vitro in concentration- and light dose-dependent manners meanwhile imposing minimal dark cytotoxicity. The accumulation of ATPP-EDTA in two malignant cell lines was time-dependent and prior compared to normal cells. It was mainly localized at lysosomes, but induced cell death by apoptotic pathway. ATPP-EDTA significantly inhibited the growth of BGC823 tumors in nude mice (160 mW/cm(2), 100 J/cm(2)). Present studies suggest that ATPP-EDTA is an effective photosensitizer for PDT to tumors. It distributed in lysosomes and caused cell apoptosis. ATPP-EDTA, as a novel photosensitizer, has a great potential for human gastric cancer treatment in PDT and deserves further investigations.

  10. Antitumor activity of sequence-specific alkylating agents: pyrolle-imidazole CBI conjugates with indole linker.

    Science.gov (United States)

    Shinohara, Ken-ichi; Bando, Toshikazu; Sasaki, Shunta; Sakakibara, Yogo; Minoshima, Masafumi; Sugiyama, Hiroshi

    2006-03-01

    DNA-targeting agents, including cisplatin, bleomycin and mitomycin C, are used routinely in cancer treatments. However, these drugs are extremely toxic, attacking normal cells and causing severe side effects. One important question to consider in designing anticancer agents is whether the introduction of sequence selectivity to DNA-targeting agents can improve their efficacy as anticancer agents. In the present study, the growth inhibition activities of an indole-seco 1,2,9,9a-tetrahydrocyclopropa[1,2-c]benz[1,2-e]indol-4-one (CBI) (1) and five conjugates with hairpin pyrrole-imidazole polyamides (2-6), which have different sequence specificities for DNA alkylation, were compared using 10 different cell lines. The average values of -log GI50 (50% growth inhibition concentration) for compounds 1-6 against the 10 cell lines were 8.33, 8.56, 8.29, 8.04, 8.23 and 8.83, showing that all of these compounds strongly inhibit cell growth. Interestingly, each alkylating agent caused significantly different growth inhibition patterns with each cell line. In particular, the correlation coefficients between the -log GI50 of compound 1 and its conjugates 2-6 showed extremely low values (Ralkylation lead to marked differences in biological activity. Comparison of the correlation coefficients between compounds 6 and 7, with the same sequence specificity as 6, and MS-247, with sequence specificity different from 6, when used against a panel of 37 human cancer cell lines further confirmed the above hypothesis.

  11. Highly active microbial phosphoantigen induces rapid yet sustained MEK/Erk- and PI-3K/Akt-mediated signal transduction in anti-tumor human gammadelta T-cells.

    Directory of Open Access Journals (Sweden)

    Daniel V Correia

    efficient cancer immunotherapy strategies critically depends on our capacity to maximize anti-tumor effector T-cell responses. By characterizing the intracellular mechanisms of HMB-PP-mediated activation of the highly cytotoxic Vgamma9(+ T-cell subset, our data strongly support the usage of this microbial antigen in novel cancer clinical trials.

  12. Study on antitumor, antioxidant and immunoregulatory activities of the purified polyphenols from pinecone of Pinus koraiensis on tumor-bearing S180 mice in vivo.

    Science.gov (United States)

    Yi, Juanjuan; Qu, Hang; Wu, Yunzhou; Wang, Zhenyu; Wang, Lu

    2017-01-01

    Pinecone polyphenols are bioactive dietary constituents that enhance health and help prevent and treat cancer through improving antioxidant and immunoregulatory activities. This study was designed to investigate the antitumor, antioxidant and immunoregulatory activities of the 40% ethanol eluent of polyphenols from pinecone of pinus koraiensis (PPP-40) in Sarcoma 180 (S180)-bearing mice models in vivo. The results of antitumor activity indicated that PPP-40 significantly inhibited S180 tumor growth and the dose of 150mg/kg exhibited the highest antitumor activity. Moreover, TdT-mediated dUTP nick end labeling (TUNEL) assay results further confirmed the apoptosis of S180 tumor cells. In addition, PPP-40 could obviously promote the expressions of Bax protein and inhibit the Bcl-2 protein, accordingly improve the expressions of activated Caspase-3 as well, which resulted in the activation of mitochondrial apoptotic pathway of tumor cells in S180 mice eventually. The results of antioxidant activity showed that the S180 mice treated with PPP-40 had the higher superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, the more glutathione (GSH) content, and the lower malondialdehyde (MDA) level in plasma comparing with non-treated control group. Moreover, the administration with PPP-40 (150mg/kg) significantly accelerated the proliferation of splenocytes (p<0.01) and increased the monocyte phagocytosis activity in vivo simultaneously. These results revealed that PPP-40 exerts an effective antitumor activity by activating the mitochondrial apoptotic pathway and improving the antioxidant and immunoregulatory activities. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Development of a Fully Human Anti-PDGFRβ Antibody That Suppresses Growth of Human Tumor Xenografts and Enhances Antitumor Activity of an Anti-VEGFR2 Antibody

    Directory of Open Access Journals (Sweden)

    Juqun Shen

    2009-06-01

    Full Text Available Platelet-derived growth factor receptor β (PDGFRβ is upregulated in most of solid tumors. It is expressed by pericytes/smooth muscle cells, fibroblast, macrophage, and certain tumor cells. Several PDGF receptor-related antagonists are being developed as potential antitumor agents and have demonstrated promising antitumor activity in both preclinical and clinical settings. Here, we produced a fully human neutralizing antibody, IMC-2C5, directed against PDGFRβ from an antibody phage display library. IMC-2C5 binds to both human and mouse PDGFRβ and blocks PDGF-B from binding to the receptor. IMC-2C5 also blocks ligand-stimulated activation of PDGFRβ and downstream signaling molecules in tumor cells. In animal studies, IMC-2C5 significantly delayed the growth of OVCAR-8 and NCI-H460 human tumor xenografts in nude mice but failed to show antitumor activities in OVCAR-5 and Caki-1 xenografts. Our results indicate that the antitumor efficacy of IMC-2C5 is primarily due to its effects on tumor stroma, rather than on tumor cells directly. Combination of IMC-2C5 and DC101, an anti-mouse vascular endothelial growth factor receptor 2 antibody, resulted in significantly enhanced antitumor activity in BxPC-3, NCI-H460, and HCT-116 xenografts, compared with DC101 alone, and the trend of additive effects to DC101 treatment in several other tumor models. ELISA analysis of NCI-H460 tumor homogenates showed that IMC-2C5 attenuated protein level of vascular endothelial growth factor and basic fibroblast growth factor elevated by DC101 treatment. Finally, IMC-2C5 showed a trend of additive effects when combined with DC101/chemotherapy in MIA-PaCa-2 and NCI-H460 models. Taken together, these results lend great support to the use of PDGFRβ antagonists in combination with other antiangiogenic agents in the treatment of a broad range of human cancers.

  14. Curcumin enhances the antitumor effect of ABT-737 via activation of the ROS-ASK1-JNK pathway in hepatocellular carcinoma cells.

    Science.gov (United States)

    Zheng, Ruinian; You, Zhijian; Jia, Jun; Lin, Shunhuan; Han, Shuai; Liu, Aixue; Long, Huidong; Wang, Senming

    2016-02-01

    At present, the therapeutic treatment strategies for patients with hepatocellular carcinoma (HCC) remain unsatisfactory, and novel methods are urgently required to treat this disease. Members of the B cell lymphoma (Bcl)-2 family are anti‑apoptotic proteins, which are commonly expressed at high levels in certain HCC tissues and positively correlate with the treatment resistance of patients with HCC. ABT-737, an inhibitor of Bcl-2 anti-apoptotic proteins, has been demonstrated to exhibit potent antitumor effects in several types of tumor, including HCC. However, treatment with ABT-737 alone also activates certain pro-survival signaling pathways, which attenuate the antitumor validity of ABT-737. Curcumin, which is obtained from Curcuma longa, is also an antitumor potentiator in multiple types of cancer. In the present study, the synergistic effect of curcumin and ABT-737 on HCC cells was investigated for the first time, to the best of our knowledge. It was found that curcumin markedly enhanced the antitumor effects of ABT-737 on HepG2 cells, which was partially dependent on the induction of apoptosis, according to western blot analysis and flow cytometric apoptosis analysis. In addition, the sustained activation of the ROS-ASK1-c-Jun N-terminal kinase pathway may be an important mediator of the synergistic effect of curcumin and ABT-737. Collectively, these results indicated that the combination of curcumin and ABT-737 can efficaciously induce the death of HCC cells, and may offer a potential treatment strategy for patients with HCC.

  15. Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer.

    Science.gov (United States)

    Chen, Weiqian; Zou, Peng; Zhao, Zhongwei; Chen, Xi; Fan, Xiaoxi; Vinothkumar, Rajamanickam; Cui, Ri; Wu, Fazong; Zhang, Qianqian; Liang, Guang; Ji, Jiansong

    2016-12-01

    Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS) inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER) pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  16. DNA interaction, antitumor and antimicrobial activities of three-dimensional chitosan ring produced from the body segments of a diplopod.

    Science.gov (United States)

    Kaya, Murat; Akyuz, Bahar; Bulut, Esra; Sargin, Idris; Tan, Gamze; Erdonmez, Demet; Maheta, Mansi; Satkauskas, Saulius; Mickevičius, Saulius

    2016-08-01

    Commercially available chitins and the chitin isolated from mushrooms, insect cuticles, shells of shrimp, crab and crayfish reported in the literature are in forms of powder, flake or granule. Three-dimensional chitins have been only known from the sponges but still three-dimensional chitosan has not been reported yet. In this study, we produced three-dimensional chitin and chitosan rings from the body segments of a diplopod species (Julus terrestris). Obtained chitin and chitosan rings were characterized (by FT-IR, SEM, TGA, XRD, dilute solution viscometry and EA) and compared with commercial chitin and chitosan. The interactions with plasmid DNA was studied at varying concentrations of chitosan (0.04, 0.4 and 4mg/mL). Antitumor activity tests were conducted (L929 and HeLa), low cytotoxicity and high antiproliferative activity was observed. Antimicrobial activities of J. terrestris chitosan were investigated on twelve microorganisms and maximum inhibition (15.6±1.154mm) was recorded for common human pathogen Staphylococcus aureus. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers.

    Science.gov (United States)

    Tang, Zhiyu; Yuan, Xi; Du, Rong; Cheung, Shing-Hu; Zhang, Guoliang; Wei, Jing; Zhao, Yuan; Feng, Yingcai; Peng, Hao; Zhang, Yi; Du, Yunguang; Hu, Xiaoxia; Gong, Wenfeng; Liu, Yong; Gao, Yajuan; Liu, Ye; Hao, Rui; Li, Shengjian; Wang, Shaohui; Ji, Jiafu; Zhang, Lianhai; Li, Shuangxi; Sutton, David; Wei, Min; Zhou, Changyou; Wang, Lai; Luo, Lusong

    2015-10-01

    Oncogenic BRAF, which drives cell transformation and proliferation, has been detected in approximately 50% of human malignant melanomas and 5% to 15% of colorectal cancers. Despite the remarkable clinical activities achieved by vemurafenib and dabrafenib in treating BRAF(V600E) metastatic melanoma, their clinical efficacy in BRAF(V600E) colorectal cancer is far less impressive. Prior studies suggested that feedback activation of EGFR and MAPK signaling upon BRAF inhibition might contribute to the relative unresponsiveness of colorectal cancer to the first-generation BRAF inhibitors. Here, we report characterization of a dual RAF kinase/EGFR inhibitor, BGB-283, which is currently under clinical investigation. In vitro, BGB-283 potently inhibits BRAF(V600E)-activated ERK phosphorylation and cell proliferation. It demonstrates selective cytotoxicity and preferentially inhibits proliferation of cancer cells harboring BRAF(V600E) and EGFR mutation/amplification. In BRAF(V600E) colorectal cancer cell lines, BGB-283 effectively inhibits the reactivation of EGFR and EGFR-mediated cell proliferation. In vivo, BGB-283 treatment leads to dose-dependent tumor growth inhibition accompanied by partial and complete tumor regressions in both cell line-derived and primary human colorectal tumor xenografts bearing BRAF(V600E) mutation. These findings support BGB-283 as a potent antitumor drug candidate with clinical potential for treating colorectal cancer harboring BRAF(V600E) mutation. ©2015 American Association for Cancer Research.

  18. Anti-helminth compound niclosamide downregulates Wnt Signaling and elicits antitumor responses in tumors with activating APC mutations

    Science.gov (United States)

    Osada, Takuya; Chen, Minyong; Yang, Xiao Yi; Spasojevic, Ivan; Vandeusen, Jeffrey B.; Hsu, David; Clary, Bryan M.; Clay, Timothy M.; Chen, Wei; Morse, Michael A.; Lyerly, H. Kim

    2011-01-01

    Wnt/β-catenin pathway activation caused by APC mutations occurs in approximately 80% of sporadic colorectal cancers. The anti-helminth compound niclosamide downregulates components of the Wnt pathway, specifically Dishevelled-2 (Dvl2) expression, resulting in diminished downstream β-catenin signaling. In this study, we determined if niclosamide could inhibit the Wnt/ β-catenin pathway in human colorectal cancers and whether its inhibition might elicit antitumor effects in the presence of APC mutations. We found that niclosamide inhibited Wnt/ β-catenin pathway activation, downregulated Dvl2, decreased downstream β-catenin signaling and exerted anti-proliferative effects in human colon cancer cell lines and colorectal cancer cells isolated by surgical resection of metastatic disease, regardless of mutations in APC. In contrast, inhibition of NF-κB or mTOR did not exert similar anti-proliferative effects in these colorectal cancer model systems. In mice implanted with human colorectal cancer xenografts, orally administered niclosamide was well tolerated, achieved plasma and tumor levels associated with biologic activity and led to tumor control. Our findings support clinical explorations to reposition niclosamide for treatment of colorectal cancer. PMID:21531761

  19. Enhanced antitumor activity of combined pretargeted radioimmunotherapy and paclitaxel in medullary thyroid cancer xenograft.

    Science.gov (United States)

    Kraeber-Bodéré, Françoise; Saï-Maurel, Catherine; Campion, Loïc; Faivre-Chauvet, Alain; Mirallié, Eric; Chérel, Michel; Supiot, Stéphane; Barbet, Jacques; Chatal, Jean-François; Thédrez, Philippe

    2002-02-01

    A significant antitumor effect associated with moderate toxicity was obtained previously with anticarcinoembryonic antigen x antidiethylene-triaminepentaacetic acid (DTPA)-indium F6-734 bispecific antibody and iodine-131-labeled DTPA-indium bivalent hapten in an animal model of medullary thyroid cancer (MTC). The purpose of this study was to determine whether the cytotoxic agents doxorubicin and paclitaxel, also known as radiosensitizers, improve efficacy of pretargeted radioimmunotherapy (RIT) in experimental MTC. Nude mice bearing TT MTC xenograft were treated with F6-734 and iodine-131-labeled DTPA-indium bivalent hapten injected 48 h apart with or without doxorubicin or paclitaxel. The maximum tolerated dose (MTD) of RIT was 92.5 MBq (as determined previously) and that of doxorubicin and paclitaxel 200 and 1000 micrograms, respectively. A control group received no treatment. Animal weight, hematotoxicity, tumor volume, and serum calcitonin were monitored for 5 months. Tumor growth inhibition induced by drugs alone, RIT alone, or combined therapy was characterized by measuring relative tumor volume 20, 40, and 60 days after treatment to detect additivity or synergism. Mean tumor volume doubling time (MTVDT) was 13 +/- 4 days in the control group, 15 +/- 8 days in the group treated with the MTD of doxorubicin, and 32 +/- 13 days in the group treated with the MTD of paclitaxel. After RIT alone at 92.5 MBq, MTVDT was 86 +/- 22 days. After RIT at 74 MBq (80% of MTD), MTVDT was 56 +/- 10 days. MTVDT was not significantly different from this value after RIT plus doxorubicin, 60 +/- 16 days (65 and 100% of the respective single-agent MTDs). Combination of RIT with paclitaxel (65 and 100% of the respective single-agent MTDs) prolonged the suppression of tumor growth. One complete response was observed, and MTVDT was 114 +/- 44 days. This value was significantly longer than the value obtained with RIT alone at 74 MBq (P < 0.05) or with RIT combined with doxorubicin (P

  20. Examination of Potential Anti-Tumor Activity of N-Thiolated b-Lactam Antibiotics in Nude Mice Bearing Human Breast Tumors

    Science.gov (United States)

    2006-08-01

    N-methylthiolated beta-lactams the name "penicillin" in 1928 after his discovery that molds from the Penicillium genus secrete powerful antimicrobial ...carboxyl grouin close pr ximin to tlhectam l initro’gen, which is required for antimicrobial activity . These antibiotics act as bactericidal agents...AD AWARD NUMBER: W81XWH-04-1-0688 TITLE: Examination of Potential Anti-Tumor Activity of N-Thiolated b-Lactam Antibiotics in Nude Mice Bearing Human

  1. Novel histone deacetylase inhibitor AR-42 exhibits antitumor activity in pancreatic cancer cells by affecting multiple biochemical pathways.

    Directory of Open Access Journals (Sweden)

    Yi-Jin Chen

    Full Text Available Pancreatic cancer is one of the most lethal types of cancer with a 5-year survival rate of ~5%. Histone deacetylases (HDACs participate in many cellular processes, including carcinogenesis, and pharmacological inhibition of HDACs has emerged as a potential therapeutic strategy. In this study, we explored antitumor activity of the novel HDAC inhibitor AR-42 in pancreatic cancer.Human pancreatic cancer cell lines BxPC-3 and PANC-1 were used in this study. Real-time PCR, RT-PCR, and western blotting were employed to investigate expression of specific genes and proteins, respectively. Translocation of apoptosis-inducing factor was investigated by immunofluorescence and subcellular fractionation. The number of apoptotic cells, cell cycle stages, and reactive oxygen species (ROS generation levels were determined by flow cytometry. Cell invasiveness was examined by the Matrigel invasion assay. Efficacy of AR-42 in vivo was evaluated by utilizing BxPC-3 xenograft mouse model.AR-42 inhibited pancreatic cancer cell proliferation by causing G2/M cell cycle arrest via regulating expression levels of genes and proteins involved in cell cycle. AR-42 also induced ROS generation and DNA damage, triggering apoptosis of pancreatic cancer cells via both caspase-3-dependent and caspase-3-independent pathways. In addition, AR-42 increased expression levels of negative regulators of p53 (miR-125b, miR-30d, and miR33, which could contribute to lower expression level of mutant p53 in pancreatic cancer cells. Cell invasion assay showed that AR-42 reduced cancer cell aggressiveness and significantly diminished BxPC-3 xenograft tumor growth in vivo.AR-42, a novel HDAC inhibitor, inhibited pancreatic cancer cells by regulating p53 expression, inducing cell cycle arrest, particularly at the G2/M stage, and activating multiple apoptosis pathways. Additionally, AR-42 inhibited cell invasiveness and potently suppressed pancreatic cancer tumors in vivo. We conclude that by

  2. HDAC inhibitor L-carnitine and proteasome inhibitor bortezomib synergistically exert anti-tumor activity in vitro and in vivo.

    Directory of Open Access Journals (Sweden)

    Hongbiao Huang

    Full Text Available Combinations of proteasome inhibitors and histone deacetylases (HDAC inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by flow cytometry and MTS, respectively. Gene, mRNA expression and protein levels were detected by gene microarray, quantitative real-time PCR and Western blot, respectively. The effect of Vel on the acetylation of histone H3 associated with the p21(cip1 gene promoter was examined by using ChIP assay and proteasome peptidase activity was detected by cell-based chymotrypsin-like (CT-like activity assay. Here we report that (i the combination of LC and Vel synergistically induces cytotoxicity in vitro; (ii the combination also synergistically inhibits tumor growth in vivo; (iii two major pathways are involved in the synergistical effects of the combinational treatment: increased p21(cip1 expression and histone acetylation in vitro and in vivo and enhanced Vel-induced proteasome inhibition by LC. The synergistic effect of LC and Vel in cancer therapy should have great potential in the future clinical trials.

  3. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway

    Energy Technology Data Exchange (ETDEWEB)

    An, Hyunsook; Kim, Ji Young; Lee, Nahyun; Cho, Youngkwan; Oh, Eunhye [Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Seo, Jae Hong, E-mail: cancer@korea.ac.kr [Division of Medical Oncology, Department of Internal Medicine, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of); Brain Korea 21 Program for Biomedicine Science, Korea University College of Medicine, Korea University, Seoul 152-703 (Korea, Republic of)

    2015-10-30

    Cancer stem cells (CSCs) play important roles in the formation, growth and recurrence of tumors, particularly following therapeutic intervention. Salinomycin has received recent attention for its ability to target breast cancer stem cells (BCSCs), but the mechanisms of action involved are not fully understood. In the present study, we sought to investigate the mechanisms responsible for salinomycin's selective targeting of BCSCs and its anti-tumor activity. Salinomycin suppressed cell viability, concomitant with the downregulation of cyclin D1 and increased p27{sup kip1} nuclear accumulation. Mammosphere formation assays revealed that salinomycin suppresses self-renewal of ALDH1-positive BCSCs and downregulates the transcription factors Nanog, Oct4 and Sox2. TUNEL analysis of MDA-MB-231-derived xenografts revealed that salinomycin administration elicited a significant reduction in tumor growth with a marked downregulation of ALDH1 and CD44 levels, but seemingly without the induction of apoptosis. Our findings shed further light on the mechanisms responsible for salinomycin's effects on BCSCs. - Highlights: • Salinomycin suppresses mammosphere formation. • Salinomycin reduces ALDH1 activity and downregulates Nanog, Oct4 and Sox2. • Salinomycin targets BCSCs via an apoptosis-independent pathway.

  4. Effects of nanoparticle size on antitumor activity of 10-hydroxycamptothecin-conjugated gold nanoparticles: in vitro and in vivo studies.

    Science.gov (United States)

    Bao, Hanmei; Zhang, Qing; Xu, Hui; Yan, Zhao

    2016-01-01

    Gold nanoparticles (AuNPs) have emerged as a promising anticancer drug delivery scaffold. However, some controversial points still require further investigation before clinical use. A complete understanding of how animal cells interact with drug-conjugated AuNPs of well-defined sizes remains poorly understood. In this study, we prepared a series of 10-hydroxycamptothecin (HCPT)-AuNP conjugates of different sizes and compared their cytotoxic effect in vitro and antitumor effect in vivo. Transmission electron micrographs showed that the NPs had a round, regular shape with a mean diameter of ~10, 25, and 50 nm. An in vitro drug release study showed that HCPT was continuously released for 120 hours. HCPT-AuNPs showed greater cytotoxic effects on the MDA-MB-231 cell line compared with an equal dose of free HCPT. Notably, HCPT-AuNPs of an average diameter of 50 nm (HCPT-AuNPs-50) had the greatest effect. Furthermore, administration of HCPT-AuNPs-50 showed the most tumor-suppressing activity against MDA-MB-231 tumor in mice among all treatment groups. The results indicate that AuNPs not only act as a carrier but also play an active role in mediating biological effects. This work gives important insights into the design of nanoscale delivery and therapeutic systems.

  5. Origin of anti-tumor activity of the cysteine-containing GO peptides and further optimization of their cytotoxic properties

    Science.gov (United States)

    Tyuryaeva, Irina I.; Lyublinskaya, Olga G.; Podkorytov, Ivan S.; Skrynnikov, Nikolai R.

    2017-01-01

    Antitumor GO peptides have been designed as dimerization inhibitors of prominent oncoprotein mucin 1. In this study we demonstrate that activity of GO peptides is independent of the level of cellular expression of mucin 1. Furthermore, these peptides prove to be broadly cytotoxic, causing cell death also in normal cells such as dermal fibroblasts and endometrial mesenchymal stem cells. To explore molecular mechanism of their cytotoxicity, we have designed and tested a number of new peptide sequences containing the key CxC or CxxC motifs. Of note, these sequences bear no similarity to mucin 1 except that they also contain a pair of proximal cysteines. Several of the new peptides turned out to be significantly more potent than their GO prototypes. The results suggest that cytotoxicity of these peptides stems from their (moderate) activity as disulfide oxidoreductases. It is expected that such peptides, which we have termed DO peptides, are involved in disulfide-dithiol exchange reaction, resulting in formation of adventitious disulfide bridges in cell proteins. In turn, this leads to a partial loss of protein function and rapid onset of apoptosis. We anticipate that coupling DO sequences with tumor-homing transduction domains can create a potentially valuable new class of tumoricidal peptides.

  6. Screening for Genes Coding for Putative Antitumor Compounds, Antimicrobial and Enzymatic Activities from Haloalkalitolerant and Haloalkaliphilic Bacteria Strains of Algerian Sahara Soils

    Directory of Open Access Journals (Sweden)

    Okba Selama

    2014-01-01

    Full Text Available Extreme environments may often contain unusual bacterial groups whose physiology is distinct from those of normal environments. To satisfy the need for new bioactive pharmaceuticals compounds and enzymes, we report here the isolation of novel bacteria from an extreme environment. Thirteen selected haloalkalitolerant and haloalkaliphilic bacteria were isolated from Algerian Sahara Desert soils. These isolates were screened for the presence of genes coding for putative antitumor compounds using PCR based methods. Enzymatic, antibacterial, and antifungal activities were determined by using cultural dependant methods. Several of these isolates are typical of desert and alkaline saline soils, but, in addition, we report for the first time the presence of a potential new member of the genus Nocardia with particular activity against the yeast Saccharomyces cerevisiae. In addition to their haloalkali character, the presence of genes coding for putative antitumor compounds, combined with the antimicrobial activity against a broad range of indicator strains and their enzymatic potential, makes them suitable for biotechnology applications.

  7. Antitumor activity and biodistribution of cisplatin nanocapsules in nude mice bearing human ovarian carcinoma xenografts

    NARCIS (Netherlands)

    Staffhorst, R.W.H.M.; van der Born, K.; Erkelens, C.A.M.; Hamelers, I.H.L.; Peters, G.J.; Boven, E.; de Kroon, A.I.P.M.

    2008-01-01

    Cisplatin nanocapsules represent a novel lipid formulation of the anticancer drug cis-diamminedichloridoplatinum(II) (cisplatin), characterized by an unprecedented cisplatin-tolipid molar ratio, and exhibiting strongly increased in-vitro cytotoxicity compared with the free drug. In this study,

  8. Enhancement of the anti-tumor activity of FGFR1 inhibition in squamous cell lung cancer by targeting downstream signaling involved in glucose metabolism

    Science.gov (United States)

    Fumarola, Claudia; Cretella, Daniele; La Monica, Silvia; Bonelli, Mara A.; Alfieri, Roberta; Caffarra, Cristina; Quaini, Federico; Madeddu, Denise; Falco, Angela; Cavazzoni, Andrea; Digiacomo, Graziana; Mazzaschi, Giulia; Vivo, Valentina; Barocelli, Elisabetta; Tiseo, Marcello; Petronini, Pier Giorgio; Ardizzoni, Andrea

    2017-01-01

    Fibroblast Growth Factor Receptor (FGFR) signaling is a complex pathway which controls several processes, including cell proliferation, survival, migration, and metabolism. FGFR1 signaling is frequently deregulated via amplification/over-expression in NSCLC of squamous histotype (SQCLC), however its inhibition has not been successfully translated in clinical setting. We determined whether targeting downstream signaling implicated in FGFR1 effects on glucose metabolism potentiates the anti-tumor activity of FGFR1 inhibition in SQCLC. In FGFR1 amplified/over-expressing SQCLC cell lines, FGF2-mediated stimulation of FGFR1 under serum-deprivation activated both MAPK and AKT/mTOR pathways and increased glucose uptake, glycolysis, and lactate production, through AKT/mTOR-dependent HIF-1α accumulation and up-regulation of GLUT-1 glucose transporter. These effects were hindered by PD173074 and NVP-BGJ398, selective FGFR inhibitors, as well as by dovitinib, a multi-kinase inhibitor. Glucose metabolism was hampered by the FGFR inhibitors also under hypoxic conditions, with consequent inhibition of cell proliferation and viability. In presence of serum, glucose metabolism was impaired only in cell models in which FGFR1 inhibition was associated with AKT/mTOR down-regulation. When the activation of the AKT/mTOR pathway persisted despite FGFR1 down-regulation, the efficacy of NVP-BGJ398 could be significantly improved by the combination with NVP-BEZ235 or other inhibitors of this signaling cascade, both in vitro and in xenotransplanted nude mice. Collectively our results indicate that inhibition of FGFR1 signaling impacts on cancer cell growth also by affecting glucose energy metabolism. In addition, this study strongly suggests that the therapeutic efficacy of FGFR1 targeting molecules in SQCLC may be implemented by combined treatments tackling on glucose metabolism. PMID:29190880

  9. SYNTHESIS, CHARACTERIZATION AND ANTITUMOR ACTIVITY OF A Ca (II COORDINATION POLYMER BASED ON 3-AMINO-2-PYRAZINECARBOXYLIC ACID

    Directory of Open Access Journals (Sweden)

    XI-SHI TAI

    2015-10-01

    Full Text Available A new Ca(II coordination polymer has been obtained by reaction of Ca(ClO42·H2O with 3-amino-2-pyrazinecarboxylic acid in CH3CH2OH/H2O. It was characterized by IR, 1HNMR, thermal analysis and X-ray single crystal diffraction analysis. X-ray analysis reveals that each Ca(II center is seven-coordination with a N2O5 distorted pentagonal bipyramidal coordination environment. The Ca(II ions are linked through the O atoms of 3-amino-2-pyrazinecarboxylic acid ligands to form 1D chain structure. And then a 3D network structure is constructed by hydrogen bonds and π-π stacking. The antitumor activity of 3-amino-2-pyrazinecarboxylic acid ligand and its Ca(II coordination polymer against human intestinal adenocarcinoma HCT-8 cells, lung adenocarcinoma HCT-116 cells and human lung adenocarcinoma A549 cells line have been investigated.

  10. Effect of Tea Polyphenol Compounds on Anticancer Drugs in Terms of Anti-Tumor Activity, Toxicology, and Pharmacokinetics.

    Science.gov (United States)

    Cao, Jianhua; Han, Jie; Xiao, Hao; Qiao, Jinping; Han, Mei

    2016-12-14

    Multidrug resistance and various adverse side effects have long been major problems in cancer chemotherapy. Recently, chemotherapy has gradually transitioned from mono-substance therapy to multidrug therapy. As a result, the drug cocktail strategy has gained more recognition and wider use. It is believed that properly-formulated drug combinations have greater therapeutic efficacy than single drugs. Tea is a popular beverage consumed by cancer patients and the general public for its perceived health benefits. The major bioactive molecules in green tea are catechins, a class of flavanols. The combination of green tea extract or green tea catechins and anticancer compounds has been paid more attention in cancer treatment. Previous studies demonstrated that the combination of chemotherapeutic drugs and green tea extract or tea polyphenols could synergistically enhance treatment efficacy and reduce the adverse side effects of anticancer drugs in cancer patients. In this review, we summarize the experimental evidence regarding the effects of green tea-derived polyphenols in conjunction with chemotherapeutic drugs on anti-tumor activity, toxicology, and pharmacokinetics. We believe that the combination of multidrug cancer treatment with green tea catechins may improve treatment efficacy and diminish negative side effects.

  11. Antitumoral activity of polysaccharide isolated from Cyttaria johowii on the growth of sarcoma 180 in normal and splenectomized mice.

    Science.gov (United States)

    Chasseing, N A; Lederkremer, R; Couto, A; Rumi, L S

    1986-01-01

    The antitumoral activity of the polysaccharide (PCj3) isolated from the Cyttaria johowii fungus on the growth of solid Sarcoma 180 (S180) in normal and splenectomized BALB/c mice was studied, observing that this treatment inhibited tumor growth in normal and splenectomized mice. At the same time, the effect of PCj3 on peripheral blood leukocyte populations on the 8th, 15th and 25th day of the experiment was evaluated. Results obtained on day 8 showed that all groups inoculated with S180 suffered an increase in the number of lymphocytes and neutrophils, corresponding the greatest values to splenectomized tumor bearing mice treated with PCj3. Neutrophils increase continued in all animals even without PCj3 treatment until the end of the experiment, while lymphocytosis was only maintained in the splenectomized groups. There was an increase in the number of monocytes on day 8 caused by PCj3 treatment with respect to normal values. It was concluded that PCj3 treatment more effectively delayed S180 growth in splenectomized mice, increasing the survival days as well as the lymphocytes, neutrophils and monocytes values on the 8th day of tumor growth with respect to the other groups.

  12. Oroxylin A induced apoptosis of human hepatocellular carcinoma cell line HepG2 was involved in its antitumor activity

    International Nuclear Information System (INIS)

    Hu Yang; Yang Yong; You Qidong; Liu Wei; Gu Hongyan; Zhao Li; Zhang Kun; Wang Wei; Wang Xiaotang; Guo Qinglong

    2006-01-01

    We previously reported that wogonin, a flavonoid compound, was a potent apoptosis inducer of human hepatoma SMMC-7721 cells and murine sarcoma S180 cells. In the present study, the effect of oroxylin A, one wogonin structurally related flavonoid isolated from Scutellariae radix, on human hepatocellular carcinoma cell line HepG2 was examined and molecular mechanisms were also investigated. Oroxylin A inhibited HepG2 cell proliferation in a concentration- and time-dependent manner measured by MTT-assay. Treatment with an apoptosis-inducing concentration of oroxylin A caused typical morphological changes and apoptotic blebbing in HepG2 cells. DNA fragmentation assay was used to examine later apoptosis induced by oroxylin A. FACScan analysis revealed a dramatic increase in the number of apoptotic and G 2 /M phase arrest cells after oroxylin A treatment. The pro-apoptotic activity of oroxylin A was attributed to its ability to modulate the concerted expression of Bcl-2, Bax, and pro-caspase-3 proteins. The expression of Bcl-2 protein and pro-caspase-3 protein was dramatically decreased after treatment with oroxylin A. These results demonstrated that oroxylin A could effectively induce programmed cell death and suggested that it could be a promising antitumor drug

  13. Allogeneic lymphocyte-licensed DCs expand T cells with improved antitumor activity and resistance to oxidative stress and immunosuppressive factors

    Directory of Open Access Journals (Sweden)

    Chuan Jin

    2014-01-01

    Full Text Available Adoptive T-cell therapy of cancer is a treatment strategy where T cells are isolated, activated, in some cases engineered, and expanded ex vivo before being reinfused to the patient. The most commonly used T-cell expansion methods are either anti-CD3/CD28 antibody beads or the “rapid expansion protocol” (REP, which utilizes OKT-3, interleukin (IL-2, and irradiated allogeneic feeder cells. However, REP-expanded or bead-expanded T cells are sensitive to the harsh tumor microenvironment and often short-lived after reinfusion. Here, we demonstrate that when irradiated and preactivated allosensitized allogeneic lymphocytes (ASALs are used as helper cells to license OKT3-armed allogeneic mature dendritic cells (DCs, together they expand target T cells of high quality. The ASAL/DC combination yields an enriched Th1-polarizing cytokine environment (interferon (IFN-γ, IL-12, IL-2 and optimal costimulatory signals for T-cell stimulation. When genetically engineered antitumor T cells were expanded by this coculture system, they showed better survival and cytotoxic efficacy under oxidative stress and immunosuppressive environment, as well as superior proliferative response during tumor cell killing compared to the REP protocol. Our result suggests a robust ex vivo method to expand T cells with improved quality for adoptive cancer immunotherapy.

  14. Effect of Tea Polyphenol Compounds on Anticancer Drugs in Terms of Anti-Tumor Activity, Toxicology, and Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Jianhua Cao

    2016-12-01

    Full Text Available Multidrug resistance and various adverse side effects have long been major problems in cancer chemotherapy. Recently, chemotherapy has gradually transitioned from mono-substance therapy to multidrug therapy. As a result, the drug cocktail strategy has gained more recognition and wider use. It is believed that properly-formulated drug combinations have greater therapeutic efficacy than single drugs. Tea is a popular beverage consumed by cancer patients and the general public for its perceived health benefits. The major bioactive molecules in green tea are catechins, a class of flavanols. The combination of green tea extract or green tea catechins and anticancer compounds has been paid more attention in cancer treatment. Previous studies demonstrated that the combination of chemotherapeutic drugs and green tea extract or tea polyphenols could synergistically enhance treatment efficacy and reduce the adverse side effects of anticancer drugs in cancer patients. In this review, we summarize the experimental evidence regarding the effects of green tea-derived polyphenols in conjunction with chemotherapeutic drugs on anti-tumor activity, toxicology, and pharmacokinetics. We believe that the combination of multidrug cancer treatment with green tea catechins may improve treatment efficacy and diminish negative side effects.

  15. Extraction, Preliminary Characterization and Evaluation of in Vitro Antitumor and Antioxidant Activities of Polysaccharides from Mentha piperita

    Directory of Open Access Journals (Sweden)

    Xin Liu

    2014-09-01

    Full Text Available This study describes the extraction, preliminary characterization and evaluation of the in vitro antitumor and antioxidant activities of polysaccharides extracted from Mentha piperita (MPP. The optimal parameters for the extraction of MPP were obtained by Box-Behnken experimental design and response surface methodology (RSM at the ratio of water to raw material of 20, extraction time of 1.5 h and extraction temperature at 80 °C. Chemical composition analysis showed that MPP was mainly composed of glucuronic acid, galacturonic acid, glucose, galactose and arabinose, and the molecular weight of its two major fractions were estimated to be about 2.843 and 1.139 kDa, respectively. In vitro bioactivity experiments showed that MPP not only inhibited the growth of A549 cells but possessed potent inhibitory action against DNA topoisomerase I (topo I, and an appreciative antioxidant action as well. These results indicate that MPP may be useful for developing safe natural health products.

  16. Correlation of antiangiogenic and antitumor efficacy of N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA), an orally-active, selective matrix metalloproteinase inhibitor.

    Science.gov (United States)

    Maekawa, R; Maki, H; Yoshida, H; Hojo, K; Tanaka, H; Wada, T; Uchida, N; Takeda, Y; Kasai, H; Okamoto, H; Tsuzuki, H; Kambayashi, Y; Watanabe, F; Kawada, K; Toda, K; Ohtani, M; Sugita, K; Yoshioka, T

    1999-03-15

    The antiangiogenic activity and antitumor efficacy of a newly developed matrix metalloproteinase (MMP) inhibitor were examined. N-biphenyl sulfonyl-phenylalanine hydroxiamic acid (BPHA) potently inhibits MMP-2, -9, and -14, but not MMP-1, -3, or -7. In contrast, (-)BPHA, an enantiomer of BPHA, was inactive against all MMPs tested. Daily oral administration of 200 mg/kg BPHA, but not (-)BPHA in mice resulted in potent inhibition of tumor-induced angiogenesis, primary tumor growth, and liver metastasis. The growth inhibition activity of BPHA was 48% and 45% in a B16-BL6 melanoma and F2 hemangio-endothelioma model, respectively. BPHA also showed 42% inhibition of the liver metastasis of C-1H human colon carcinoma cells. These results indicate that selective MMP inhibition is correlated with antiangiogenic and antitumor efficacy and that the selective MMP inhibitor BPHA has therapeutic potential.

  17. Correlation between the expression of PTEN and anti-tumor activity of PARP inhibitor and radiation in cultured endometrial carcinoma cells

    International Nuclear Information System (INIS)

    Miyasaka, Aki; Oda, Katsutoshi

    2014-01-01

    PTEN inactivation is the most frequent genetic aberration in endometrial cancer. One of the phosphatase-independent roles of PTEN is associated with homologous recombination (HR) in the nucleus. Poly (ADP-ribose) polymerase (PARP) plays key roles in the repair of DNA single-strand breaks, and a PARP inhibitor induces synthetic lethality in cancer cells with HR deficiency. Radiation also causes double strand break, which is repaired through HR. We examined the anti-tumor activity of PARP inhibitor and radiation on endometrial cancer cell lines with different PTEN status. Here we introduce this work, which was recently published (Aki Miyasaka, Katsutoshi Oda, Yuji Ikeda et al. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cell line BMC Cancer 2014, 14: 179). (author)

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

    Science.gov (United States)

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

    2013-02-01

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

  19. SYNTHESIS AND ANTITUMOR ACTIVITY OF COPPER, NICKEL AND COBALT COORDINATION COMPOUNDS WITH 1-(2-HYDROXYPHENYL)ETHANONE N(4)-ALLYL-3-THIOSEMICARBAZONE

    OpenAIRE

    Vasilii GRAUR; Serghei SAVCIN; Victor TSAPKOV; Aurelian GULEA

    2015-01-01

    The paper presents the synthesis of the ligand 1-(2-hydroxyphenyl)ethanone N(4)-allyl-3-thiosemicarbazone (H2L) and six coordination compounds of copper, nickel and cobalt with this ligand. The structure of thiosemicarbazone H2L was studied using 1H and 13С NMR spectroscopy. The synthesized coordination compounds were studied using elemental analysis, gravimetric analysis of water content, molar conductivity, and magnetochemistry. For H2L the antitumor activity towards human leukemia HL-60 ce...

  20. OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models.

    Science.gov (United States)

    Garton, Andrew J; Crew, Andrew P A; Franklin, Maryland; Cooke, Andrew R; Wynne, Graham M; Castaldo, Linda; Kahler, Jennifer; Winski, Shannon L; Franks, April; Brown, Eric N; Bittner, Mark A; Keily, John F; Briner, Paul; Hidden, Chris; Srebernak, Mary C; Pirrit, Carrie; O'Connor, Matthew; Chan, Anna; Vulevic, Bojana; Henninger, Dwight; Hart, Karen; Sennello, Regina; Li, An-Hu; Zhang, Tao; Richardson, Frank; Emerson, David L; Castelhano, Arlindo L; Arnold, Lee D; Gibson, Neil W

    2006-01-15

    OSI-930 is a novel inhibitor of the receptor tyrosine kinases Kit and kinase insert domain receptor (KDR), which is currently being evaluated in clinical studies. OSI-930 selectively inhibits Kit and KDR with similar potency in intact cells and also inhibits these targets in vivo following oral dosing. We have investigated the relationships between the potency observed in cell-based assays in vitro, the plasma exposure levels achieved following oral dosing, the time course of target inhibition in vivo, and antitumor activity of OSI-930 in tumor xenograft models. In the mutant Kit-expressing HMC-1 xenograft model, prolonged inhibition of Kit was achieved at oral doses between 10 and 50 mg/kg and this dose range was associated with antitumor activity. Similarly, prolonged inhibition of wild-type Kit in the NCI-H526 xenograft model was observed at oral doses of 100 to 200 mg/kg, which was the dose level associated with significant antitumor activity in this model as well as in the majority of other xenograft models tested. The data suggest that antitumor activity of OSI-930 in mouse xenograft models is observed at dose levels that maintain a significant level of inhibition of the molecular targets of OSI-930 for a prolonged period. Furthermore, pharmacokinetic evaluation of the plasma exposure levels of OSI-930 at these effective dose levels provides an estimate of the target plasma concentrations that may be required to achieve prolonged inhibition of Kit and KDR in humans and which would therefore be expected to yield a therapeutic benefit in future clinical evaluations of OSI-930.

  1. Structure elucidation, protein profile and the antitumor effect of the biological active substance extracted from sea cucumber Holothuria polii.

    Science.gov (United States)

    Omran, Nahla Ee; Khedr, Abdalla M

    2015-01-01

    Holothuria polii (Delle Chiaje, 1823) (Holothuriidae) is a sea cucumber inhabiting Mediterranean Sea coast of Egypt. The bioactive compound of its tegument has antifungal, antibacterial and antiparasitic effects. The present study aims to elucidate the structure of the bioactive material of H. polii for pharmacological and chemotaxonomic purposes. Furthermore, the study demonstrates its efficacy as a cytotoxic agents against two tumor cell lines HCT116 (colon adenocarcinoma cell line) and MCF7 (breast adenocarcinoma cell line). The biological active compound of the ethanol extract has been characterized by means of infrared (IR), proton-nuclear magnetic resonance ((1)H NMR), ultraviolet-visible (UV-Vis) and mass spectra. Protein profile was carried out using sodium dodecyl sulfate polyacrylamide gel electrophoresis. Cytotoxic activity was carried out according to sulforhodamine-B assay. IR, (1)H NMR, UV-Vis and mass spectra showed that the extracted bioactive material is a nonsulfated hexaosides called bivittoside. This glycoside is composed of aglycone and a glycosidic chain (carbohydrate chain) enclosed with six sugar units, including xylose, glucose, 3-O-methylglucose and quinovose. There were no traces of dissolved proteins. The preliminary cytotoxic assay of bivittoside exhibited significant cytotoxic activity against two types of cultured tumor cell lines of HCT116 and MCF7. The half-maximal inhibitory concentration was 17.4 µg/ml and 18 µg/ml for MCF7 and HCT116, respectively. Although H. polii belongs to the genus Holothuria, the lacking of sulfate group and the fact that it contains up to six monosaccharides make it different from this genus. The present study suggests separation of H. polii from its genus to a new one. On the other hand, results support the hypothesis that H. polii bioactive compound has an antitumor effect. © The Author(s) 2012.

  2. Combination of Vorinostat and caspase-8 inhibition exhibits high anti-tumoral activity on endometrial cancer cells.

    Science.gov (United States)

    Bergadà, Laura; Sorolla, Annabel; Yeramian, Andree; Eritja, Nuria; Mirantes, Cristina; Matias-Guiu, Xavier; Dolcet, Xavier

    2013-08-01

    Histone deacetylase inhibitors such as Vorinostat display anti-neoplastic activity against a variety of solid tumors. Here, we have investigated the anti-tumoral activity of Vorinostat on endometrial cancer cells. We have found that Vorinostat caused cell growth arrest, loss of clonogenic growth and apoptosis of endometrial cancer cells. Vorinostat-induced the activation of caspase-8 and -9, the initiators caspases of the extrinsic and the intrinsic apoptotic pathways, respectively. Next, we investigated the role of the extrinsic pathway in apoptosis triggered by Vorinostat. We found that Vorinostat caused a dramatic decrease of FLIP mRNA and protein levels. However, overexpression of the long from of FLIP did not block Vorinostat-induced apoptosis. To further investigate the role of extrinsic apoptotic pathway in Vorinostat-induced apoptosis, we performed an shRNA-mediated knock-down of caspase-8. Surprisingly, downregulation of caspase-8 alone caused a marked decrease in clonogenic ability and reduced the growth of endometrial cancer xenografts in vivo, revealing that targeting caspase-8 may be an attractive target for anticancer therapy on endometrial tumors. Furthermore, combination of caspase-8 inhibition and Vorinostat treatment caused an enhancement of apoptotic cell death and a further decrease of clonogenic growth of endometrial cancer cells. More importantly, combination of Vorinostat and caspase-8 inhibition caused a nearly complete inhibition of tumor xenograft growth. Finally, we demonstrate that cell death triggered by Vorinostat alone or in combination with caspase-8 shRNAs was inhibited by the anti-apoptotic protein Bcl-XL. Our results suggest that combinatory therapies using Vorinostat treatment and caspase-8 inhibition can be an effective treatment for endometrial carcinomas. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  3. Anti-tumor activity of a novel compound-CDF is mediated by regulating miR-21, miR-200, and PTEN in pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Bin Bao

    2011-03-01

    Full Text Available The existence of cancer stem cells (CSCs or cancer stem-like cells in a tumor mass is believed to be responsible for tumor recurrence because of their intrinsic and extrinsic drug-resistance characteristics. Therefore, targeted killing of CSCs would be a newer strategy for the prevention of tumor recurrence and/or treatment by overcoming drug-resistance. We have developed a novel synthetic compound-CDF, which showed greater bioavailability in animal tissues such as pancreas, and also induced cell growth inhibition and apoptosis, which was mediated by inactivation of NF-κB, COX-2, and VEGF in pancreatic cancer (PC cells.In the current study we showed, for the first time, that CDF could significantly inhibit the sphere-forming ability (pancreatospheres of PC cells consistent with increased disintegration of pancreatospheres, which was associated with attenuation of CSC markers (CD44 and EpCAM, especially in gemcitabine-resistant (MIAPaCa-2 PC cells containing high proportion of CSCs consistent with increased miR-21 and decreased miR-200. In a xenograft mouse model of human PC, CDF treatment significantly inhibited tumor growth, which was associated with decreased NF-κB DNA binding activity, COX-2, and miR-21 expression, and increased PTEN and miR-200 expression in tumor remnants.These results strongly suggest that the anti-tumor activity of CDF is associated with inhibition of CSC function via down-regulation of CSC-associated signaling pathways. Therefore, CDF could be useful for the prevention of tumor recurrence and/or treatment of PC with better treatment outcome in the future.

  4. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines

    Science.gov (United States)

    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert

    2016-03-01

    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behaviour was explained by the fast formation of a 5(4 H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was observed when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were observed to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as additional evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equilibrium processes.

  5. 'Click Chemistry' Synthesis of Novel Natural Product-Like Caged Xanthones Bearing a 1,2,3-Triazole Moiety with Improved Druglike Properties as Orally Active Antitumor Agents.

    Science.gov (United States)

    Li, Xiang; Wu, Yue; Wang, Yanyan; You, Qidong; Zhang, Xiaojin

    2017-10-27

    DDO-6101 , a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of the Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro, but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo antitumor potency, a novel series of ten triazole-bearing caged xanthone derivatives of DDO-6101 has been efficiently synthesized by 'click chemistry' and evaluated for their in vitro antitumor activity and druglike properties. Most of the target compounds have sustained cytotoxicity against A549, HepG2, HCT116, and U2OS cancer cells and possess improved aqueous solubility, as well as permeability. Notably, these caged xanthones are also active towards taxol-resistant or cisplatin-resistant A549 cancer cells. Taking both the in vitro activities and druglike properties into consideration, compound 8g has been advanced into in vivo efficacy experiments. The results reveal that 8g (named as DDO-6318 ), both by intravenous or per os administration, are much more potent than the lead DDO-6101 in A549-transplanted mice models and it could be a promising antitumor candidate for further evaluation.

  6. Inhibition of Hypoxia Inducible Factor Alpha and Astrocyte-Elevated Gene-1 Mediates Cryptotanshinone Exerted Antitumor Activity in Hypoxic PC-3 Cells

    Directory of Open Access Journals (Sweden)

    Hyo-Jeong Lee

    2012-01-01

    Full Text Available Although cryptotanshinone (CT was known to exert antitumor activity in several cancers, its molecular mechanism under hypoxia still remains unclear. Here, the roles of AEG-1 and HIF-1α in CT-induced antitumor activity were investigated in hypoxic PC-3 cells. CT exerted cytotoxicity against prostate cancer cells and suppressed HIF-1α accumulation and AEG-1 expression in hypoxic PC-3 cells. Also, AEG-1 was overexpressed in prostate cancer cells. Interestingly, HIF-1α siRNA transfection enhanced the cleavages of caspase-9,3, and PAPR and decreased expression of Bcl-2 and AEG1 induced by CT in hypoxic PC-3 cells. Of note, DMOG enhanced the stability of AEG-1 and HIF-1α during hypoxia. Additionally, CT significantly reduced cellular level of VEGF in PC-3 cells and disturbed tube formation of HUVECs. Consistently, ChIP assay revealed that CT inhibited the binding of HIF-1α to VEGF promoter. Furthermore, CT at 10 mg/kg suppressed the growth of PC-3 cells in BALB/c athymic nude mice by 46.4% compared to untreated control. Consistently, immunohistochemistry revealed decreased expression of Ki-67, CD34, VEGF, carbonic anhydrase IX, and AEG-1 indices in CT-treated group compared to untreated control. Overall, our findings suggest that CT exerts antitumor activity via inhibition of HIF-1α, AEG1, and VEGF as a potent chemotherapeutic agent.

  7. A novel nucleic acid analogue shows strong angiogenic activity

    Energy Technology Data Exchange (ETDEWEB)

    Tsukamoto, Ikuko, E-mail: tukamoto@med.kagawa-u.ac.jp [Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Sakakibara, Norikazu; Maruyama, Tokumi [Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, 1314-1 Shido, Sanuki, Kagawa 769-2193 (Japan); Igarashi, Junsuke; Kosaka, Hiroaki [Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Kubota, Yasuo [Department of Dermatology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Tokuda, Masaaki [Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan); Ashino, Hiromi [The Tokyo Metropolitan Institute of Medical Science, 1-6 Kamikitazawa2-chome, Setagaya-ku, Tokyo 156-8506 (Japan); Hattori, Kenichi; Tanaka, Shinji; Kawata, Mitsuhiro [Teikoku Seiyaku Co., Ltd., Sanbonmatsu, Higashikagawa, Kagawa 769-2695 (Japan); Konishi, Ryoji [Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa 761-0793 (Japan)

    2010-09-03

    Research highlights: {yields} A novel nucleic acid analogue (2Cl-C.OXT-A, m.w. 284) showed angiogenic potency. {yields} It stimulated the tube formation, proliferation and migration of HUVEC in vitro. {yields} 2Cl-C.OXT-A induced the activation of ERK1/2 and MEK in HUVEC. {yields} Angiogenic potency in vivo was confirmed in CAM assay and rabbit cornea assay. {yields} A synthesized small angiogenic agent would have great clinical therapeutic value. -- Abstract: A novel nucleic acid analogue (2Cl-C.OXT-A) significantly stimulated tube formation of human umbilical endothelial cells (HUVEC). Its maximum potency at 100 {mu}M was stronger than that of vascular endothelial growth factor (VEGF), a positive control. At this concentration, 2Cl-C.OXT-A moderately stimulated proliferation as well as migration of HUVEC. To gain mechanistic insights how 2Cl-C.OXT-A promotes angiogenic responses in HUVEC, we performed immunoblot analyses using phospho-specific antibodies as probes. 2Cl-C.OXT-A induced robust phosphorylation/activation of MAP kinase ERK1/2 and an upstream MAP kinase kinase MEK. Conversely, a MEK inhibitor PD98059 abolished ERK1/2 activation and tube formation both enhanced by 2Cl-C.OXT-A. In contrast, MAP kinase responses elicited by 2Cl-C.OXT-A were not inhibited by SU5416, a specific inhibitor of VEGF receptor tyrosine kinase. Collectively these results suggest that 2Cl-C.OXT-A-induces angiogenic responses in HUVEC mediated by a MAP kinase cascade comprising MEK and ERK1/2, but independently of VEGF receptor tyrosine kinase. In vivo assay using chicken chorioallantoic membrane (CAM) and rabbit cornea also suggested the angiogenic potency of 2Cl-C.OXT-A.

  8. Juglans mandshurica Maxim extracts exhibit antitumor activity on HeLa cells in vitro.

    Science.gov (United States)

    Xin, Nian; Hasan, Murtaza; Li, Wei; Li, Yan

    2014-04-01

    The present study examined the potential application of Juglans mandshurica Maxim extracts (HT) for cancer therapy by assessing their anti‑proliferative activity, reduction of telomerase activity, induction of apoptosis and cell cycle arrest in S phase in HeLa cells. From the perspective of using HT as a herbal medicine, photomicroscopy and florescent microscopy techniques were utilized to characterize the effect of the extracts on telomerase activity and cell morphology. Flow cytometry was employed to study apoptosis and cell cycle of HeLa cells, and DNA laddering was performed. The results showed that HT inhibited cell proliferation and telomerase activity, induced apoptosis and caused S phase arrest of HeLa cells in vitro. HT inhibited HeLa cell proliferation significantly, and the highest inhibition rate was 83.7%. A trap‑silver staining assay showed that HT was capable of markedly decreasing telomerase activity of HeLa cells and this inhibition was enhanced in a time‑ and dose‑dependent manner. Results of a Hoechst 33258 staining assay showed that HeLa cells treated by HT induced cell death. Through DNA agarose gel electrophoresis, DNA ladders of HeLa cells treated with HT were observed, indicating apoptosis. In conclusion, the present study demonstrated that HT exhibited anti‑tumor effects comprising the inhibition of growth and telomerase activity as well as apoptosis and cell cycle arrest in HeLa cells.

  9. DMPD: Distinct functions of IRF-3 and IRF-7 in IFN-alpha gene regulation and controlof anti-tumor activity in primary macrophages. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available trolof anti-tumor activity in primary macrophages. Solis M, Goubau D, Romieu-Mourez R, Genin P, Civas A, Hiscott... D, Romieu-Mourez R, Genin P, Civas A, Hiscott J. Publication Biochem Pharmacol.

  10. Optimization of Ultrasonic-Assisted Enzymatic Extraction Conditions for Improving Total Phenolic Content, Antioxidant and Antitumor Activities In Vitro from Trapa quadrispinosa Roxb. Residues.

    Science.gov (United States)

    Li, Feng; Mao, Yi-Dan; Wang, Yi-Fan; Raza, Aun; Qiu, Li-Peng; Xu, Xiu-Quan

    2017-03-06

    Stems are the important residues of Trapa quadrispinosa Roxb., which are abundant in phenolic compounds. Ultrasonic-assisted enzymatic extraction (UAEE) is confirmed as a novel extraction technology with main advantages of enhancing extraction yield and physiological activities of the extracts from various plants. In this study, UAEE was applied to obtain the highest yield of phenolic content, strongest antioxidant, and antitumor activities and to optimize the extraction conditions using response surface methodology (RSM). The extracts from the stems of T. quadrispinosa were characterized by determination of their antioxidant activities through 2,2-azinobis(3-ethylbenzthiazoline)-6-sulfonic acid (ABTS), 1,1-Diphenyl-2-picrylhydrazxyl (DPPH) radical scavenging, total antioxidant capacity (TAC), ferric reducing antioxidant capacity (FRAC) methods and of their antitumor activity by MTT method. The selected key independent variables were cellulase concentration ( X ₁: 1.5%-2.5%), extraction time ( X ₂: 20-30 min) and extraction temperature ( X ₃: 40-60 °C). The optimal extraction conditions for total phenolic content (TPC) value of the extracts were determined as 1.74% cellulase concentration, 25.5 min ultrasonic extraction time and 49.0 °C ultrasonic temperature. Under these conditions, the highest TPC value of 53.6 ± 2.2 mg Gallic acid equivalent (GAE)/g dry weight (DW) was obtained, which agreed well with the predicted value (52.596 mg GAE/g·DW. Furthermore, the extracts obtained from UAEE presented highest antioxidant activities through ABTS, DPPH, TAC and FRAC methods were of 1.54 ± 0.09 mmol Trolox equivalent (TE)/g·DW; 1.45 ± 0.07 mmol·TE/g·DW; 45.2 ± 2.2 mg·GAE/g·DW; 50.4 ± 2.6 μmol FeSO₄ equivalent/g·DW and lowest IC 50 values of 160.4 ± 11.6 μg/mL, 126.1 ± 10.8 μg/mL, and 178.3 ± 13.1 μg/mL against Hela, HepG-2 and U251 tumor cells, respectively. The results indicated that the UAEE was an efficient alternative to improve

  11. Working life and physical activity in ankylosing spondylitis pre and post anti-tumor necrosis factor-alpha therapy.

    Science.gov (United States)

    Prince, David S; McGuigan, Louis E; McGirr, Ellen E

    2014-02-01

    To assess effects of ankylosing spondylitis (AS) on working life and physical activity in Australia; to quantify changes in working life and physical activity that occur after anti-tumor necrosis factor-alpha (TNF-α) treatment; and to assess efficacy of anti-TNF-α therapy for AS in an Australian context. This is a multi-centre observational study of people with AS on anti-TNF-α therapy. All participants satisfied the New York Modified Criteria and had active and refractory disease at anti-TNF-α therapy commencement. Participation involved a standardized interview, a metrology assessment, assessment of disease remission and medical record review. Interviews and patients' records were used to compare working life (employment, sick leave and productivity) and physical activity (participation rate, hours/week, and physical intensity) between the pre-AS, post-AS and post-anti-TNF-α therapy periods. Fifty-two patients took part. Participants were on average 44.8 years old, predominately male (86.5%) and had been on anti-TNF-α therapy for 29 months; 39% were in partial remission and 75% had 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Responders to anti-TNF-α therapy were 10.5 years younger than non-responders (P = 0.004). Post-anti-TNF-α therapy participants gained 6.6 h/week of work (P = 0.02), and productivity improved 31% (P treatment. Physical activity participation increased from 71% to 85% (P = 0.039) and activity intensity increased by 33% (P = 0.002) post-treatment. Participants gained 1.8 h/week of sport (P = 0.001) and 2.2 h/week of recreational physical activity (P Treatment with anti-TNF-α therapy results in significant improvement in these parameters. © 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  12. Monocyte-derived dendritic cells are essential for CD8+ T cell activation and anti-tumor responses after local immunotherapy

    Directory of Open Access Journals (Sweden)

    Sabine eKuhn

    2015-11-01

    Full Text Available Tumors harbor several populations of dendritic cells with the ability to prime tumor-specific T cells. However, these T cells mostly fail to differentiate into armed effectors and are unable to control tumor growth. We have previously shown that treatment with immunostimulatory agents at the tumor site can activate anti-tumor immune responses, and is associated with the appearance of a population of monocyte-derived dendritic cells in the tumor and tumor-draining lymph node. Here we use dendritic cell or monocyte depletion and monocyte transfer to show that these monocyte-derived dendritic cells are critical to the activation of anti-tumor immune responses. Treatment with the immunostimulatory agents Monosodium Urate crystals and Mycobacterium smegmatis induced the accumulation of monocytes in the draining lymph node, their upregulation of CD11c and MHCII, and expression of iNOS, TNFα and IL12p40. Blocking monocyte entry into the lymph node and tumor through neutralization of the chemokine CCL2 or inhibition of Colony Stimulating Factor-1 receptor signaling prevented the generation of monocyte-derived dendritic cells, the infiltration of tumor-specific T cells into the tumor, and anti-tumor responses. In a reciprocal fashion, monocytes transferred into mice depleted of CD11c+ cells were sufficient to rescue CD8+ T cell priming in lymph node and delay tumor growth. Thus monocytes exposed to the appropriate conditions become powerful activators of tumor-specific CD8+ T cells and anti-tumor immunity.

  13. Antitumor Allium Sulfides.

    Science.gov (United States)

    Nohara, Toshihiro; Fujiwara, Yukio; El-Aasr, Mona; Ikeda, Tsuyoshi; Ono, Masateru; Nakano, Daisuke; Kinjo, Junei

    2017-01-01

    We examined the sulfides in onion (Allium cepa L.), Welsh onion (A. fistulosum L.), and garlic (A. sativum L.), and obtained three new thiolane-type sulfides (onionins A 1 -A 3 ) from onion; two new thiabicyclic-type sulfides (welsonins A 1 , A 2 ), together with onionins A 1 -A 3 , from Welsh onion; and six new acyclic-type sulfides (garlicnins L-1-L-4, E, and F), ten new thiolane-type sulfides (garlicnins A, B 1 -B 4 , C 1 -C 3 , K 1 , and K 2 ), and three new atypical cyclic-type sulfides (garlicnins G, I, and J) from garlic. Acetone extracts showed the potential of these sulfides in inhibiting the polarization of M2 activated macrophages that are capable of suppressing tumor-cell proliferation. The effect of the thiolane-type sulfide of a major component, onionin A 1 , on tumor progression and metastasis in both osteosarcoma and ovarian cancer-bearing mouse models was then examined. Tumor proliferation was depressed, and tumor metastasis was controlled by regulating macrophage activation. These results showed that onionin A 1 is an effective agent for controlling tumors in both in vitro and in vivo models, and that the antitumor effects observed in vivo are likely caused by reversing the antitumor immune system. Activation of the antitumor immune system by onionin A 1 might be an effective adjuvant therapy for patients with osteosarcoma, ovarian cancer and other malignant tumors. Based on these findings, pharmacological investigations will be conducted in the future to develop natural and healthy foods and anti-cancer agents that can prevent or combat disease.

  14. Thermodynamic Study of Water Activity of Single Strong Electrolytes

    Directory of Open Access Journals (Sweden)

    Seyed Hossein Hashemi

    2017-06-01

    Full Text Available Today, due to the natural decline of oil exploitation, the use of methods of oil recovery, has made significant progress. However, these methods are accompanied by accumulation and deposition of mineral deposits in oil field installations. In the present study, aqueous solutions, strontium sulfate, barium sulfate, manganese sulfate and nickel sulfate are studied, in terms of EUNIQUAC model and genetic algorithms. Based on the findings of this article, as temperature increases, in order to increase the solubility of the system, the ionic strength decreases; but with increasing pressure, the solubility of barium sulfate increases. Meanwhile, in this article, to evaluate water activity, aqueous solutions of manganese sulfate and nickel sulfate is studied.

  15. Anticoagulant, Antioxidant and Antitumor Activities of Heterofucans from the Seaweed Dictyopteris delicatula

    Directory of Open Access Journals (Sweden)

    Hugo Alexandre Oliveira Rocha

    2011-05-01

    Full Text Available In the present study, six families of sulfated polysaccharides were obtained from seaweed Dictyopteris delicatula by proteolytic digestion, followed by acetone fractionation and molecular sieving on Sephadex G-100. Chemical analyses demonstrated that all polysaccharides contain heterofucans composed mainly of fucose, xylose, glucose, galactose, uronic acid, and sulfate. The fucans F0.5v and F0.7v at 1.0 mg/mL showed high ferric chelating activity (~45%, whereas fucans F1.3v (0.5 mg/mL showed considerable reducing power, about 53.2% of the activity of vitamin C. The fucan F1.5v presented the most prominent anticoagulant activity. The best antiproliferative activity was found with fucans F1.3v and F0.7v. However, F1.3v activity was much higher than F0.7v inhibiting almost 100% of HeLa cell proliferation. These fucans have been selected for further studies on structural characterization as well as in vivo experiments, which are already in progress.

  16. A novel colchicine-based microtubule inhibitor exhibits potent antitumor activity by inducing mitochondrial mediated apoptosis in MIA PaCa-2 pancreatic cancer cells.

    Science.gov (United States)

    Kumar, Ashok; Singh, Baljinder; Mahajan, Girish; Sharma, Parduman R; Bharate, Sandip B; Mintoo, Mubashir J; Mondhe, Dilip M

    2016-10-01

    Colchicine, an antimitotic alkaloid isolated from Colchicum autumnale, is a classical drug for treatment of gout and familial Mediterranean fever. It causes antiproliferative effects through the inhibition of microtubule formation, which leads to mitotic arrest and cell death by apoptosis. Here, we report that a novel colchicine analog, 4o (N-[(7S)-1,2,3-trimethoxy-9-oxo-10-[3-(trifluoromethyl)-4-chlorophenylamino]-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide), which exhibited potent anticancer activities both in vitro and in vivo. In this study, 4o with excellent pharmacokinetic profile and no P-gp induction liability displayed strong inhibition of proliferation against various human cancer cell lines. However, pancreatic cancer cell line MIA PaCa-2 was found to be more sensitive towards 4o and showed strong inhibition in concentration and time-dependent manner. By increasing intracellular reactive oxygen species (ROS) levels, 4o induced endoplasmic reticular stress and mitochondrial dysfunction in MIA PaCa-2 cells. Blockage of ROS production reversed 4o-induced endoplasmic reticulum (ER) stress, calcium release, and cell death. More importantly, it revealed that increased ROS generation might be an effective strategy in treating human pancreatic cancer. Further 4o treatment induced mitotic arrest, altered the expression of cell cycle-associated proteins, and disrupted the microtubules in MIA PaCa-2 cells. 4o treatment caused loss of mitochondrial membrane potential, cytochrome c release, upregulation of Bax, downregulation of Bcl-2, and cleavage of caspase-3, thereby showing activation of mitochondrial mediated apoptosis. The in vivo anticancer activity of the compound was studied using sarcoma-180 (ascitic) and leukemia (P388 lymphocytic and L1210 lymphoid) models in mice and showed promising antitumor activity with the least toxicity unlike colchicine. Such studies have hitherto not been reported. Taken together, these findings highlighted that 4o, a

  17. The anti-tumor drug bleomycin preferentially cleaves at the transcription start sites of actively transcribed genes in human cells.

    Science.gov (United States)

    Murray, Vincent; Chen, Jon K; Galea, Anne M

    2014-04-01

    The genome-wide pattern of DNA cleavage at transcription start sites (TSSs) for the anti-tumor drug bleomycin was examined in human HeLa cells using next-generation DNA sequencing. It was found that actively transcribed genes were preferentially cleaved compared with non-transcribed genes. The 143,600 identified human TSSs were split into non-transcribed genes (82,596) and transcribed genes (61,004) for HeLa cells. These transcribed genes were further split into quintiles of 12,201 genes comprising the top 20, 20-40, 40-60, 60-80, and 80-100 % of expressed genes. The bleomycin cleavage pattern at highly transcribed gene TSSs was greatly enhanced compared with purified DNA and non-transcribed gene TSSs. The top 20 and 20-40 % quintiles had a very similar enhanced cleavage pattern, the 40-60 % quintile was intermediate, while the 60-80 and 80-100 % quintiles were close to the non-transcribed and purified DNA profiles. The pattern of bleomycin enhanced cleavage had peaks that were approximately 200 bp apart, and this indicated that bleomycin was identifying the presence of phased nucleosomes at TSSs. Hence bleomycin can be utilized to detect chromatin structures that are present at actively transcribed genes. In this study, for the first time, the pattern of DNA damage by a clinically utilized cancer chemotherapeutic agent was performed on a human genome-wide scale at the nucleotide level.

  18. Aqueous extracts of Lentinula edodes and Pleurotus sajor-caju exhibit high antioxidant capability and promising in vitro antitumor activity.

    Science.gov (United States)

    Finimundy, T C; Gambato, G; Fontana, R; Camassola, M; Salvador, M; Moura, S; Hess, J; Henriques, J A P; Dillon, A J P; Roesch-Ely, M

    2013-01-01

    Mushroom extracts are increasingly sold as dietary supplements because of several of their properties, including the enhancement of immune function and antitumor activity. We hypothesized that soluble polar substances present in mushroom extracts may show antioxidant and anticancer properties. This report shows that Brazilian aqueous extracts of Lentinula edodes and Pleurotus sajor-caju exert inhibitory activity against the proliferation of the human tumor cell lines laryngeal carcinoma (Hep-2) and cervical adenocarcinoma (HeLa). Cell viability was determined after using 3 different temperatures (4°C, 22°C, and 50°C) for mushroom extraction. Biochemical assays carried out in parallel indicated higher amounts of polyphenols in the L edodes extracts at all extraction temperatures investigated. The scavenging ability of the 2,2-diphenyl-1-picrylhydrazyl radical showed higher activity for L edodes extracts. Superoxide dismutase-like activity showed no statistically significant difference among the groups for the 2 tested extracts, and catalase-like activity was increased with the L edodes extracts at 4°C. The results for the cytotoxic activity from P sajor-caju extracts at 22°C revealed the half maximal inhibitory concentration values of 0.64% ± 0.02% for Hep-2 and 0.25% ± 0.02% for HeLa. A higher cytotoxic activity was found for the L edodes extract at 22°C, with half maximal inhibitory concentration values of 0.78% ± 0.02% for Hep-2 and 0.57% ± 0.01% for HeLa. Substantial morphological modifications in cells were confirmed by Giemsa staining after treatment with either extract, suggesting inhibition of proliferation and induction of apoptosis with increasing extract concentrations. These results indicate that the aqueous extracts of Brazilian L edodes and P sajor-caju mushrooms are potential sources of antioxidant and anticancer compounds. However, further investigations are needed to exploit their valuable therapeutic uses and to elucidate their modes of

  19. Interactions with polynucleotides and antitumor activity of amidino and imidazolinyl substituted 2-phenylbenzothiazole mesylates.

    Science.gov (United States)

    Racané, Livio; Stojković, Ranko; Tralić-Kulenović, Vesna; Cerić, Helena; Đaković, Marijana; Ester, Katja; Krpan, Ana Mišir; Stojković, Marijana Radić

    2014-10-30

    Based on previously reported antiproliferative activity screening, four most promising disubstituted 2-phenylbenzothiazole hydrochlorides were chosen for detailed study. Water solubility, as well as liphophilicity/hydrophilicity balance of organic core were modified by conversion to mesylate salts. For purpose of structure/activity studies their structures were determined by X-ray structure analysis. Detailed analysis of interactions of new compounds with double stranded (ds-) DNA/RNA by UV/Vis and CD titrations, thermal melting and viscometry experiments revealed that most of studied compounds intercalate into ds-RNA but bind into minor groove of AT-DNA, and agglomerate along GC-DNA. Furthermore, compounds also interact with ss-RNA, but only amino-imidazolinyl 2-phenylbenzothiazole, 4b displayed well defined orientation and dominant binding mode (by induced CD signals) with poly A and poly G. Besides, in vitro investigations revealed moderate to high antiproliferative activity of benzothiazoles against seven human cancer cell lines, while in some cases (HTC 116, SW620, MIA PaCa-2) high correlation between the type of the amidino group and cytotoxic activity was observed. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  20. In vitro antitumor activity of Gracilaria corticata (a red alga) against ...

    African Journals Online (AJOL)

    ) assay. The results showed that 9.336 and 9.726 μg/μl of algal extract were the most effective concentrations against Jurkat and molt-4 cells, respectively. The water crude extract of red alga G. corticata had significant anticancer activity and it ...

  1. Antitumor activity of vorinostat-incorporated nanoparticles against human cholangiocarcinoma cells

    OpenAIRE

    Kwak, Tae Won; Kim, Do Hyung; Jeong, Young-Il; Kang, Dae Hwan

    2015-01-01

    Background The aim of this study is to evaluate the anticancer activity of vorinostat-incorporated nanoparticles (vorinostat-NPs) against HuCC-T1 human cholangiocarcinoma cells. Vorinostat-NPs were fabricated by a nanoprecipitation method using poly(dl-lactide-co-glycolide)/poly(ethylene glycol) copolymer. Results Vorinostat-NPs exhibited spherical shapes with sizes

  2. Treatment with rituximab, dexamethasone, high-dose cytarabine, and oxaliplatin (R-DHAOx) produces a strong long-term antitumor effect in previously treated patients with follicular non-Hodgkin's lymphoma.

    Science.gov (United States)

    Machover, D; Delmas-Marsalet, B; Misra, S C; Ulusakarya, A; Gumus, Y; Frénoy, N; Guettier, C; Saffroy, R; Innominato, P; Almohamad, W; Brahimi, N; Haydar, M; Goldschmidt, E

    2010-02-01

    We explored the addition of rituximab to high-dose cytarabine (ara-C), oxaliplatin (L-OHP), and dexamethasone [R-DHAOx], in resistant and relapsed patients with CD20-positive follicular non-Hodgkin's lymphoma. Twenty-two patients were included; they were treated previously with one to five chemotherapy regimens, including 13 patients who had also received rituximab. R-DHAOx consisted of rituximab, 375mg/m(2), day 1; dexamethasone, 40mg/d, days one to four; L-OHP, 130mg/m(2), day 1; and ara-C, 2000mg/m(2) every 12 h, day 2. Courses were repeated every 21 days for eight courses. Twenty-one patients (95%) achieved a complete response and one had a partial response. Responses were obtained in patients with and without resistance to prior treatment, either alone or combined with rituximab. The median follow-up time was 58.3 months (range, 8.7-92.6 months). Progression-free survival reached a plateau at 84% at 38.2 months. Only two of the 21 complete responders have relapsed. Tumor molecular markers disappeared in all 10 complete responders whose markers were found before treatment. Peripheral neuropathy related to the cumulative dose of L-OHP, and myelosuppression were the most prominent toxic effects. R-DHAOx is highly active for salvage treatment of patients with follicular non-Hodgkin's lymphoma, and it produces long-term antitumor efficacy. 2009 Elsevier Masson SAS. All rights reserved.

  3. The protein kinase C inhibitor enzastaurin exhibits antitumor activity against uveal melanoma.

    Directory of Open Access Journals (Sweden)

    Xinqi Wu

    Full Text Available GNAQ mutations at codon 209 have been recently identified in approximately 50% of uveal melanomas (UM and are reported to be oncogenic through activating the MAPK/Erk1/2 pathway. Protein kinase C (PKC is a component of signaling from GNAQ to Erk1/2. Inhibition of PKC might regulate GNAQ mutation-induced Erk1/2 activation, resulting in growth inhibition of UM cells carrying GNAQ mutations. UM cells carrying wild type or mutant GNAQ were treated with the PKC inhibitor enzastaurin. Effects on proliferation, apoptosis, and signaling events were evaluated. Enzastaurin downregulated the expression of several PKC isoforms including PKCβII PKCθ, PKCε and/or their phosphorylation in GNAQ mutated cells. Downregulation of these PKC isoforms in GNAQ mutated cells by shRNA resulted in reduced viability. Enzastaurin exhibited greater antiproliferative effect on GNAQ mutant cells than wild type cells through induction of G1 arrest and apoptosis. Enzastaurin-induced G1 arrest was associated with inhibition of Erk1/2 phosphorylation, downregulation of cyclin D1, and accumulation of cyclin dependent kinase inhibitor p27(Kip1. Furthermore, enzastaurin reduced the expression of antiapoptotic Bcl-2 and survivin in GNAQ mutant cells. Inhibition of Erk1/2 phosphorylation with a MEK specific inhibitor enhanced the sensitivity of GNAQ wild type cells to enzastaurin, accompanied by p27(Kip1 accumulation and/or inhibition of enzastaurin-induced survivin and Bcl-2 upregulation. PKC inhibitors such as enzastaurin have activity against UM cells carrying GNAQ mutations through inhibition of the PKC/Erk1/2 pathway and induction of G1 arrest and apoptosis. Inhibition of the PKC pathway provides a basis for clinical investigation in patients with UM.

  4. Structural analysis and antitumor activity of androstane D-seco-mesyloxy derivatives

    Energy Technology Data Exchange (ETDEWEB)

    Okljesa, Aleksandar M.; Jovanovic-Santa, Suzana S.; Sakac, Marija N.; Djurendic, Evgenija A.; Gasi, Katarina M. Penov, E-mail: suzana.jovanovic-santa@dh.uns.ac [University of Novi Sad (Serbia). Faculty of Sciences. Department of Chemistry, Biochemistry and Environmental Protection; Klisuric, Oliveira R. [University of Novi Sad (Serbia). Faculty of Sciences. Department of Physics; Jakimov, Dimitar S.; Aleksic, Lidija D. [Oncology Institute of Vojvodina, Sremska Kamenica (Serbia)

    2013-10-15

    he study of the influence of steroidal compounds on tumor cell cultures, cell growth, induction of apoptosis and/or cell cycle changes, is a common way of discovering potential therapeutics for treating people suffering from hormone-dependent problems and diseases. Because of the very high mortality rate associated with this class of disease, therapeutics for treating different types of cancers are among the most important. This work presents the synthesis of two stereoisomeric 16,17-secoandrostane mesyloxy derivatives and their 17-hydroxy precursors. Compounds were structurally analyzed by X-ray crystallography, and their antiproliferative activity, influence on the cell cycle and potential to induce apoptosis were investigated. (author)

  5. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma.

    Directory of Open Access Journals (Sweden)

    Tim F Cloughesy

    2008-01-01

    Full Text Available There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population.Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR, we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation varied substantially. Tumor cell proliferation (measured by Ki-67 staining was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test

  6. Nitric Oxide Synthase Type III Overexpression By Gene Therapy Exerts Antitumoral Activity In Mouse Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Raúl González

    2015-08-01

    Full Text Available Hepatocellular carcinoma develops in cirrhotic liver. The nitric oxide (NO synthase type III (NOS-3 overexpression induces cell death in hepatoma cells. The study developed gene therapy designed to specifically overexpress NOS-3 in cultured hepatoma cells, and in tumors derived from orthotopically implanted tumor cells in fibrotic livers. Liver fibrosis was induced by CCl4 administration in mice. Hepa 1-6 cells were used for in vitro and in vivo experiments. The first generation adenovirus was designed to overexpress NOS-3 (or GFP and luciferase cDNA under the regulation of murine alpha-fetoprotein (AFP and Rous Sarcoma Virus (RSV promoters, respectively. Both adenoviruses were administered through the tail vein two weeks after orthotopic tumor cell implantation. AFP-NOS-3/RSV-Luciferase increased oxidative-related DNA damage, p53, CD95/CD95L expression and caspase-8 activity in cultured Hepa 1-6 cells. The increased expression of CD95/CD95L and caspase-8 activity was abolished by l-NAME or p53 siRNA. The tail vein infusion of AFP-NOS- 3/RSV-Luciferase adenovirus increased cell death markers, and reduced cell proliferation of established tumors in fibrotic livers. The increase of oxidative/nitrosative stress induced by NOS-3 overexpression induced DNA damage, p53, CD95/CD95L expression and cell death in hepatocellular carcinoma cells. The effectiveness of the gene therapy has been demonstrated in vitro and in vivo.

  7. Cellular and antitumor activity of a new diethylene glycol benzoporphyrin derivative (lemuteporfin).

    Science.gov (United States)

    Boch, Ron; Canaan, Alice J; Cho, Angela; Dolphin, David D; Hong, Lina; Jain, Ashok K; North, John R; Richter, Anna M; Smits, Claire; Sternberg, Ethan D

    2006-01-01

    A newly synthesized diethylene glycol functionalized chlorin-type photosensitizer, lemuteporfin, was characterized for use in photodynamic therapy (PDT) in a panel of in vitro and in vivo test systems. The photosensitizer was highly potent, killing cells at low nanomolar concentrations upon exposure to activating light. The cellular uptake of lemuteporfin was rapid, with maximum levels reached within 20 min. Mitogen-activated lymphoid cells accumulated more of the lemuteporfin than their quiescent equivalents, supporting selectivity. Photosensitizer fluorescence in the skin increased rapidly within the first few minutes following intravenous administration to mice, then decreased over the next 24 h. Skin photosensitivity reactions indicated rapid clearance of the photosensitizer. Intravenous doses as low as 1.4 micromol/kg combined with exposure to 50 J/cm2 red light suppressed tumor growth in a mouse model. In conclusion, this new benzoporphyrin was found to be an effective photosensitizer, showing rapid uptake and clearance both in vitro and in vivo. This rapid photosensitization of tumors could be useful in therapies requiring a potent, rapidly accumulating photosensitizer, while minimizing the potential for skin photosensitivity reactions to sunlight following treatment.

  8. Intratumoral delivery of CpG-conjugated anti-MUC1 antibody enhances NK cell anti-tumor activity.

    Science.gov (United States)

    Schettini, Jorge; Kidiyoor, Amritha; Besmer, Dahlia M; Tinder, Teresa L; Roy, Lopamudra Das; Lustgarten, Joseph; Gendler, Sandra J; Mukherjee, Pinku

    2012-11-01

    Monoclonal antibodies (mAbs) against tumor-associated antigens are useful anticancer agents. Antibody-dependent cellular cytotoxicity (ADCC) is one of the major mechanisms responsible for initiating natural killer cell (NK)-mediated killing of tumors. However, the regulation of ADCC via NK cells is poorly understood. We have investigated the cytolytic activity of NK cells against pancreatic cancer cells that were coated with an antibody directed against the human tumor antigen, Mucin-1 designated HMFG-2, either alone or conjugated to CpG oligodeoxynucleotide (CpG ODN). Conjugated antibodies were tested for their ability to elicit ADCC in vitro and in vivo against pancreatic cancer cells. NK cells cultured in the presence of immobilized CpG ODN, HMFG-2 Ab, or CpG ODN-conjugated HMFG-2 Ab were able to up-regulate perforin similarly. Interestingly, a significant higher ADCC was observed when CpG ODN-conjugated HMFG-2-coated tumor cells were co-cultured with NK cells compared to unconjugated HMFG-2 Ab or CpG ODN alone. Moreover, MyD88-deficient NK cells can perform ADCC in vitro. Furthermore, intratumoral injections of CpG ODN-conjugated HMFG-2 induced a significant reduction in tumor burden in vivo in an established model of pancreatic tumor in nude mice compared to CpG ODN or the HMFG-2 alone. Depletion of macrophages or NK cells before treatment confirmed that both cells were required for the anti-tumor response in vivo. Results also suggest that CpG ODN and HMFG-2 Ab could be sensed by NK cells on the mAb-coated tumor cells triggering enhanced ADCC in vitro and in vivo.

  9. Antitumor activities of the synthetic retinoid ST1926 in two-dimensional and three-dimensional human breast cancer models.

    Science.gov (United States)

    Aouad, Patrick; Saikali, Melody; Abdel-Samad, Rana; Fostok, Sabreen; El-Houjeiri, Leeanna; Pisano, Claudio; Talhouk, Rabih; Darwiche, Nadine

    2017-08-01

    Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/β-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development.

  10. Comparison between linear and star-like HPMA conjugated pirarubicin (THP) in pharmacokinetics and antitumor activity in tumor bearing mice.

    Science.gov (United States)

    Nakamura, Hideaki; Koziolová, Eva; Etrych, Tomáš; Chytil, Petr; Fang, Jun; Ulbrich, Karel; Maeda, Hiroshi

    2015-02-01

    Previously we showed that linear poly(N-(2-hydroxypropyl)methacrylamide) conjugates of pirarubicin (THP), LP-THP, with MW about 39 kDa, exhibited far better tumor accumulation and therapeutic effect than that of parental free THP. To improve the pharmacokinetics of LP-THP further, high-MW conjugate of poly(amido amine) (PAMAM) dendrimer grafted with semitelechelic HPMA copolymer (PHPMA) was synthesized [star polymer (SP); 400 kDa] and conjugated with THP via hydrazone bond-containing spacer (SP-THP). THP was conjugated to SP to form SP-THP via acid cleavable hydrazone bonding, which responds to acidic milieu of tumor tissue. As a consequence, it would release free THP, by active therapeutic principle. SP-THP exhibits larger hydrodynamic diameter (25.9 nm) in aqueous solution than that of LP-THP (8.2 nm) as observed by light scattering and size exclusion chromatography. Because of the larger size, the tumor AUC5h-72 h of SP-THP was 3.3 times higher than that of LP-THP. More importantly, released free THP was retained selectively in the tumor tissue for at least up to 72 h after administration of SP-THP. We found that SP-THP exhibited superior antitumor effect to LP-THP against both S-180 tumor-bearing mice in vivo, and with chemically AOM/DSS-induced colon tumor-bearing mice, most probably due to their different molecular size. In our comparison study of in vitro and in vivo behavior of SP-THP and LP-THP we concluded that SP-THP exhibited enhanced therapeutic efficacy not only in implanted tumor but also in orthotopic/spontaneous tumor despite its higher toxicity compared to LP-THP. Upon these findings further investigation using various tumors including transgenic, and metastatic tumors is going to be conducted soon. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Antitumor Activity of Total Flavonoids from Daphne genkwa in Colorectal Cancer.

    Science.gov (United States)

    Du, Wen-Juan; Yang, Xiao-Lin; Song, Zi-Jing; Wang, Jiao-Ying; Zhang, Wen-Jun; He, Xin; Zhang, Run-Qi; Zhang, Chun-Feng; Li, Fei; Yu, Chun-Hao; Wang, Chong-Zhi; Yuan, Chun-Su

    2016-02-01

    Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to investigate the anticancer effects of total flavonoids in D. genkwa (TFDG) in vitro and in vivo. HT-29 and SW-480 human colorectal cancer cells were cultured to investigate the anticancer activity of TFDG. In addition, the Apc(Min/+) mouse model was applied in the in vivo experiment. Results of the cell experiment revealed that TFDG possessed significant inhibitory effects on HT-29 and SW-480 human colorectal cancer cells (both p colon (both p cancer therapeutics, and TFDG's action is likely linked to its ability to regulate immune function and inhibit the production of inflammatory cytokines. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Synthesis and Antitumor Activity of Diterpenylhydroquinone Derivatives of Natural Ent-Labdanes

    Directory of Open Access Journals (Sweden)

    Mauricio Cuellar Fritis

    2010-09-01

    Full Text Available Two new compounds 2β-acetoxy-15-phenyl-(22,25-acetoxy-ent-labda-8(17, 13(E-diene (9 and 2β-hydroxy-15-phenyl-(22,24,26-trimethoxy-ent-labda-8(17,13(E-diene (10 have been prepared by an Electrophilic Aromatic Substitution (EAS reaction between diterpenyl allylic alcohols and 1,4-hydroquinone or 1,3,5-trimethoxybenzene using BF3.Et2O as a catalyst. These compounds, along with a series of natural ent-labdanes 3-8, have been evaluated for their in vitro cytotoxic activities against cultured human cancer cells of PC-3 and DU-145 human prostate cancer, MCF-7 and MDA-MB-231 breast carcinoma and dermal human fibroblasts (DHF. Some compounds displayed inhibition at µM IC50 values.

  13. Anti-tumor activity of non-steroidal anti-inflammatory drugs: Cyclooxygenase-independent targets

    Science.gov (United States)

    Liggett, Jason L.; Zhang, Xiaobo; Eling, Thomas E.; Baek, Seung Joon

    2014-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for analgesic and antipyretic treatments. In addition, NSAIDs reduce the risk and mortality to several cancers. Their mechanisms in anti-tumorigenesis are not fully understood, but both cyclooxygenase (COX)-dependent and -independent pathways play a role. We and others have been interested in elucidating molecular targets of NSAID-induced apoptosis. In this review, we summarize updated literature regarding cellular and molecular targets modulated by NSAIDs. Among those NSAIDs, sulindac sulfide and tolfenamic acid are emphasized in this review because these two drugs have been well investigated for their anti-tumorigenic activity in many different types of cancer. PMID:24486220

  14. Isoquinoline-pyridine-based protein kinase B/Akt antagonists: SAR and in vivo antitumor activity.

    Science.gov (United States)

    Zhu, Gui-Dong; Gong, Jianchun; Claiborne, Akiyo; Woods, Keith W; Gandhi, Viraj B; Thomas, Sheela; Luo, Yan; Liu, Xuesong; Shi, Yan; Guan, Ran; Magnone, Shayna R; Klinghofer, Vered; Johnson, Eric F; Bouska, Jennifer; Shoemaker, Alexander; Oleksijew, Anatol; Stoll, Vincent S; De Jong, Ron; Oltersdorf, Tilman; Li, Qun; Rosenberg, Saul H; Giranda, Vincent L

    2006-06-15

    The structure-activity relationships of a series of isoquinoline-pyridine-based protein kinase B/Akt antagonists have been investigated in an effort to improve the major short-comings of the lead compound 3, including poor pharmacokinetic profiles in several species (e.g., mouse i.v. t(1/2) = 0.3 h, p.o. F = 0%). Chlorination at C-1 position of the isoquinoline improved its pharmacokinetic property in mice (i.v. t(1/2) = 5.0 h, p.o. F = 51%) but resulted in >500-fold drop in potency. In a mouse MiaPaCa-2 xenograft model, an amino analog 10y significantly slowed the tumor growth, however was accompanied by toxicity.

  15. Derivatives of grindelic acid: from a non-active natural diterpene to synthetic antitumor derivatives.

    Science.gov (United States)

    Reta, Guillermo F; Chiaramello, Alejandra I; García, Celina; León, Leticia G; Martín, Víctor S; Padrón, José M; Tonn, Carlos E; Donadel, Osvaldo J

    2013-09-01

    Using several reactions that include homologations and asymmetric epoxidations as well as Ugi and Huisgen couplings, we generated a small focused library of new derivatives from the labdane-type diterpene grindelic acid. These compounds were evaluated as cytotoxic agents against a panel of five human solid tumor cell lines (HBL-100, HeLa, SW1573, T-47D, and WiDr). The presence of the diamide functionalizations enhanced the cytotoxic effect. N-Benzyl-N-(1-(benzylamino)-2-methyl-1-oxopropan-2-yl)grindelicamide, proved to be the most active product in all cell lines tested, with values of 0.95 (±0.38) μM against HBL-100 cells. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  16. Activation of antitumor cytotoxic T lymphocytes by fusions of human dendritic cells and breast carcinoma cells

    Science.gov (United States)

    Gong, Jianlin; Avigan, David; Chen, Dongshu; Wu, Zekui; Koido, Shigeo; Kashiwaba, Masahiro; Kufe, Donald

    2000-03-01

    We have reported that fusions of murine dendritic cells (DCs) and murine carcinoma cells reverse unresponsiveness to tumor-associated antigens and induce the rejection of established metastases. In the present study, fusions were generated with primary human breast carcinoma cells and autologous DCs. Fusion cells coexpressed tumor-associated antigens and DC-derived costimulatory molecules. The fusion cells also retained the functional potency of DCs and stimulated autologous T cell proliferation. Significantly, the results show that autologous T cells are primed by the fusion cells to induce MHC class I-dependent lysis of autologous breast tumor cells. These findings demonstrate that fusions of human breast cancer cells and DCs activate T cell responses against autologous tumors.

  17. ANTITUMOR ACTIVITY OF HYALURONIC ACID SYNTHESIS INHIBITOR 4-METHYLUMBELLIFERONE IN PROSTATE CANCER CELLS

    Science.gov (United States)

    Lokeshwar, Vinata B.; Lopez, Luis E.; Munoz, Daniel; Chi, Andrew; Shirodkar, Samir P.; Lokeshwar, Soum D.; Escudero, Diogo O.; Dhir, Neetika; Altman, Norman

    2010-01-01

    4-methylumbelliferone (4-MU) is a hyaluronic acid (HA) synthesis inhibitor with anticancer properties; the mechanism of its anticancer effects is unknown. We evaluated the effects of 4-MU on prostate cancer cells. 4-MU inhibited proliferation, motility and invasion of DU145, PC3-ML, LNCaP, C4-2B and/or LAPC-4 cells. At IC50 for HA synthesis (0.4 mM), 4-MU induced > 3-fold apoptosis in prostate cancer cells, which could be prevented by HA addition. 4-MU induced caspase-8, -9 and -3 activation, PARP cleavage, up-regulation of Fas-L, Fas, FADD and DR4 and down regulation of bcl-2, phospho-bad, bcl-XL, phospho-Akt, phospho-IKB, phospho-ErbB2 and phospho-EGFR. At IC50, 4-MU also caused > 90% inhibition of NFkB reporter activity which was prevented partially by HA addition. With the exception of caveolin-1, HA prevented the 4-MU induced down regulation of HA receptors (CD44, RHAMM), matrix-degrading enzymes (MMP-2, MMP-9), IL-8, and chemokine receptors (CXCR1, CXCR4, CXCR7) at protein and mRNA levels. Expression of myristoylated-Akt rescued 4-MU induced apoptosis and inhibition of cell growth and IL-8, RHAMM, HAS2, CD44 and MMP-9 expression. Oral administration of 4-MU significantly decreased PC3-ML tumor growth (> 3-fold), when treatment was started either on the day of tumor cell injection or after the tumors became palpable, without organ toxicity, changes in serum chemistry or body weight. Tumors from 4-MU treated animals showed reduced microvessel density (~ 3-fold) and HA expression but increased TUNEL positive cells and expression of apoptosis-related molecules. Therefore, anticancer effects of 4-MU, an orally bioavailable and relatively non-toxic agent, are primarily mediated by inhibition of HA signaling. PMID:20332231

  18. Conjugation with polyamines enhances the antitumor activity of naphthoquinones against human glioblastoma cells.

    Science.gov (United States)

    Romão, Luciana; do Canto, Vanessa P; Netz, Paulo A; Moura-Neto, Vivaldo; Pinto, Ângelo C; Follmer, Cristian

    2018-03-20

    Glioblastoma multiform (GBM) is the most common and devastating type of primary brain tumor, being considered the deadliest of human cancers. In this context, extensive efforts have been undertaken to develop new drugs that exhibit both antiproliferation and antimetastasis effects on GBM. 1,4-Naphthoquinone (1,4-NQ) scaffold has been found in compounds able to inhibit important biological targets associated with cancer, which includes DNA topoisomerase, Hsp90 and monoamine oxidase. Among potential antineoplastic 1,4-NQs is the plant-derived lapachol (2-hydroxy-3-prenyl-1,4-naphthoquinone) that was found to be active against the Walker-256 carcinoma and Yoshida sarcoma. In the present study, we examined the effect of polyamine (PA)-conjugated derivatives of lapachol, nor-lapachol and lawsone on the growth and invasion of the human GBM cells. The conjugation with PA (a spermidine analog) resulted in dose-dependent and time-dependent increase of cytotoxicity of the 1,4-NQs. In addition, in-vitro inhibition of GBM cell invasion by lapachol was increased upon PA conjugation. Previous biochemical experiments indicated that these PA-1,4-NQs are capable of inhibiting DNA human topoisomerase II-α (topo2α), a major enzyme involved in maintaining DNA topology. Herein, we applied molecular docking to investigate the binding of PA-1,4-NQs to the ATPase site of topo2α. The most active molecules preferentially bind at the ATP-binding site of topo2α, which is energetically favored by the conjugation with PA. Taken together, these findings suggested that the PA-1,4-NQ conjugates might represent potential molecules in the development of new drugs in chemotherapy for malignant brain tumors.

  19. Antitumor Activities of the Novel Isosteviol Derivative 10C Against Liver Cancer.

    Science.gov (United States)

    Malki, Ahmed; El-Sharkawy, Ahmed; El Syaed, Mohamed; Bergmeier, Stephen

    2017-04-01

    Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the fifth most common primary malignancy with worldwide increasing incidence. The current study aimed to investigate the anticancer activities of novel isosteviol derivatives towards human HepG2 hepatocellular cancer cells and in an animal model of hepatocellular carcinoma. Twelve isosteviol derivatives were screened for their anti-proliferative activities against HepG2 and IC 50 was calculated for all designed derivatives. The impact of the potent isosteviol derivative 10C on HepG2 cells was further studied by MTT assay, Annexin V/PI staining, flow cytometry and western blotting. In vivo studies were performed to assess the anticancer effect of isosteviol derivative 10C on Diethyl Nitrosamine-induced liver cancer in female rats by evaluating the physiological processes. isosteviol derivative 10C induced growth inhibition with IC 50 of 2 μM mainly through induction of apoptosis in HepG2 cells. Additionally, isosteviol derivative 10C induced G 1 phase arrest, which was further confirmed by increased expression of cyclin dependent kinase inhibitor 1A (CDKN1A, p21). It also increased BAX, BID and PARP-1 and while it reduced pro-CASPASE-3 expression and phosphorylation levels of AKT in HepG2 cells. Furthermore, western blotting data showed that E-cadherin, β-catenin, VEGF and COX-2 expressions were suppressed by isosteviol derivative 10C in HepG2 cells. The in vivo study demonstrated that dose-dependent treatment of isosteviol derivative 10C led to significant reduction in tumor size compared to the untreated group after the fourth injection with no significant effects on major physiological processes. Taken together, in vitro and in vivo studies revealed that isosteviol derivative 10C induced apoptosis in HepG2 cells, blocked angiogenic signaling and it did not induce any apparent toxicity towards the treated hosts which merits further investigation at clinical level. Copyright© 2017

  20. A Rationally Designed Histone Deacetylase Inhibitor with Distinct Antitumor Activity against Ovarian Cancer

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    Ya-Ting Yang

    2009-06-01

    Full Text Available Histone deacetylase inhibitors (HDACIs are a class of antineoplastic agents previously demonstrating preclinical chemosensitizing activity against drug-resistant cancer cells and mouse xenografts. However, whereas clinical studies have shown efficacy against human hematologic malignancies, solid tumor trials have proved disappointing. We previously developed a novel HDACI, “OSU-HDAC42,” and herein examine its activity against ovarian cancer cell lines and xenografts. OSU-HDAC42, (i unlike most HDACIs, elicited a more than five-fold increase in G2-phase cells, at 2.5 µM, with G2 arrest followed by apoptosis; (ii at 1.0 µM, completely repressed messenger RNA expression of the cell cycle progression gene cdc2; (iii at low doses (0.25–1.0 µM for 24 hours, induced tumor cell epithelial differentiation, as evidenced by morphology changes and a more than five-fold up-regulation of epithelium-specific cytokeratins; (iv potently abrogated the growth of numerous ovarian cancer cells, with IC50 values of 0.5 to 1.0 µM, whereas also remaining eight-fold less toxic (IC50 of 8.6 µM to normal ovarian surface epithelial cells; and (v chemosensitizated platinum-resistant mouse xenografts to cisplatin. Compared with the clinically approved HDACI suberoylanilide hydroxamic acid (vorinostat, 1.0 µM OSU-HDAC42 was more biochemically potent (i.e., enzyme-inhibitory, as suggested by greater gene up-regulation and acetylation of both histone and nonhistone proteins. In p53-dysfunctional cells, however, OSU-HDAC42 was two- to eight-fold less inductive of p53-regulated genes, whereas also having a two-fold higher IC50 than p53-functional cells, demonstrating some interaction with p53 tumor-suppressive cascades. These findings establish OSU-HDAC42 as a promising therapeutic agent for drug-resistant ovarian cancer and justify its further investigation.

  1. Solution Properties and in Vitro Anti-Tumor Activities of Polysaccharides from Longan Pulp

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    Yang Yi

    2013-09-01

    Full Text Available The solution properties of four fractions (LPI–IV from crude longan pulp polysaccharides (LP3 were analyzed by size-exclusion chromatography combined with laser light scattering, viscometry, complex formation with Congo red, and atomic force microscopy. Their radii of gyration (z1/2 were 43.3, 62.6, 43.2 and 77.3 nm, exponents of z1/2 = k Mwv were 0.04, 0.50, 0.52 and 0.02, and intrinsic viscosities ([η] were 9.945, 25.38, 308.2 and 452.1 mL/g, respectively. Moreover, the dependence of [η] on Mw was established to be [η] = 5.3 × 10−2Mw0.61 (mL/g. LPI had both a sphere-like conformation and a triple-helix structure, and LPII–IV existed as flexible chains. LP3, LPI, LPII and LPIII all exhibited direct inhibitory effects on A549, HeLa and HepG2 cells in a positive dose-dependent manner in the range of 50–400 µg/mL. The activities of LPIII, especially the inhibition of HepG2 cell proliferation, were stronger than those of others, which may be partly related to its flexible conformation. The present results support the cancer therapeutic potential of longan polysaccharides.

  2. Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy

    International Nuclear Information System (INIS)

    Yu, Yao; Cai, Wei; Pei, Chong-gang; Shao, Yi

    2015-01-01

    Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo

  3. Mitoxantrone – an anthraquinone antibiotic with antitumor activity applied for the treatment of multiple sclerosis

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    Marzena Szwed

    2014-02-01

    Full Text Available Mitoxantrone is an antineoplastic agent approved for clinical use in the secondary progressive phase of multiple sclerosis (MS. Several scientific reports indicate that mitoxantrone acts through the induction of short-term cell lysis at high concentrations and long-term induction of programmed cell death at lower concentrations of antigen-presenting cells. In this paper, we present the potential cytotoxic effects of mitoxantrone on the cells of the immune system, whose activity is associated with their degenerative effects on axonal myelin sheaths. The article also evaluates the results from the hospital treatment of patients diagnosed with MS. The presented data indicate that, apart from the cytostatic properties, mitoxantrone also exhibits side effects of its clinical application. This drug has high cardiotoxicity, and is associated with decreased left ventricular ejection fraction and increased risk of congestive heart failure. Therefore researchers are currently looking for new substances that can reduce the toxic effects of mitoxantrone in healthy tissues, resulting in the generation of reactive oxygen species during its metabolism.

  4. Antitumor activity of the combination of synthetic retinoid ST1926 and cisplatin in ovarian carcinoma models.

    Science.gov (United States)

    Pisano, C; Vesci, L; Foderà, R; Ferrara, F F; Rossi, C; De Cesare, M; Zuco, V; Pratesi, G; Supino, R; Zunino, F

    2007-09-01

    The novel adamantyl retinoid ST1926 is a potent inducer of apoptosis in ovarian carcinoma cells. Since the pro-apoptotic effect is associated with activation of p53, in this study we have investigated the efficacy of combination of ST1926 with cisplatin, a DNA-damaging agent that is known to induce p53-dependent apoptosis. The efficacy of ST1926 and its combination with cisplatin was evaluated in human ovarian carcinoma models, including resistant tumors. Oral treatment with ST1926 alone caused a marginal tumor growth inhibition (cisplatin resulted in an improved efficacy, most evident in terms of tumor growth delay without a substantial increase of toxicity. The combination therapy achieved the best effects against the HOC18 ovarian carcinoma tumor, resulting in an appreciable number of animals without evidence of disease at the end of the experiment. In contrast to the marginal effect of ST1926 alone against the subcutaneous-growing tumors, loco-regional (intraperitoneal) treatment achieved a marked increase of survival of animals with ascitic IGROV-1 tumor. The present results document the efficacy of the combination of cisplatin with ST1926 and provide a rational basis for the design of novel, well-tolerated platinum-based treatment approaches in human ovarian carcinoma.

  5. Minocycline attenuates ototoxicity and enhances antitumor activity of cisplatin treatment in vitro.

    Science.gov (United States)

    Du, Bo; Zhang, Yan; Tang, Yong; Wang, Ping

    2011-05-01

    Some agents have been shown to prevent cisplatin-induced ototoxicity. The objective is to show that the agent minocycline protects the cochlea against cisplatin damage and enhances the cytotoxicity of anticancer therapies. In vitro chemotherapeutic assessments of minocycline. Research laboratory. Hep-2 cells were cultured with and without 100 μM cisplatin, and cell growth inhibition was assessed. Autophagy in the samples was visually evaluated by electron microscopy and by beclin-1 expression using Western blotting. In another experiment, cochlear basilar membranes of 3-day-old rats were isolated and cultured. The cultures were treated with the same concentration of cisplatin or cisplatin combined with minocycline. Immunofluorescence staining was used to identify changes in spiral ganglions. Cell growth was inhibited in a dose-dependent manner following minocycline treatment. Furthermore, the combination of cisplatin and minocycline effectively increased tumor cell death (P experiment evaluating cochlear spiral ganglion neuron survival, it was found that the number of surviving cochlear neurons significantly increased in the minocycline pretreatment group compared with the group treated with cisplatin alone (P < .01). This study shows that minocycline alone, or in combination with chemotherapeutic drugs, inhibits the growth of tumor cells and attenuates ototoxicity. It is also shown that minocycline activates cell autophagy via the beclin-1 signaling pathway, which may be an additional underlying cause of Hep- 2 cell death.

  6. Synthesis, crystal structure and antitumor activities of water soluble protonated salt of 20(S)-camptothecin

    Science.gov (United States)

    Lu, Wen; Wang, Yong; Wang, Luna; Zhao, Fengyi; Yang, Shilong; Xi, Chengjie; Yang, Yu; Xu, Li; Chi, Xingwei

    2018-03-01

    A water soluble camptothecin protonated salt has been synthesized; single crystals were grown by slow evaporation solution growth technique at room temperature and characterized by single crystal X-ray diffraction, FT-IR and 1H NMR. The CPT was protonated as (CPT+H+) cations, the cationic protonation occurred on the N position at pyridine group, which fromed a cation-anion compound with perchlorate ion that determined by X-Ray diffraction. Its activities against Hela (cervix), MCF-7 (breast), A549 (lung), HepG2 (liver) and HUVEC (umbilical vein, normal cell) were investigated. The toxicity of the protonated salt was slightly lower than camptothecin. IC50 values of 7.01 μM against HepG-2 cell, 8.61 μM against A549 cell, 17.82 μM against McF-7 cell, all of them are lower than the IC50 values of CPT against these cells except Hela cell.

  7. Gold(I)-NHC complexes of antitumoral diarylimidazoles: structures, cellular uptake routes and anticancer activities.

    Science.gov (United States)

    Kaps, Leonard; Biersack, Bernhard; Müller-Bunz, Helge; Mahal, Katharina; Münzner, Julienne; Tacke, Matthias; Mueller, Thomas; Schobert, Rainer

    2012-01-01

    Five new heterocyclic gold carbene complexes were prepared, four chlorido-[1,3-dimethyl-4,5-diarylimidazol-2-ylidene]gold complexes 6a-d and a chlorido-[1,3-dibenzylimidazol-2-ylidene]gold complex 11, and three of them were characterised by X-ray single crystal analyses. They were tested for cytotoxicity against a panel of four human cancer cell lines and non-malignant fibroblasts, for tubulin interaction, and for the pathways of their uptake into 518A2 melanoma cells. All complexes showed cytotoxic activity in the micromolar IC(50) range with distinct selectivities for certain cell lines. In stark contrast to related metal-free 1-methyl-4,5-diarylimidazoles, the complexes 6 and 11 did not noticeably inhibit the polymerisation of tubulin to give microtubules. The cellular uptake of complexes 6 occurred mainly via the copper transporter (Ctr1) and the organic cation transporters (OCT-1/2). Complex 11 was accumulated preferentially via the organic cation transporters and by Na(+)/K(+)-dependent endocytosis. The new gold carbene complexes seem to operate by a mechanism different from that of the parent 1-methylimidazolium ligands. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Antioxidant and Antitumor Activity of a Bioactive Polyphenolic Fraction Isolated from the Brewing Process

    Science.gov (United States)

    Tatullo, Marco; Simone, Grazia Maria; Tarullo, Franco; Irlandese, Gianfranco; Vito, Danila De; Marrelli, Massimo; Santacroce, Luigi; Cocco, Tiziana; Ballini, Andrea; Scacco, Salvatore

    2016-10-01

    There is increasing interest in identifying natural bioactive compounds that can improve mitochondrial functionality and regulate apoptosis. The brewery industry generates wastewater that could yield a natural extract containing bioactive phenolic compounds. Polyphenols act as antioxidants and have been documented to protect the human body from degenerative diseases such as cardiovascular diseases or cancer. The main aims of our research were to determine the phenolic profile of a crude extract obtained (at pilot scale) from a brewery waste stream and to evaluate the biochemical activity of this extract on the mitochondrial function of a cancer cell line (SH-SY5Y). This work is a basic translational pilot study. The total phenolic content was determined by the Folin-Ciocalteu assay, which revealed that 2.30% of the extract consisted of phenolic compounds. The polyphenols, identified and quantified by reverse-phase-high-performance liquid chromatography and mass spectrometry (RP-HPLC/MS), were mainly flavonoids. After cell culture, the tumoral cells treated with the polyphenolic extract showed enhanced mitochondrial oxidative function, which is likely related to a decrease in oxidative stress and an increase in mitochondrial biogenesis. This type of brewery waste stream, properly treated, may be a promising source of natural antioxidants to replace the synthetic antioxidants currently used in the food industry.

  9. Resistance to degradation and cellular distribution are important features for the antitumor activity of gomesin.

    Science.gov (United States)

    Buri, Marcus V; Domingues, Tatiana M; Paredes-Gamero, Edgar J; Casaes-Rodrigues, Rafael L; Rodrigues, Elaine Guadelupe; Miranda, Antonio

    2013-01-01

    Many reports have shown that antimicrobial peptides exhibit anticancer abilities. Gomesin (Gm) exhibits potent cytotoxic activity against cancer cells by a membrane pore formation induced after well-orchestrated intracellular mechanisms. In this report, the replacements of the Cys by Ser or Thr, and the use D-amino acids in the Gm structure were done to investigate the importance of the resistance to degradation of the molecule with its cytotoxicity. [Thr(2,6,11,15)]-Gm, and [Ser(2,6,11,15)]-Gm exhibits low cytotoxicity, and low resistance to degradation, and after 24 h are present in localized area near to the membrane. Conversely, the use of D-amino acids in the analogue [D-Thr(2,6,11,15)]-D-Gm confers resistance to degradation, increases its potency, and maintained this peptide spread in the cytosol similarly to what happens with Gm. Replacements of Cys by Thr and Gln by L- or D-Pro ([D-Thr(2,6,11,15), Pro(9)]-D-Gm, and [Thr(2,6,11,15), D-Pro(9)]-Gm), which induced a similar β-hairpin conformation, also increase their resistance to degradation, and cytotoxicity, but after 24 h they are not present spread in the cytosol, exhibiting lower cytotoxicity in comparison to Gm. Additionally, chloroquine, a lysosomal enzyme inhibitor potentiated the effect of the peptides. Furthermore, the binding and internalization of peptides was determined, but a direct correlation among these factors was not observed. However, cholesterol ablation, which increase fluidity of cellular membrane, also increase cytotoxicity and internalization of peptides. β-hairpin spatial conformation, and intracellular localization/target, and the capability of entry are important properties of gomesin cytotoxicity.

  10. Resistance to degradation and cellular distribution are important features for the antitumor activity of gomesin.

    Directory of Open Access Journals (Sweden)

    Marcus V Buri

    Full Text Available Many reports have shown that antimicrobial peptides exhibit anticancer abilities. Gomesin (Gm exhibits potent cytotoxic activity against cancer cells by a membrane pore formation induced after well-orchestrated intracellular mechanisms. In this report, the replacements of the Cys by Ser or Thr, and the use D-amino acids in the Gm structure were done to investigate the importance of the resistance to degradation of the molecule with its cytotoxicity. [Thr(2,6,11,15]-Gm, and [Ser(2,6,11,15]-Gm exhibits low cytotoxicity, and low resistance to degradation, and after 24 h are present in localized area near to the membrane. Conversely, the use of D-amino acids in the analogue [D-Thr(2,6,11,15]-D-Gm confers resistance to degradation, increases its potency, and maintained this peptide spread in the cytosol similarly to what happens with Gm. Replacements of Cys by Thr and Gln by L- or D-Pro ([D-Thr(2,6,11,15, Pro(9]-D-Gm, and [Thr(2,6,11,15, D-Pro(9]-Gm, which induced a similar β-hairpin conformation, also increase their resistance to degradation, and cytotoxicity, but after 24 h they are not present spread in the cytosol, exhibiting lower cytotoxicity in comparison to Gm. Additionally, chloroquine, a lysosomal enzyme inhibitor potentiated the effect of the peptides. Furthermore, the binding and internalization of peptides was determined, but a direct correlation among these factors was not observed. However, cholesterol ablation, which increase fluidity of cellular membrane, also increase cytotoxicity and internalization of peptides. β-hairpin spatial conformation, and intracellular localization/target, and the capability of entry are important properties of gomesin cytotoxicity.

  11. Curcumin inhibits glyoxalase 1: a possible link to its anti-inflammatory and anti-tumor activity.

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    Thore Santel

    Full Text Available BACKGROUND: Glyoxalases (Glo1 and Glo2 are involved in the glycolytic pathway by detoxifying the reactive methylglyoxal (MGO into D-lactate in a two-step reaction using glutathione (GSH as cofactor. Inhibitors of glyoxalases are considered as anti-inflammatory and anti-carcinogenic agents. The recent finding that various polyphenols modulate Glo1 activity has prompted us to assess curcumin's potency as an Glo1 inhibitor. METHODOLOGY/PRINCIPAL FINDINGS: Cultures of whole blood cells and tumor cell lines (PC-3, JIM-1, MDA-MD 231 and 1321N1 were set up to investigate the effect of selected polyphenols, including curcumin, on the LPS-induced cytokine production (cytometric bead-based array, cell proliferation (WST-1 assay, cytosolic Glo1 and Glo2 enzymatic activity, apoptosis/necrosis (annexin V-FITC/propidium iodide staining; flow cytometric analysis as well as GSH and ATP content. Results of enzyme kinetics revealed that curcumin, compared to the polyphenols quercetin, myricetin, kaempferol, luteolin and rutin, elicited a stronger competitive inhibitory effect on Glo1 (K(i = 5.1+/-1.4 microM. Applying a whole blood assay, IC(50 values of pro-inflammatory cytokine release (TNF-alpha, IL-6, IL-8, IL-1beta were found to be positively correlated with the K(i-values of the aforementioned polyphenols. Moreover, whereas curcumin was found to hamper the growth of breast cancer (JIMT-1, MDA-MB-231, prostate cancer PC-3 and brain astrocytoma 1321N1 cells, no effect on growth or vitality of human primary hepatocytes was elucidated. Curcumin decreased D-lactate release by tumor cells, another clue for inhibition of intracellular Glo1. CONCLUSIONS/SIGNIFICANCE: The results described herein provide new insights into curcumin's biological activities as they indicate that inhibition of Glo1 by curcumin may result in non-tolerable levels of MGO and GSH, which, in turn, modulate various metabolic cellular pathways including depletion of cellular ATP and GSH content

  12. Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo.

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    Yong-Qing Liu

    Full Text Available Previously, we reported that retigeric acid B (RB, a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its DNA binding activity, which correlated with suppression of NF-κB-regulated proteins including Bcl-2, Bcl-x(L, cyclin D1 and survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (lipopolysaccharide-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in tumor tissues. Additionally, DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-tumor effect of RB in other types of cancers as well.

  13. TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding.

    Science.gov (United States)

    Petrova, Penka S; Viller, Natasja Nielsen; Wong, Mark; Pang, Xinli; Lin, Gloria H Y; Dodge, Karen; Chai, Vien; Chen, Hui; Lee, Vivian; House, Violetta; Vigo, Noel T; Jin, Debbie; Mutukura, Tapfuma; Charbonneau, Marilyse; Truong, Tran; Viau, Stephane; Johnson, Lisa D; Linderoth, Emma; Sievers, Eric L; Maleki Vareki, Saman; Figueredo, Rene; Pampillo, Macarena; Koropatnick, James; Trudel, Suzanne; Mbong, Nathan; Jin, Liqing; Wang, Jean C Y; Uger, Robert A

    2017-02-15

    Purpose: The ubiquitously expressed transmembrane glycoprotein CD47 delivers an anti-phagocytic (do not eat) signal by binding signal-regulatory protein α (SIRPα) on macrophages. CD47 is overexpressed in cancer cells and its expression is associated with poor clinical outcomes. TTI-621 (SIRPαFc) is a fully human recombinant fusion protein that blocks the CD47-SIRPα axis by binding to human CD47 and enhancing phagocytosis of malignant cells. Blockade of this inhibitory axis using TTI-621 has emerged as a promising therapeutic strategy to promote tumor cell eradication. Experimental Design: The ability of TTI-621 to promote macrophage-mediated phagocytosis of human tumor cells was assessed using both confocal microscopy and flow cytometry. In vivo antitumor efficacy was evaluated in xenograft and syngeneic models and the role of the Fc region in antitumor activity was evaluated using SIRPαFc constructs with different Fc tails. Results: TTI-621 enhanced macrophage-mediated phagocytosis of both hematologic and solid tumor cells, while sparing normal cells. In vivo , TTI-621 effectively controlled the growth of aggressive AML and B lymphoma xenografts and was efficacious in a syngeneic B lymphoma model. The IgG1 Fc tail of TTI-621 plays a critical role in its antitumor activity, presumably by engaging activating Fcγ receptors on macrophages. Finally, TTI-621 exhibits minimal binding to human erythrocytes, thereby differentiating it from CD47 blocking antibodies. Conclusions: These data indicate that TTI-621 is active across a broad range of human tumors. These results further establish CD47 as a critical regulator of innate immune surveillance and form the basis for clinical development of TTI-621 in multiple oncology indications. Clin Cancer Res; 23(4); 1068-79. ©2016 AACR . ©2016 American Association for Cancer Research.

  14. The tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) imposes a brake on antitumor activity of CD8 T cells.

    Science.gov (United States)

    Giordano, Marilyn; Roncagalli, Romain; Bourdely, Pierre; Chasson, Lionel; Buferne, Michel; Yamasaki, Sho; Beyaert, Rudi; van Loo, Geert; Auphan-Anezin, Nathalie; Schmitt-Verhulst, Anne-Marie; Verdeil, Grégory

    2014-07-29

    The transcription factor NF-κB is central to inflammatory signaling and activation of innate and adaptive immune responses. Activation of the NF-κB pathway is tightly controlled by several negative feedback mechanisms, including A20, an ubiquitin-modifying enzyme encoded by the tnfaip3 gene. Mice with selective deletion of A20 in myeloid, dendritic, or B cells recapitulate some human inflammatory pathology. As we observed high expression of A20 transcripts in dysfunctional CD8 T cells in an autochthonous melanoma, we analyzed the role of A20 in regulation of CD8 T-cell functions, using mice in which A20 was selectively deleted in mature conventional T cells. These mice developed lymphadenopathy and some organ infiltration by T cells but no splenomegaly and no detectable pathology. A20-deleted CD8 T cells had increased sensitivity to antigen stimulation with production of large amounts of IL-2 and IFNγ, correlated with sustained nuclear expression of NF-κB components reticuloendotheliosis oncogene c-Rel and p65. Overexpression of A20 by retroviral transduction of CD8 T cells dampened their intratumor accumulation and antitumor activity. In contrast, relief from the A20 brake in NF-κB activation in adoptively transferred antitumor CD8 T cells led to improved control of melanoma growth. Tumor-infiltrating A20-deleted CD8 T cells had enhanced production of IFNγ and TNFα and reduced expression of the inhibitory receptor programmed cell death 1. As manipulation of A20 expression in CD8 T cells did not result in pathologic manifestations in the mice, we propose it as a candidate to be targeted to increase antitumor efficiency of adoptive T-cell immunotherapy.

  15. The Reaction of Cyanoacetylhydrazine with ω-Bromo(4-methylacetophenone: Synthesis of Heterocyclic Derivatives with Antitumor Activity

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    Rafat M. Mohareb

    2010-05-01

    Full Text Available New approaches for the synthesis of hydrazide-hydrazone derivatives were demonstrated as well as some heterocyclizations of such derivatives to afford 1,3,4-triazine, pyridine and 1,3,4-oxadiazine derivatives. The antitumor evaluation of the newly synthesized products against three cancer cell lines, namely breast adenocarcinoma (MCF-7, non-small cell lung cancer (NCI-H460 and CNS cancer (SF-268 were recorded. Most of the synthesized compounds showed high inhibitory effects.

  16. HDAC Inhibitor L-Carnitine and Proteasome Inhibitor Bortezomib Synergistically Exert Anti-Tumor Activity In Vitro and In Vivo

    OpenAIRE

    Huang, Hongbiao; Liu, Ningning; Yang, Changshan; Liao, Siyan; Guo, Haiping; Zhao, Kai; Li, Xiaofen; Liu, Shouting; Guan, Lixia; Liu, Chunjiao; Xu, Li; Zhang, Change; Song, Wenbin; Li, Bing; Tang, Ping

    2012-01-01

    Combinations of proteasome inhibitors and histone deacetylases (HDAC) inhibitors appear to be the most potent to produce synergistic cytotoxicity in preclinical trials. We have recently confirmed that L-carnitine (LC) is an endogenous HDAC inhibitor. In the current study, the anti-tumor effect of LC plus proteasome inhibitor bortezomib (velcade, Vel) was investigated both in cultured hepatoma cancer cells and in Balb/c mice bearing HepG2 tumor. Cell death and cell viability were assayed by fl...

  17. Anti-tumor activity of olaparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, in cultured endometrial carcinoma cells

    International Nuclear Information System (INIS)

    Miyasaka, Aki; Inaba, Kanako; Sone, Kenbun; Uehara, Yuriko; Kurikawa, Reiko; Nagasaka, Kazunori; Matsumoto, Yoko; Arimoto, Takahide; Nakagawa, Shunsuke; Kuramoto, Hiroyuki; Miyagawa, Kiyoshi; Oda, Katsutoshi; Yano, Tetsu; Kawana, Kei; Osuga, Yutaka; Fujii, Tomoyuki; Ikeda, Yuji; Wada-Hiraike, Osamu; Kashiyama, Tomoko; Enomoto, Atsushi; Hosoya, Noriko; Koso, Takahiro; Fukuda, Tomohiko

    2014-01-01

    PTEN inactivation is the most frequent genetic aberration in endometrial cancer. One of the phosphatase-independent roles of PTEN is associated with homologous recombination (HR) in nucleus. Poly (ADP-ribose) polymerase (PARP) plays key roles in the repair of DNA single-strand breaks, and a PARP inhibitor induces synthetic lethality in cancer cells with HR deficiency. We examined the anti-tumor activity of olaparib, a PARP inhibitor, and its correlation between the sensitivity and status of PTEN in endometrial cancer cell lines. The response to olaparib was evaluated using a clonogenic assay with SF50 values (concentration to inhibit cell survival to 50%) in 16 endometrial cancer cell lines. The effects of PTEN on the sensitivity to olaparib and ionizing radiation (IR) exposure were compared between parental HEC-6 (PTEN-null) and HEC-6 PTEN + (stably expressing wild-type PTEN) cells by clonogenic assay, foci formation of RAD51 and γH2AX, and induction of cleaved PARP. The effects of siRNA to PTEN were analyzed in cells with wild-type PTEN. The SF50 values were 100 nM or less in four (25%: sensitive) cell lines; whereas, SF50 values were 1,000 nM or more in four (25%: resistant) cell lines. PTEN mutations were not associated with sensitivity to olaparib (Mutant [n = 12]: 746 ± 838 nM; Wild-type [n = 4]: 215 ± 85 nM, p = 0.26 by Student’s t test). RAD51 expression was observed broadly and was not associated with PTEN status in the 16 cell lines. The number of colonies in the clonogenic assay, the foci formation of RAD51 and γH2AX, and the induction of apoptosis were not affected by PTEN introduction in the HEC-6 PTEN + cells. The expression level of nuclear PTEN was not elevated within 24 h following IR in the HEC-6-PTEN + cells. In addition, knocking down PTEN by siRNA did not alter the sensitivity to olaparib in 2 cell lines with wild-type PTEN. Our results suggest that olaparib, a PARP inhibitor, is effective on certain endometrial cancer cell lines

  18. Acylated mono-, bis- and tris- Cinchona-Based Amines Containing Ferrocene or Organic Residues: Synthesis, Structure and in Vitro Antitumor Activity on Selected Human Cancer Cell Lines

    OpenAIRE

    Károlyi, Benedek Imre; Bősze, Szilvia; Orbán, Erika; Sohár, Pál; Drahos, László; Gál, Emese; Csámpai, Antal

    2012-01-01

    A series of novel functionalized mono-, bis- and tris-(S)-{[(2S,4R,8R)-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl)}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60), human neuroblastoma (SH-SY5Y), human hepatoma (HepG2) and human breast cancer (MCF-7) cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoli...

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

    International Nuclear Information System (INIS)

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

    2013-01-01

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

  20. SYNTHESIS AND ANTITUMOR ACTIVITY OF COPPER, NICKEL AND COBALT COORDINATION COMPOUNDS WITH 1-(2-HYDROXYPHENYLETHANONE N(4-ALLYL-3-THIOSEMICARBAZONE

    Directory of Open Access Journals (Sweden)

    Vasilii GRAUR

    2015-12-01

    Full Text Available The paper presents the synthesis of the ligand 1-(2-hydroxyphenylethanone N(4-allyl-3-thiosemicarbazone (H2L and six coordination compounds of copper, nickel and cobalt with this ligand. The structure of thiosemicarbazone H2L was studied using 1H and 13С NMR spectroscopy. The synthesized coordination compounds were studied using elemental analysis, gravimetric analysis of water content, molar conductivity, and magnetochemistry. For H2L the antitumor activity towards human leukemia HL-60 cells and cervical cancer HeLa cells was determined. It was established that the substitution of hydrogen atom with methyl group in the azomethinic fragment leads to the growth of antitumor activity.SINTEZA ŞI ACTIVITATEA ANTITUMORALĂ A COMPUŞILOR COMPLECŞI AI CUPRULUI, NICHELULUI ŞI COBALTULUI CU N(4-ALIL-3-TIOSEMICARBAZONA 1-(2-HIDROXIFENILETANONEILucrarea conţine descrierea sintezei N(4-alil-3-tiosemicarbazonei 1-(2-hidroxifeniletanonei (H2L şi a şase compuşi coordinativi ai cuprului, nichelului şi cobaltului cu acest ligand. Structura tiosemicarbazonei H2L a fost stabilită în baza datelor spectroscopiei RMN 1H şi 13C. Compuşi coordinativi au fost studiaţi cu ajutorul analizei elementale, analizei gravimetrice a conţinutului de apă, conductivitaţii molare şi magnetochimiei. Pentru H2L a fost determinată activitatea antitumorală faţă de celulele leucemiei umane HL-60 şi ale cancerului cervical HeLa. S-a stabilit că înlocuirea atomului de hidrogen cu o grupare metil în fragmentul azomethinic conduce la creşterea activitaţii antitumorale.

  1. Bystander activation and anti-tumor effects of CD8+ T cells following Interleukin-2 based immunotherapy is independent of CD4+ T cell help.

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    Arta M Monjazeb

    Full Text Available We have previously demonstrated that immunotherapy combining agonistic anti-CD40 and IL-2 (IT results in synergistic anti-tumor effects. IT induces expansion of highly cytolytic, antigen-independent "bystander-activated" (CD8(+CD44high T cells displaying a CD25(-NKG2D(+ phenotype in a cytokine dependent manner, which were responsible for the anti-tumor effects. While much attention has focused on CD4(+ T cell help for antigen-specific CD8(+ T cell expansion, little is known regarding the role of CD4(+ T cells in antigen-nonspecific bystander-memory CD8(+ T cell expansion. Utilizing CD4 deficient mouse models, we observed a significant expansion of bystander-memory T cells following IT which was similar to the non-CD4 depleted mice. Expanded bystander-memory CD8(+ T cells upregulated PD-1 in the absence of CD4(+ T cells which has been published as a hallmark of exhaustion and dysfunction in helpless CD8(+ T cells. Interestingly, compared to CD8(+ T cells from CD4 replete hosts, these bystander expanded cells displayed comparable (or enhanced cytokine production, lytic ability, and in vivo anti-tumor effects suggesting no functional impairment or exhaustion and were enriched in an effector phenotype. There was no acceleration of the post-IT contraction phase of the bystander memory CD8(+ response in CD4-depleted mice. The response was independent of IL-21 signaling. These results suggest that, in contrast to antigen-specific CD8(+ T cell expansion, CD4(+ T cell help is not necessary for expansion and activation of antigen-nonspecific bystander-memory CD8(+ T cells following IT, but may play a role in regulating conversion of these cells from a central memory to effector phenotype. Additionally, the expression of PD-1 in this model appears to be a marker of effector function and not exhaustion.

  2. Adenovirus-mediated interleukin-12 gene transfer combined with cytosine deaminase followed by 5-fluorocytosine treatment exerts potent antitumor activity in Renca tumor-bearing mice

    International Nuclear Information System (INIS)

    Hwang, Kyung-Sun; Cho, Won-Kyung; Yoo, Jinsang; Yun, Hwan-Jung; Kim, Samyong; Im, Dong-Soo

    2005-01-01

    Therapeutic gene transfer affords a clinically feasible and safe approach to cancer treatment but a more effective modality is needed to improve clinical outcomes. Combined transfer of therapeutic genes with different modes of actions may be a means to this end. Interleukin-12 (IL-12), a heterodimeric immunoregulatory cytokine composed of covalently linked p35 and p40 subunits, has antitumor activity in animal models. The enzyme/prodrug strategy using cytosine deaminase (CD) and 5-fluorocytosine (5-FC) has been used for cancer gene therapy. We have evaluated the antitumor effect of combining IL-12 with CD gene transfer in mice bearing renal cell carcinoma (Renca) tumors. Adenoviral vectors were constructed encoding one or both subunits of murine IL-12 (Ad.p35, Ad.p40 and Ad.IL-12) or cytosine deaminase (Ad.CD). The functionality of the IL-12 or CD gene products expressed from these vectors was validated by splenic interferon (IFN)-γ production or viability assays in cultured cells. Ad.p35 plus Ad.p40, or Ad.IL-12, with or without Ad.CD, were administered (single-dose) intratumorally to Renca tumor-bearing mice. The animals injected with Ad.CD also received 5-FC intraperitoneally. The antitumor effects were then evaluated by measuring tumor regression, mean animal survival time, splenic natural killer (NK) cell activity and IFN-γ production. The inhibition of tumor growth in mice treated with Ad.p35 plus Ad.p40 and Ad.CD, followed by injection of 5-FC, was significantly greater than that in mice treated with Ad.CD/5-FC, a mixture of Ad.p35 plus Ad.p40, or Ad.GFP (control). The combined gene transfer increased splenic NK cell activity and IFN-γ production by splenocytes. Ad.CD/5-FC treatment significantly increased the antitumor effect of Ad.IL-12 in terms of tumor growth inhibition and mean animal survival time. The results suggest that adenovirus-mediated IL-12 gene transfer combined with Ad.CD followed by 5-FC treatment may be useful for treating cancers

  3. Antitumor activity of erlotinib (OSI-774, Tarceva) alone or in combination in human non-small cell lung cancer tumor xenograft models.

    Science.gov (United States)

    Higgins, Brian; Kolinsky, Kenneth; Smith, Melissa; Beck, Gordon; Rashed, Mohammad; Adames, Violeta; Linn, Michael; Wheeldon, Eric; Gand, Laurent; Birnboeck, Herbert; Hoffmann, Gerhard

    2004-06-01

    Our objective was the preclinical assessment of the pharmacokinetics, monotherapy and combined antitumor activity of the epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor erlotinib in athymic nude mice bearing non-small cell lung cancer (NSCLC) xenograft models. Immunohistochemistry determined the HER1/EGFR status of the NSCLC tumor models. Pharmacokinetic studies assessed plasma drug concentrations of erlotinib in tumor- and non-tumor-bearing athymic nude mice. These were followed by maximum tolerated dose (MTD) studies for erlotinib and each chemotherapy. Erlotinib was then assessed alone and in combination with these chemotherapies in the NSCLC xenograft models. Complete necropsies were performed on most of the animals in each study to further assess antitumor or toxic effects. Erlotinib monotherapy dose-dependently inhibited tumor growth in the H460a tumor model, correlating with circulating levels of drug. There was antitumor activity at the MTD with each agent tested in both the H460a and A549 tumor models (erlotinib 100 mg/kg: 71 and 93% tumor growth inhibition; gemcitabine 120 mg/kg: 93 and 75% tumor growth inhibition; cisplatin 6 mg/kg: 81 and 88% tumor growth inhibition). When each compound was given at a fraction of the MTD, tumor growth inhibition was suboptimal. Combinations of gemcitabine or cisplatin with erlotinib were assessed at 25% of the MTD to determine efficacy. In both NSCLC models, doses of gemcitabine (30 mg/kg) or cisplatin (1.5 mg/kg) with erlotinib (25 mg/kg) at 25% of the MTD were well tolerated. For the slow growing A549 tumor, there was significant tumor growth inhibition in the gemcitabine/erlotinib and cisplatin/erlotinib combinations (above 100 and 98%, respectively), with partial regressions. For the faster growing H460a tumor, there was significant but less remarkable tumor growth inhibition in these same combinations (86 and 53% respectively). These results show that in NSCLC xenograft tumors with similar

  4. [Advances in study on anti-tumor mechanism of andrographolide].

    Science.gov (United States)

    Qi, Cui-Ling; Wang, Li-Jing; Zhou, Xin-Lei

    2007-10-01

    In recent years, more and more attention was payed to the study of andrographolide. Andrographolide has the extensive pharmacological actions, such as anti-tumor, dephlogisticate and antibiosis and anti-virus. It was dected that andrographolide had the action of anti-tumor in gastric cancer, liver cancer, lung cancer and breast cancer. The anti-tumor mechanism of andrographolide was versatile, for instance, andrographolide can induce the apoptosis of cancer cell, inhibit the cell cycle, and increase the antitumor activity of lymphocyte. The following review was about the recent progress of study on the anti-tumor mechanism of andrographolide.

  5. Enhancement of antitumor activity by using a fully human gene encoding a single-chain fragmented antibody specific for carcinoembryonic antigen

    Science.gov (United States)

    Kuroki, Motomu; Kuroki, Masahide

    2017-01-01

    Human leukocyte antigen and/or costimulatory molecules are frequently lacking in metastatic tumor cells, and thus tumor cells are able to escape from the immune system. Although lymphocytes with a chimeric antigen receptor (CAR) is a promising approach for overcoming this challenge in cancer immunotherapy, administration of modified T cells alone often demonstrates little efficacy in patients. Therefore, in order to enhance the antitumor activity of immune cells in the cancer microenvironment, we used lymphocytes expressing CAR in combination with a fusion protein of IL-2 that contained the single-chain fragmented antibody (scFv) specific for the carcinoembryonic antigen. Among a series of CAR constructs, with or without a spacer and the intracellular domain of CD28, the CAR construct containing CD8α, CD28, and CD3ζ most effectively activated and expressed INF-γ in CAR-bearing T cells. Furthermore, in comparison with free IL-2, the combination of peripheral blood mononuclear cells expressing CAR and the fusion protein containing IL-2 significantly enhanced the antitumor activity against MKN-45 cells, a human gastric cancer cell line. In conclusion, this novel combination therapy of CAR and a fusion protein consisting of a functional cytokine and a fully human scFv may be a promising approach for adoptive cancer immunotherapy. PMID:28860806

  6. Purification of a protein from coelomic fluid of the earthworm Eisenia foetida and evaluation of its hemolytic, antibacterial, and antitumor activities.

    Science.gov (United States)

    Hua, Zhang; Wang, Yan-Hong; Cao, Hong-Wei; Pu, Li-Jun; Cui, Yu-Dong

    2011-03-01

    Earthworm Eisenia foetida (Lumbricus rubellus), a traditional Chinese medicine, is used for treating many diseases, and its coelomic fluid has extensive biological functions. The hemolytic, antibacterial and antitumor activities of an earthworm protein purified from coelomic fluid were investigated in vitro. We used ultrafiltration, gel chromatography, and ion exchange chromatography in sequence to isolate and purify an earthworm protein from coelomic fluid (ECFP), and ECFP was characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Hemolytic assay and antibacterial tests were applied to determine the cytolytic activity of ECFP. The MTT method was carried out to evaluate the antitumor effect of ECFP on HeLa cells and LTEP-A2 cells. ECFP, with molecular weight determined to be approximately 38.6 kilodaltons (KDa), was shown to possess significant hemolytic activity to chicken red blood cells (CRBC) (minimal hemolytic concentration 0.39 µg/mL). Antibacterial effect of ECFP obviously tested against Escherichia coli (minimal bactericidal concentration, MBC 180 µg/ mL) and Staphylococcus aureus (MBC 90 µg/mL) were observed. Moreover, ECFP notably inhibited the proliferation of HeLa cells (IC₅₀ 77 µg/mL) and LTEP-A2 cells (IC₅₀ 126 µg/mL) both in a time- and dose-dependent manner. ECFP could serve as a component of the innate defense system of earthworms against foreign organisms, and thus it has potential pharmaceutical application in the future.

  7. Telmisartan Exerts Anti-Tumor Effects by Activating Peroxisome Proliferator-Activated Receptor-γ in Human Lung Adenocarcinoma A549 Cells

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    Juan Li

    2014-03-01

    Full Text Available Telmisartan, a member of the angiotensin II type 1 receptor blockers, is usually used for cardiovascular diseases. Recent studies have showed that telmisartan has the property of PPARγ activation. Meanwhile, PPARγ is essential for tumor proliferation, invasion and metastasis. In this work we explore whether telmisartan could exert anti-tumor effects through PPARγ activation in A549 cells. MTT and trypan blue exclusion assays were included to determine the survival rates and cell viabilities. RT-PCR and western blotting were used to analyze the expression of ICAM-1, MMP-9 and PPARγ. DNA binding activity of PPARγ was evaluated by EMSA. Our data showed that the survival rates and cell viabilities of A549 cells were all reduced by telmisartan in a time- and concentration-dependent manner. Meanwhile, our results also demonstrated that telmisartan dose-dependently inhibited the expression of ICAM-1 and MMP-9. Moreover, the cytotoxic and anti-proliferative effects, ICAM-1 and MMP-9 inhibitive properties of telmisartan were totally blunted by the PPARγ antagonist GW9662. Our findings also showed that the expression of PPARγ was up-regulated by telmisartan in a dose dependent manner. And, the EMSA results also figured out that DNA binding activity of PPARγ was dose-dependently increased by telmisartan. Additionally, our data also revealed that telmisartan-induced PPARγ activation was abrogated by GW9662. Taken together, our results indicated that telmisartan inhibited the expression of ICAM-1 and MMP-9 in A549 cells, very likely through the up-regulation of PPARγ synthesis.

  8. An IL12-IL2-antibody fusion protein targeting Hodgkin's lymphoma cells potentiates activation of NK and T cells for an anti-tumor attack.

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    Tobias Jahn

    Full Text Available Successful immunotherapy of Hodgkin's disease is so far hampered by the striking unresponsiveness of lymphoma infiltrating immune cells. To mobilize both adoptive and innate immune cells for an anti-tumor attack we fused the pro-inflammatory cytokines IL2 and IL12 to an anti-CD30 scFv antibody in a dual cytokine fusion protein to accumulate both cytokines at the malignant CD30(+ Hodgkin/Reed-Sternberg cells in the lymphoma lesion. The tumor-targeted IL12-IL2 fusion protein was superior in activating resting T cells to amplify and secrete pro-inflammatory cytokines compared to targeted IL2 or IL12 alone. NK cells were also activated by the dual cytokine protein to secrete IFN-γ and to lyse target cells. The tumor-targeted IL12-IL2, when applied by i.v. injection to immune-competent mice with established antigen-positive tumors, accumulated at the tumor site and induced tumor regression. Data demonstrate that simultaneous targeting of two cytokines in a spatial and temporal simultaneous fashion to pre-defined tissues is feasible by a dual-cytokine antibody fusion protein. In the case of IL12 and IL2, this produced superior anti-tumor efficacy implying the strategy to muster a broader immune cell response in the combat against cancer.

  9. Artemisinic acid exhibits antitumor activity in MCF-7 breast cancer cells through the inhibition of angiogenesis, VEGF, m-TOR and AKT signalling pathways

    Directory of Open Access Journals (Sweden)

    Yan Cui

    2016-09-01

    Full Text Available The aim of the present study was to evaluate the antitumor and anti-angiogenic effects of artemisinic acid in MCF-7 human breast cancer cells. Various cell signalling pathways (VEGF, m-TOR and AKT signalling pathways and MTT assay were used. The in vivo antitumor activity of artemisinic acid was evaluated by means of tumor xenograft mouse model. Transwell cell migration assay was used to examine the chemotactic motility of the human umbilical vascular endothelial cells (HUVECs, while as endothelial cell capillary-like tube formation assay was used to evaluate the effect of artemisinic acid on the tube formation in HUVECs. We found that artemisinic acid considerably reduced both the volume and weight of concrete tumors and reduced angiogenesis in a xenograft mouse tumor model in vivo. Further, artemisinic acid suppressed the VEGF-induced cell migration and capillary-like tube formation of HUVECs in a dose-dependent manner. Artemisinic acid was found to suppress the VEGF-induced phosphorylation of VEGFR2 and also the activity of AKT and m-TOR.

  10. Synthesis, structure, antitumor activity of novel pharmaceutical co-crystals based on bispyridyl-substituted α, β-unsaturated ketones with gallic acid

    Science.gov (United States)

    Liu, Lian-Dong; Liu, Shu-Lian; Liu, Zhi-Xian; Hou, Gui-Ge

    2016-05-01

    Three novel pharmaceutical co-crystals, (A)·(gallic acid) (1), (B)·(gallic acid) (2), and (C)·(gallic acid) (3) were generated based on 2,6-bis((pyridin-4-yl)methylene)cyclohexanone (A), N-methyl-3,5-bis((pyridin-3-yl)methylene)-4-piperidone (B), N-methyl-3,5-bis((pyridin-4-yl)methylene)-4-piperidone (C) with gallic acid, respectively. They are characterized by elemental analysis, FTIR spectroscopy, 1H NMR and single-crystal X-ray diffraction. Structural analysis reveals that two pharmaceutical ingredients link each other into H-bonding-driven 3D network in 1, 2, or 2D plane in 3. In addition, their antitumor activities against human neoplastic cell lines A549, SGC-7901, MCF-7, OVCA-433, HePG2 and cytotoxicity for HUVEC cell lines by CCK-8 method were evaluated primarily. Compared with gallic acid and free A, B and C, their antitumor activities have improved distinctly, while cytotoxicities have reduced markedly, especially for co-crystal 1. This is mainly because of the synergistic effect between pharmaceutical ingredients A, B, and C and gallic acid.

  11. Acylated mono-, bis- and tris- cinchona-based amines containing ferrocene or organic residues: synthesis, structure and in vitro antitumor activity on selected human cancer cell lines.

    Science.gov (United States)

    Károlyi, Benedek Imre; Bösze, Szilvia; Orbán, Erika; Sohár, Pál; Drahos, László; Gál, Emese; Csámpai, Antal

    2012-02-24

    A series of novel functionalized mono-, bis- and tris-(S)-{[(2S,4R,8R)-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl)}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60), human neuroblastoma (SH-SY5Y), human hepatoma (HepG2) and human breast cancer (MCF-7) cells by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-assay and the 50% inhibitory concentration (IC(50)) values were determined. Our data indicate that the precursor amine has no antitumor activity in vitro, but the bis-methanamines with ureido-, thioureido and amide-type linkers display attractive in vitro cytotoxicity and cytostatic effects on HL-60, HepG2, MCF-7 and SH-SY5Y cells. Besides 1H- and 13C-NMR methods the structures of the new model compounds were also studied by DFT calculations.

  12. Acylated mono-, bis- and tris- Cinchona-Based Amines Containing Ferrocene or Organic Residues: Synthesis, Structure and in Vitro Antitumor Activity on Selected Human Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Emese Gál

    2012-02-01

    Full Text Available A series of novel functionalized mono-, bis- and tris-(S-{[(2S,4R,8R-8-ethyl-quinuclidin-2-yl](6-methoxyquinolin-4-yl}methanamines including ferrocene-containing derivatives was obtained by the reaction of the precursor amine with a variety of acylation agents. Their in vitro antitumor activity was investigated against human leukemia (HL-60, human neuroblastoma (SH-SY5Y, human hepatoma (HepG2 and human breast cancer (MCF-7 cells by the 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT-assay and the 50% inhibitory concentration (IC50 values were determined. Our data indicate that the precursor amine has no antitumor activity in vitro, but the bis-methanamines with ureido-, thioureido and amide-type linkers display attractive in vitro cytotoxicity and cytostatic effects on HL-60, HepG2, MCF-7 and SH-SY5Y cells. Besides 1H- and 13C-NMR methods the structures of the new model compounds were also studied by DFT calculations.

  13. Antitumor activity of docetaxel-loaded polymeric nanoparticles fabricated by Shirasu porous glass membrane-emulsification technique

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    Yu YN

    2013-07-01

    residence time, respectively, compared with those of PLGA nanoparticles, and 2.23-, 13.2-, 8.51-fold higher than those of Taxotere, respectively. In vivo real-time distribution of nanoparticles was measured on tumor-bearing mice by near-infrared fluorescence imaging, which demonstrated that the PLA-TPGS nanoparticles achieved much higher concentration and longer retention in tumors than PLGA nanoparticles after intravenous injection. This is consistent with the pharmacokinetic behavior of the nanoparticles. The tumor-inhibitory effect of DTX-loaded nanoparticles was observed in vivo in an H22 tumor-bearing mice model via intravenous administration. This indicated that PLA-TPGS nanoparticles are a feasible drug-delivery formulation with a pilot fabrication technique and have superior pharmacokinetic and anticancer effects compared to the commercially available Taxotere. Keywords: SPG membrane emulsification, nanoparticles, docetaxel, pharmacokinetics, antitumor activity

  14. Mangiferin exerts antitumor activity in breast cancer cells by regulating matrix metalloproteinases, epithelial to mesenchymal transition, and β-catenin signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hongzhong; Huang, Jing; Yang, Bing; Xiang, Tingxiu; Yin, Xuedong; Peng, Weiyan; Cheng, Wei [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Wan, Jingyuan; Luo, Fuling [Department of Pharmacology, Chongqing Medical University, Chongqing (China); Li, Hongyuan [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China); Ren, Guosheng, E-mail: rgs726@163.com [Molecular Oncology and Epigenetics Laboratory, The First Affiliated Hospital of Chongqing Medical University, Chongqing (China)

    2013-10-01

    Although mangiferin which is a naturally occurring glucosylxanthone has exhibited promising anticancer activities, the detailed molecular mechanism of mangiferin on cancers still remains enigmatic. In this study, the anticancer activity of mangiferin was evaluated in breast cancer cell line-based in vitro and in vivo models. We showed that mangiferin treatment resulted in decreased cell viability and suppression of metastatic potential in breast cancer cells. Further mechanistic investigation revealed that mangiferin induced decreased matrix metalloproteinase (MMP)-7 and -9, and reversal of epithelial–mesenchymal transition (EMT). Moreover, it was demonstrated that mangiferin significantly inhibited the activation of β-catenin pathway. Subsequent experiments showed that inhibiting β-catenin pathway might play a central role in mangiferin-induced anticancer activity through modulation of MMP-7 and -9, and EMT. Consistent with these findings in vitro, the antitumor potential was also verified in mangiferin-treated MDA-MB-231 xenograft mice where significantly decreased tumor volume, weight and proliferation, and increased apoptosis were obtained, with lower expression of MMP-7 and -9, vimentin and active β-catenin, and higher expression of E-cadherin. Taken together, our study suggests that mangiferin might be used as an effective chemopreventive agent against breast cancer. - Highlights: • Mangiferin inhibits growth and metastatic potential in breast cancer cells. • Mangiferin down-regulates MMP-7 and -9 in breast cancer cells. • Mangiferin induces the reversal of EMT in metastatic breast cancer cells. • Mangiferin inhibits the activation of β-catenin pathway in breast cancer cells. • Inhibiting β-catenin is responsible for the antitumor activity of mangiferin.

  15. Antitumor Activity of Doxorubicin-Loaded Carbon Nanotubes Incorporated Poly(Lactic-Co-Glycolic Acid) Electrospun Composite Nanofibers

    Science.gov (United States)

    Yu, Yuan; Kong, Lijun; Li, Lan; Li, Naie; Yan, Peng

    2015-08-01

    The drug-loaded composite electrospun nanofiber has attracted more attention in biomedical field, especially in cancer therapy. In this study, a composite nanofiber was fabricated by electrospinning for cancer treatment. Firstly, the carbon nanotubes (CNTs) were selected as carriers to load the anticancer drug—doxorubicin (DOX) hydrochloride. Secondly, the DOX-loaded CNTs (DOX@CNTs) were incorporated into the poly(lactic-co-glycolic acid) (PLGA) nanofibers via electrospinning. Finally, a new drug-loaded nanofibrous scaffold (PLGA/DOX@CNTs) was formed. The properties of the prepared composite nanofibrous mats were characterized by various techniques. The release profiles of the different DOX-loaded nanofibers were measured, and the in vitro antitumor efficacy against HeLa cells was also evaluated. The results showed that DOX-loaded CNTs can be readily incorporated into the nanofibers with relatively uniform distribution within the nanofibers. More importantly, the drug from the composite nanofibers can be released in a sustained and prolonged manner, and thereby, a significant antitumor efficacy in vitro is obtained. Thus, the prepared composite nanofibrous mats are a promising alternative for cancer treatment.

  16. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

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    Shaowei Wu

    2016-04-01

    Full Text Available Abrus cantoniensis (Hance is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L. Fourier-transform infrared spectroscopy (FT-IR and gas chromatography (GC were used to characterize these Abrus polysaccharides fractions (APF. In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%, arabinose (8.9%, fructose (3.0%, galactose (9.9%, glucose (4.3%, galacturonic acid (3.0% and glucuronic acid (61.1% with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent.

  17. The Effects of Different Purifying Methods on the Chemical Properties, in Vitro Anti-Tumor and Immunomodulatory Activities of Abrus cantoniensis Polysaccharide Fractions

    Science.gov (United States)

    Wu, Shaowei; Fu, Xiong; Brennan, Margaret A.; Brennan, Charles S.; Chun, Chen

    2016-01-01

    Abrus cantoniensis (Hance) is a popular Chinese vegetable consumed as a beverage, soup or folk medicine. To fully exploit the potential of the polysaccharide in Abrus cantoniensis, nine polysaccharide fractions of Abrus cantoniensis were isolated and purified (AP-AOH30-1, AP-AOH30-2, AP-AOH80-1, AP-AOH80-2, AP-ACl-1, AP-ACl-2, AP-ACl-3, AP-H and AP-L). Fourier-transform infrared spectroscopy (FT-IR) and gas chromatography (GC) were used to characterize these Abrus polysaccharides fractions (APF). In vitro anti-tumor and immunomodulatory activities were also investigated and compared using the rank-sum ratio (RSR) method. Results demonstrated significant differences in the structure and bioactivities among APF, which were associated to the process used for their purification. Among the APF, AP-ACl-3 yield was 613.5 mg/kg of product and consisted of rhamnose (9.8%), arabinose (8.9%), fructose (3.0%), galactose (9.9%), glucose (4.3%), galacturonic acid (3.0%) and glucuronic acid (61.1%) with a molecular weight of 4.4 × 104 Da. Furthermore, AP-ACl-3 exhibited considerable bioactivities significantly preventing the migration of MCF-7 cells and stimulating lymphocyte proliferation along with nitric oxide (NO) production of peritoneal macrophages. AP-ACl-3 could be explored as a novel potential anti-tumor and immunomodulatory agent. PMID:27058538

  18. TMPYP4 exerted antitumor effects in human cervical cancer cells through activation of p38 mitogen-activated protein kinase.

    Science.gov (United States)

    Cheng, Ming-Jun; Cao, Yun-Gui

    2017-07-03

    The aim of the present study was to investigate the potential effects of the 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4) on the proliferation and apoptosis of human cervical cancer cells and the underlying mechanisms by which TMPyP4 exerted its actions. After human cervical cancer cells were treated with different doses of TMPyP4, cell viability was determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) method, the apoptosis was observed by flow cytometry (FCM), and the expression of p38 mitogen-activated protein kinase (MAPK), phosphated p38 MAPK (p-p38 MAPK), capase-3, MAPKAPK2 (MK-2) and poly ADP-ribose polymerase (PARP) was measured by Western blot analysis. The analysis revealed that TMPyP4 potently suppressed cell viability and induced the apoptosis of human cervical cancer cells in a dose-dependent manner. In addition, the up-regulation of p-p38 MAPK expression levels was detected in TMPyP4-treated human cervical cancer cells. However, followed by the block of p38 MAPK signaling pathway using the inhibitor SB203580, the effects of TMPyP4 on proliferation and apoptosis of human cervical cancer cells were significantly changed. It was indicated that TMPyP4-inhibited proliferation and -induced apoptosis in human cervical cancer cells was accompanied by activating the p38 MAPK signaling pathway. Taken together, our study demonstrates that TMPyP4 may represent a potential therapeutic method for the treatment of cervical carcinoma.

  19. Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N-Docosahexaenoyl 2′, 2′-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity

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    Youssef W. Naguib

    2016-01-01

    Full Text Available In this study, a new compound, 4-(N-docosahexaenoyl 2′, 2′-difluorodeoxycytidine (DHA-dFdC, was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3 Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80–based solution is 12.86 kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 105-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58 minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio. DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

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

    Science.gov (United States)

    Huang, Jingcao; Wang, Shuiliang; Lyu, Hui; Cai, Bo; Yang, XiaoHe; Wang, Jianxiang; Liu, Bolin

    2013-11-11

    Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27(kip1). Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor

  1. Evaluation of a recombinant double mutant of staphylococcal enterotoxin B (SEB-H32Q/K173E with enhanced antitumor activity effects and decreased pyrexia.

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    Liwei Gu

    Full Text Available BACKGROUND: Immunotherapy has been used to improve patient immune function, inhibit tumor growth and has become a highly promising method of cancer treatment. Highly agglutinative staphylococcin (HAS, a mixture of Staphylococcus aureus culture filtrates, which include staphylococcal enterotoxin (SE C as the active ingredient, has been used clinically as an immunomodifier in the treatment of a number of tumors for many years. However, the use of HAS has been associated with some unavoidable side-effects such as fever. Previous studies have shown that SEB stimulates a more potent activation of T lymphocytes than SEC3, and mutations of the histidine residues eliminated the toxicity of SEB. SE mutants with decreased side-effects and/or more potent antitumor activities are required. METHODOLOGY/PRINCIPAL FINDINGS: We built a structural model of the MHC II-SEB-TCR complex and found that a mutation of SEB at Lys173 might decrease the repulsion force between the SEB-TCR, which would facilitate their interaction. From the above results, we designed SEB-H32Q/K173E (mSEB. Analysis of in vitro stimulation of the proliferation of human peripheral blood mononuclear cells (PBMCs, IFN-γ secretion and inhibition of the growth of various tumor cell lines demonstrated that mSEB exhibited higher antitumor activity compared with wild-type SEB (wtSEB. Notably, mSEB inhibited the growth of various tumors at an extremely low concentration with little cytotoxicity against normal cells. Three animal tumor models (C57BL/6 mouse, New Zealand rabbit and a humanized NOD/SCID mouse were used to evaluate the in vivo immunotherapeutic effects. Compared with wtSEB, mSEB significantly enhanced antitumor effect in more than one animal model with reduced pyrexia toxicity and prolonged the survival of tumor-bearing mice. CONCLUSIONS/SIGNIFICANCE: Our results suggest that SEB-H32Q/K173E retains superantigen (SAg characteristics and enhances the host immune response to neoplastic

  2. Combined ALK and MDM2 inhibition increases antitumor activity and overcomes resistance in humanALKmutant neuroblastoma cell lines and xenograft models.

    Science.gov (United States)

    Wang, Hui Qin; Halilovic, Ensar; Li, Xiaoyan; Liang, Jinsheng; Cao, Yichen; Rakiec, Daniel P; Ruddy, David A; Jeay, Sebastien; Wuerthner, Jens U; Timple, Noelito; Kasibhatla, Shailaja; Li, Nanxin; Williams, Juliet A; Sellers, William R; Huang, Alan; Li, Fang

    2017-04-20

    The efficacy of ALK inhibitors in patients with ALK -mutant neuroblastoma is limited, highlighting the need to improve their effectiveness in these patients. To this end, we sought to develop a combination strategy to enhance the antitumor activity of ALK inhibitor monotherapy in human neuroblastoma cell lines and xenograft models expressing activated ALK. Herein, we report that combined inhibition of ALK and MDM2 induced a complementary set of anti-proliferative and pro-apoptotic proteins. Consequently, this combination treatment synergistically inhibited proliferation of TP53 wild-type neuroblastoma cells harboring ALK amplification or mutations in vitro, and resulted in complete and durable responses in neuroblastoma xenografts derived from these cells. We further demonstrate that concurrent inhibition of MDM2 and ALK was able to overcome ceritinib resistance conferred by MYCN upregulation in vitro and in vivo. Together, combined inhibition of ALK and MDM2 may provide an effective treatment for TP53 wild-type neuroblastoma with ALK aberrations.

  3. Anti-tumor activities of a novel chlorin derivative for photodynamic therapy in vitro and in vivo

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    Li-Jun Zhang

    2015-01-01

    Full Text Available In this study, a novel photosensitizer meso-tetra (3-pyrrolidinomethyl-4-methoxyphenyl chlorin (TPMC was reported. It displays a characteristic long wavelength absorption peak at 656 nm and it shows a singlet oxygen quantum yield of 0.48. After light irradiation with 650 nm laser, it can kill Eca-109 and SMMC-7721 cells in vitro (25 mW/cm2, 1.2 to 3.6 J/cm2 and destroy Eca-109 tumor in nude mice (50 mW/cm2, 90 J/cm2. It has the perspective to be developed as a new anti-tumor drug in photodynamic therapy (PDT photodiagnosis, and deserves further investigation.

  4. Effects of Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici on the nematode Caenorhabditis elegans include possible antitumor activity.

    Science.gov (United States)

    Fasseas, Michael K; Fasseas, Costas; Mountzouris, Konstantinos C; Syntichaki, Popi

    2013-03-01

    This study examined the effects of three lactic acid bacteria (LAB) strains on the nematode Caenorhabditis elegans. Lactobacillus salivarius, Lactobacillus reuteri, and Pediococcus acidilactici were found to inhibit the development and growth of the worm. Compared to Escherichia coli used as the control, L. reuteri and P. acidilactici reduced the lifespan of wild-type and short-lived daf-16 worms. On the contrary, L. salivarius extended the lifespan of daf-16 worms when used live, but reduced it as UV-killed bacteria. The three LAB induced the expression of genes involved in pathogen response and inhibited the growth of tumor-like germ cells, without affecting DAF16 localization or increasing corpse cells. Our results suggest the possible use of C. elegans as a model for studying the antitumor attributes of LAB. The negative effects of these LAB strains on the nematode also indicate their potential use against parasitic nematodes.

  5. Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis.

    Science.gov (United States)

    Yang, Shucai; Ma, Jing; Xiao, Jianbing; Lv, Xiaohong; Li, Xinlei; Yang, Huike; Liu, Ying; Feng, Sijia; Zhang, Yafang

    2012-08-01

    Bladder cancer is the most common neoplasm in the urinary system. This study assesses arctigenin anti-tumor activity in human bladder cancer T24 cells in vitro and the underlying molecular events. The flow cytometry analysis was used to detect cell-cycle distribution and apoptosis. Western blotting was used to detect changes in protein expression. The data showed that arctigenin treatment reduced viability of bladder cancer T24 cells in a dose- and time-dependent manner after treatment with arctigenin (10, 20, 40, 80, and 100 μmol/L) for 24 hr and 48 hr. Arctigenin treatment clearly arrested tumor cells in the G1 phase of the cell cycle. Apoptosis was detected by hoechst stain and flow cytometry after Annexin-V-FITC/PI double staining. Early and late apoptotic cells were accounted for 2.32-7.01% and 3.07-7.35%, respectively. At the molecular level, arctigenin treatment decreased cyclin D1 expression, whereas CDK4 and CDK6 expression levels were unaffected. Moreover, arctigenin selectively altered the phosphorylation of members of the MAPK superfamily, decreasing phosphorylation of ERK1/2 and activated phosphorylation of p38 significantly in a dose-dependent manner. These results suggest that arctigenin may inhibit cell viability and induce apoptosis by direct activation of the mitochondrial pathway, and the mitogen-activated protein kinase pathway may play an important role in the anti-tumor effect of arctigenin. The data from the current study demonstrate the usefulness of arctigenin in bladder cancer T24 cells, which should further be evaluated in vivo before translation into clinical trials for the chemoprevention of bladder cancer. Copyright © 2012 Wiley Periodicals, Inc.

  6. Extraction of a Novel Cold-Water-Soluble Polysaccharide from Astragalus membranaceus and Its Antitumor and Immunological Activities

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    An-jun Liu

    2017-12-01

    Full Text Available The polysaccharides of Astragalus membranaceus have received extensive study and attention, but there have been few reports on the extraction of these polysaccharides using cold water (4 °C. In this study, we fractionated a novel cold-water-soluble polysaccharide (cAMPs-1A from Astragalus membranaceus with a 92.00% carbohydrate content using a DEAE-cellulose 52 anion exchange column and a Sephadex G-100 column. Our UV, Fourier-transform infrared spectroscopy (FTIR, high-performance gel permeation chromatography, and ion chromatography analysis results indicated the monosaccharide composition of cAMPs-1A with 1.23 × 104 Da molecular weight to be fucose, arabinose, galactose, glucose, and xylose, with molar ratios of 0.01:0.06:0.20:1.00:0.06, respectively. The UV spectroscopy detected no protein and nucleic acid in cAMPs-1A. We used FTIR analysis to characterize the α-d-pyranoid configuration in cAMPs-1A. In addition, we performed animal experiments in vivo to evaluate the antitumor and immunomodulatory effects of cAMPs-1A. The results suggested that cAMPs-1A oral administration could significantly inhibit tumor growth with the inhibitory rate of 20.53%, 36.50% and 44.49%, respectively, at the dosage of 75,150, and 300 mg/kg. Moreover, cAMPs-1A treatment could also effectively protect the immune organs, promote macrophage pinocytosis, and improve the percentages of lymphocyte subsets in the peripheral blood of tumor-bearing mice. These findings demonstrate that the polysaccharide cAMPs-1A has an underlying application as natural antitumor agents.

  7. Exceptionally strong sorption of infochemicals to activated carbon reduces their bioavailability to fish

    NARCIS (Netherlands)

    Jonker, Michiel T O; van Mourik, Louise

    2014-01-01

    The addition of activated carbon (AC) to sediments is a relatively new approach to remediate contaminated sites. Activated carbon strongly sorbs hydrophobic organic contaminants, thereby reducing their bioavailability and uptake in organisms. Because of its high sorption capacity, AC might, however,

  8. ChLpMab-23: Cancer-Specific Human-Mouse Chimeric Anti-Podoplanin Antibody Exhibits Antitumor Activity via Antibody-Dependent Cellular Cytotoxicity.

    Science.gov (United States)

    Kaneko, Mika K; Nakamura, Takuro; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Yamada, Shinji; Yanaka, Miyuki; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Ogasawara, Satoshi; Kato, Yukinari

    2017-06-01

    Podoplanin is expressed in many cancers, including oral cancers and brain tumors. The interaction between podoplanin and its receptor C-type lectin-like receptor 2 (CLEC-2) has been reported to be involved in cancer metastasis and tumor malignancy. We previously established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-23 (IgG 1 , kappa), one of the mouse anti-podoplanin mAbs, was shown to be a CasMab. However, we have not shown the usefulness of LpMab-23 for antibody therapy against podoplanin-expressing cancers. In this study, we first determined the minimum epitope of LpMab-23 and revealed that Gly54-Leu64 peptide, especially Gly54, Thr55, Ser56, Glu57, Asp58, Arg59, Tyr60, and Leu64 of podoplanin, is a critical epitope of LpMab-23. We further produced human-mouse chimeric LpMab-23 (chLpMab-23) and investigated whether chLpMab-23 exerts antibody-dependent cellular cytotoxicity (ADCC) and antitumor activity. In flow cytometry, chLpMab-23 showed high sensitivity against a podoplanin-expressing glioblastoma cell line, LN319, and an oral cancer cell line, HSC-2. chLpMab-23 also showed ADCC activity against podoplanin-expressing CHO cells (CHO/podoplanin). In xenograft models with HSC-2 and CHO/podoplanin, chLpMab-23 exerts antitumor activity using human natural killer cells, indicating that chLpMab-23 could be useful for antibody therapy against podoplanin-expressing cancers.

  9. Enhancement of antitumor activity by using a fully human gene encoding a single-chain fragmented antibody specific for carcinoembryonic antigen

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    Shibaguchi H

    2017-08-01

    Full Text Available Hirotomo Shibaguchi,1,* Naixiang Luo,1,* Naoto Shirasu,1,* Motomu Kuroki,2 Masahide Kuroki1 1Department of Biochemistry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 2School of Nursing, Faculty of Medicine, Fukuoka University, Fukuoka, Japan *These authors equally contributed to this work Abstract: Human leukocyte antigen and/or costimulatory molecules are frequently lacking in metastatic tumor cells, and thus tumor cells are able to escape from the immune system. Although lymphocytes with a chimeric antigen receptor (CAR is a promising approach for overcoming this challenge in cancer immunotherapy, administration of modified T cells alone often demonstrates little efficacy in patients. Therefore, in order to enhance the antitumor activity of immune cells in the cancer microenvironment, we used lymphocytes expressing CAR in combination with a fusion protein of IL-2 that contained the single-chain fragmented antibody (scFv specific for the carcinoembryonic antigen. Among a series of CAR constructs, with or without a spacer and the intracellular domain of CD28, the CAR construct containing CD8α, CD28, and CD3ζ most effectively activated and expressed INF-γ in CAR-bearing T cells. Furthermore, in comparison with free IL-2, the combination of peripheral blood mononuclear cells expressing CAR and the fusion protein containing IL-2 significantly enhanced the antitumor activity against MKN-45 cells, a human gastric cancer cell line. In conclusion, this novel combination therapy of CAR and a fusion protein consisting of a functional cytokine and a fully human scFv may be a promising approach for adoptive cancer immunotherapy. Keywords: chimeric antigen receptor, fusion protein, human scFv, CEA, combination therapy

  10. 1.2.2.Synthesis, crystal structure and in vitro anti-tumor activity of dibutyltin complex of 2,4-dichloro-5-fluorobenzoic acid

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    Ming Li, Liqin Wang, Zhenlei Zhang, Yue Xin, Laijin Tian*

    2014-04-01

    Full Text Available The dibutyltin complex of 2,4-dichloro-5- fluorobenzoic acid, [(2,4-Cl2 -5-FC6 H2 C(OOSnBu2 2 O]2 (Bu = CH2 CH2 CH2 CH3 (1 , has been synthesized and characterized by elemental analysis, FT-IR, 119 Sn NMR spectroscopy, and Xray single crystal diffraction. Compound 1 is a centrosymmetric dimmer with two distinct types of carboxylate moieties and tin atoms with distorted trigonal bipyramidal geometries. The in vitro  anti-tumor activity of 1 against two human tumor cell lines was found to be higher than that for cis-platin [cis diaminedichloroplatinum( II] used clinically. Supporting information : FT-IR, 119 Sn NMR, X-Ray, Proliferation inhibitory rate, Cif file.

  11. Pyruvate induces transient tumor hypoxia by enhancing mitochondrial oxygen consumption and potentiates the anti-tumor effect of a hypoxia-activated prodrug TH-302.

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    Yoichi Takakusagi

    Full Text Available BACKGROUND: TH-302 is a hypoxia-activated prodrug (HAP of bromo isophosphoramide mustard that is selectively activated within hypoxic regions in solid tumors. Our recent study showed that intravenously administered bolus pyruvate can transiently induce hypoxia in tumors. We investigated the mechanism underlying the induction of transient hypoxia and the combination use of pyruvate to potentiate the anti-tumor effect of TH-302. METHODOLOGY/RESULTS: The hypoxia-dependent cytotoxicity of TH-302 was evaluated by a viability assay in murine SCCVII and human HT29 cells. Modulation in cellular oxygen consumption and in vivo tumor oxygenation by the pyruvate treatment was monitored by extracellular flux analysis and electron paramagnetic resonance (EPR oxygen imaging, respectively. The enhancement of the anti-tumor effect of TH-302 by pyruvate treatment was evaluated by monitoring the growth suppression of the tumor xenografts inoculated subcutaneously in mice. TH-302 preferentially inhibited the growth of both SCCVII and HT29 cells under hypoxic conditions (0.1% O2, with minimal effect under aerobic conditions (21% O2. Basal oxygen consumption rates increased after the pyruvate treatment in SCCVII cells in a concentration-dependent manner, suggesting that pyruvate enhances the mitochondrial respiration to consume excess cellular oxygen. In vivo EPR oxygen imaging showed that the intravenous administration of pyruvate globally induced the transient hypoxia 30 min after the injection in SCCVII and HT29 tumors at the size of 500-1500 mm(3. Pretreatment of SCCVII tumor bearing mice with pyruvate 30 min prior to TH-302 administration, initiated with small tumors (∼ 550 mm(3, significantly delayed tumor growth. CONCLUSIONS/SIGNIFICANCE: Our in vitro and in vivo studies showed that pyruvate induces transient hypoxia by enhancing mitochondrial oxygen consumption in tumor cells. TH-302 therapy can be potentiated by pyruvate pretreatment if started at the

  12. The antitumor activity of tumor-homing peptide-modified thermosensitive liposomes containing doxorubicin on MCF-7/ADR: in vitro and in vivo.

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    Wang, Chao; Wang, Xin; Zhong, Ting; Zhao, Yang; Zhang, Wei-Qiang; Ren, Wei; Huang, Dan; Zhang, Shuang; Guo, Yang; Yao, Xin; Tang, Yi-Qun; Zhang, Xuan; Zhang, Qiang

    2015-01-01

    Clotted plasma proteins are present on the walls of tumor vessels and in tumor stroma. Tumor-homing peptide Cys-Arg-Glu-Lys-Ala (CREKA) could recognize the clotted plasma proteins in tumor vessels. Thermosensitive liposomes could immediately release the encapsulated drug in the vasculature of the heated tumor. In this study, we designed a novel form of targeted thermosensitive liposomes, CREKA-modified lysolipid-containing thermosensitive liposomes (LTSLs), containing doxorubicin (DOX) (DOX-LTSL-CREKA), to investigate the hypothesis that DOX-LTSL-CREKA might target the clotted plasma proteins in tumor vessels as well as tumor stroma and then exhibit burst release of the encapsulated DOX at the heated tumor site. We also hypothesized that the high local drug concentration produced by these thermosensitive liposomes after local hyperthermia treatment will be useful for treatment of multidrug resistance. The multidrug-resistant human breast adenocarcinoma (MCF-7/ADR) cell line was chosen as a tumor cell model, and the targeting and immediate release characteristics of DOX-LTSL-CREKA were investigated in vitro and in vivo. Furthermore, the antitumor activity of DOX-LTSL-CREKA was evaluated in MCF-7/ADR tumor-bearing nude mice in vivo. The targeting effect of the CREKA-modified thermosensitive liposomes on the clotted plasma proteins was confirmed in our in vivo imaging and immunohistochemistry experiments. The burst release of this delivery system was observed in our in vitro temperature-triggered DOX release and flow cytometry analysis and also by confocal microscopy experiments. The antitumor activity of the DOX-LTSL-CREKA was confirmed in tumor-bearing nude mice in vivo. Our findings suggest that the combination of targeting the clotted plasma proteins in the tumor vessel wall as well as tumor stroma by using CREKA peptide and temperature-triggered drug release from liposomes by using thermosensitive liposomes offers an attractive strategy for chemotherapeutic drug

  13. The Whole-Genome Sequence of Bacillus velezensis Strain SB1216 Isolated from the Great Salt Plains of Oklahoma Reveals the Presence of a Novel Extracellular RNase with Antitumor Activity.

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    Marasini, Daya; Cornell, Carolyn R; Oyewole, Opeoluwa; Sheaff, Robert J; Fakhr, Mohamed K

    2017-11-22

    The whole-genome sequence of Bacillus velezensis strain SB1216, isolated from the Great Salt Plains of Oklahoma, showed the presence of a 3,814,720-bp circular chromosome and no plasmids. The presence of a novel 870-bp extracellular RNase gene is predicted to be responsible for this strain's antitumor activity. Copyright © 2017 Marasini et al.

  14. The Whole-Genome Sequence of Bacillus velezensis Strain SB1216 Isolated from the Great Salt Plains of Oklahoma Reveals the Presence of a Novel Extracellular RNase with Antitumor Activity

    OpenAIRE

    Marasini, Daya; Cornell, Carolyn R.; Oyewole, Opeoluwa; Sheaff, Robert J.; Fakhr, Mohamed K.

    2017-01-01

    ABSTRACT The whole-genome sequence of Bacillus velezensis strain SB1216, isolated from the Great Salt Plains of Oklahoma, showed the presence of a 3,814,720-bp circular chromosome and no plasmids. The presence of a novel 870-bp extracellular RNase gene is predicted to be responsible for this strain’s antitumor activity.

  15. Synergistic antitumor activity of oncolytic reovirus and chemotherapeutic agents in non-small cell lung cancer cells

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    Coffey Matthew C

    2009-07-01

    Full Text Available Abstract Background Reovirus type 3 Dearing strain (ReoT3D has an inherent propensity to preferentially infect and destroy cancer cells. The oncolytic activity of ReoT3D as a single agent has been demonstrated in vitro and in vivo against various cancers, including colon, pancreatic, ovarian and breast cancers. Its human safety and potential efficacy are currently being investigated in early clinical trials. In this study, we investigated the in vitro combination effects of ReoT3D and chemotherapeutic agents against human non-small cell lung cancer (NSCLC. Results ReoT3D alone exerted significant cytolytic activity in 7 of 9 NSCLC cell lines examined, with the 50% effective dose, defined as the initial virus dose to achieve 50% cell killing after 48 hours of infection, ranging from 1.46 ± 0.12 ~2.68 ± 0.25 (mean ± SD log10 pfu/cell. Chou-Talalay analysis of the combination of ReoT3D with cisplatin, gemcitabine, or vinblastine demonstrated strong synergistic effects on cell killing, but only in cell lines that were sensitive to these compounds. In contrast, the combination of ReoT3D and paclitaxel was invariably synergistic in all cell lines tested, regardless of their levels of sensitivity to either agent. Treatment of NSCLC cell lines with the ReoT3D-paclitaxel combination resulted in increased poly (ADP-ribose polymerase cleavage and caspase activity compared to single therapy, indicating enhanced apoptosis induction in dually treated NSCLC cells. NSCLC cells treated with the ReoT3D-paclitaxel combination showed increased proportions of mitotic and apoptotic cells, and a more pronounced level of caspase-3 activation was demonstrated in mitotically arrested cells. Conclusion These data suggest that the oncolytic activity of ReoT3D can be potentiated by taxanes and other chemotherapeutic agents, and that the ReoT3D-taxane combination most effectively achieves synergy through accelerated apoptosis triggered by prolonged mitotic arrest.

  16. [Structural analysis and anti-tumor activity in vivo of polysaccharide APS-2a from Angelica sinensis].

    Science.gov (United States)

    Cao, Wei; Li, Xiao-Qiang; Hou, Ying; Fan, Hui-Ting; Zhang, Xiao-Nan; Mei, Qi-Bing

    2008-02-01

    The polysaccharide APS-2a was isolated from Angelica sinensis (Oliv.) Diels through water extraction, deprotein, ethanol precipitation and DEAE-sephades A-25 column chromatography respectively,and was further purified by Sephacryl S-400 and Sephadex G-100 column chromatography. The phenol-sulfuric acid assay and Bradford method were used to determine the contents of carbohydrate and protein, respectively. The molecular weight was carried out with high-performance size exclusion chromatography (HPSEC) combined with a differential refractometer detector. The monosaccharide compositions were determined by gas chromatography after complete hydrolysis with acid. The models of mice transplanted sarcoma S-180 were used to study the anti-tumor effects in vivo. Thymus indexes, spleen indexes were determined. The HPSEC result showed the APS-2a was a single homogeneous component and its weight average molecular weight was 7.4 x 10(5) Da. The monosaccharide composition of APS-2a was glucose, galactose, arabinose, rhamnose, galcturonic acid. Furthermore, APS-2a (20.50 mg/kg) could inhibit the proliferation of tumor cells in mice transplanted S-180. The thymus indexes and spleen indexes in the groups treated with APS-2a were higher than control group.

  17. Antitumor Activity of Portulaca Oleracea L. Polysaccharide on HeLa Cells Through Inducing TLR4/NF-κB Signaling.

    Science.gov (United States)

    Zhao, Rui; Zhang, Tao; Ma, Baoling; Li, Xing

    2017-01-01

    Abstarct We have previously shown that Portulaca oleracea L. polysaccharide (POL-P3b) possesses the ability to inhibit cervical cancer cell growth in vitro and in vivo. In this study, we explored how toll-like receptor 4 (TLR4) signaling correlated with the antitumor mechanism of POL-P3b. Western blotting was utilized to detect the expression of TLR4 and the downstream signaling pathway. The level of inflammatory mediator was quantified using enzyme-linked immunosorbent assay (ELISA) kits. The effects of POL-P3b on the proliferation and apoptosis in HeLa cells were determined by WST-8 assay and Hoechst 33342/propidium iodide (PI) assay. Our results demonstrated that lipopolysaccharide (LPS) binding to TLR4 on tumor cells could enhance HeLa cell proliferation and increase the expression of TLR4 and the downstream molecules. Treating HeLa cells with POL-P3b could decrease the proliferation of HeLa cells, and upregulate Bax level and downregulate Bcl-2 level in a concentration-dependent manner. In addition, POL-P3b inhibited the protein expression levels of TLR4, MyD88, TRAF6, Activator Protein-1 (AP-1) and nuclear factor-κB (NF-κB) subunit P65 in HeLa cells. Furthermore, POL-P3b also reduced the production of cytokine/chemokine. Taken together, the present work suggested the antitumor mechanism of POL-P3b by downregulating TLR4 downstream signaling pathway and inducing cell apoptosis. Our results may provide direct evidence to suggest that POL-P3b should be considered as a potent nutrient supplement for oncotherapy.

  18. Optimization of Purification, Identification and Evaluation of the in Vitro Antitumor Activity of Polyphenols from Pinus Koraiensis Pinecones.

    Science.gov (United States)

    Yi, Juanjuan; Wang, Zhenyu; Bai, Haina; Yu, Xiaojin; Jing, Jing; Zuo, Lili

    2015-06-05

    In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93 ± 0.14% (n = 3), which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line), A549 (human lung cancer cell line), SH-SY5Y (human neuroblastoma cell line), LOVO (human colon cancer stem cell line), MCF-7 (human breast cancer cell line), HeLa (human cervical cancer line), and HT29 (human colon cancer line), were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC50 value of 0.317 ± 0.0476 mg/mL. Finally, Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS) was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstrate that Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods.

  19. Optimization of Purification, Identification and Evaluation of the in Vitro Antitumor Activity of Polyphenols from Pinus Koraiensis Pinecones

    Directory of Open Access Journals (Sweden)

    Juanjuan Yi

    2015-06-01

    Full Text Available In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93 ± 0.14% (n = 3, which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line, A549 (human lung cancer cell line, SH-SY5Y (human neuroblastoma cell line, LOVO (human colon cancer stem cell line, MCF-7 (human breast cancer cell line, HeLa (human cervical cancer line, and HT29 (human colon cancer line, were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC50 value of 0.317 ± 0.0476 mg/mL. Finally, Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstrate that Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods.

  20. Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo.

    Science.gov (United States)

    Chakrabarti, Mrinmay; Ray, Swapan K

    2016-03-01

    Glioblastoma is the deadliest brain tumor in humans. High systemic toxicity of conventional chemotherapies prompted the search for natural compounds for controlling glioblastoma. The natural flavonoids luteolin (LUT) and silibinin (SIL) have anti-tumor activities. LUT inhibits autophagy, cell proliferation, metastasis, and angiogenesis and induces apoptosis; while SIL activates caspase-8 cascades to induce apoptosis. However, synergistic anti-tumor effects of LUT and SIL in glioblastoma remain unknown. Overexpression of tumor suppressor microRNA (miR) could enhance the anti-tumor effects of LUT and SIL. Here, we showed that 20 µM LUT and 50 µM SIL worked synergistically for inhibiting growth of two different human glioblastoma U87MG (wild-type p53) and T98G (mutant p53) cell lines and natural combination therapy was more effective than conventional chemotherapy (10 µM BCNU or 100 µM TMZ). Combination of LUT and SIL caused inhibition of growth of glioblastoma cells due to induction of significant amounts of apoptosis and complete inhibition of invasion and migration. Further, combination of LUT and SIL inhibited rapamycin (RAPA)-induced autophagy, a survival mechanism, with suppression of PKCα and promotion of apoptosis through down regulation of iNOS and significant increase in expression of the tumor suppressor miR-7-1-3p in glioblastoma cells. Our in vivo studies confirmed that overexpression of miR-7-1-3p augmented anti-tumor activities of LUT and SIL in RAPA pre-treated both U87MG and T98G tumors. In conclusion, our results clearly demonstrated that overexpression of miR-7-1-3p augmented the anti-tumor activities of LUT and SIL to inhibit autophagy and induce apoptosis for controlling growth of different human glioblastomas in vivo.

  1. Synthesis, antitumor activity and mechanism of action of novel 1,3-thiazole derivatives containing hydrazide-hydrazone and carboxamide moiety.

    Science.gov (United States)

    He, Haifeng; Wang, Xiaoyan; Shi, Liqiao; Yin, Wenyan; Yang, Ziwen; He, Hongwu; Liang, Ying

    2016-07-15

    A series of novel 2,4,5-trisubstituted 1,3-thiazole derivatives containing hydrazide-hydrazine, and carboxamide moiety including 46 compounds T were synthesized, and evaluated for their antitumor activity in vitro against a panel of five human cancer cell lines. Eighteen title compounds T displayed higher inhibitory activity than that of 5-Fu against MCF-7, HepG2, BGC-823, Hela, and A549 cell lines. Especially, T1, T26 and T38 exhibit best cytotoxic activity with IC50 values of 2.21μg/mL, 1.67μg/mL and 1.11μg/mL, against MCF-7, BCG-823, and HepG2 cell lines, respectively. These results suggested that the combination of 1,3-thiazole, hydrazide-hydrazone, and carboxamide moiety was much favorable to cytotoxicity activity. Furthermore, the flow cytometry analysis revealed that compounds T1 and T38 could induce apoptosis in HepG2 cells, and it was confirmed T38 led the induction of cell apoptosis by S cell-cycle arrest. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Antioxidant and cytotoxic activities of carob tree fruit pulps are strongly influenced by gender and cultivar.

    Science.gov (United States)

    Custodio, L; Fernandes, E; Escapa, A L; Fajardo, A; Aligue, R; Albericio, F; Neng, N R; Nogueira, J M F; Romano, A

    2011-07-13

    Extracts from fruit pulps of six female cultivars and two hermaphrodite Portuguese carob trees [(Ceratonia siliqua L., Fabaceae)] exhibited strong antioxidant activity and were rich in phenolic compounds. The extracts decreased the viability of different human cancer cell lines on a dose- and time-dependent manner. Gender and cultivar significantly influenced the chemical content and the biological activities of the extracts. Extracts from hermaphrodite trees had a higher content of phenolic compounds, and exhibited higher antioxidant and cytotoxic activities. Among females, cv. Aida had the highest radical scavenging activity and total content of phenolics, Mulata the highest capacity to inhibit lipid oxidation and Gasparinha the strongest cytotoxic activity on HeLa cells. The decrease in cell viability was associated with apoptosis on HeLa and MDA-MB-231 lines. (+)-Catechin and gallic acid (GA) were the main compounds identified in the extracts, and GA contributed to the antioxidant activity. Our results show that the antioxidant and cytotoxic activities of carob tree fruit pulps are strongly influenced by gender and cultivar, and provide new knowledge about the advantages of hermaphrodite trees over female cultivars, namely, as a source of compounds with biological interest, which may represent an increase of their agronomic interest.

  3. Structurally related antitumor effects of flavanones in vitro and in vivo: involvement of caspase 3 activation, p21 gene expression, and reactive oxygen species production

    International Nuclear Information System (INIS)

    Shen, S.-C.; Ko, C.H.; Tseng, S.-W.; Tsai, S.-H.; Chen, Y.-C.

    2004-01-01

    Flavonoids exist extensively in plants and Chinese herbs, and several biological effects of flavonoids have been demonstrated. The antitumor effects in colorectal carcinoma cells (HT29, COLO205, and COLO320HSR) of eight flavanones including flavanone, 2'-OH flavanone, 4'-OH flavanone, 6-OH flavanone, 7-OH flavanone, naringenin, nargin, and taxifolin were investigated. Results of the MTT assay indicate that 2'-OH flavanone showed the most potent cytotoxic effect on these three cells, and cell death induced by 2'-OH flavanone was via the occurrence of DNA ladders, apoptotic bodies, and hypodiploid cells, all characteristics of apoptosis. Induction of caspase 3 protein processing and enzyme activity associated with cleavage of poly(ADP-ribose) polymerase (PARP) was identified in 2'-OH flavanone-treated cells, and a peptidyl inhibitor (Ac-DEVD-FMK) of caspase 3 attenuated the cytotoxicity of 2'-OH flavanone in COLO205 and HT-29 cells. Elevation of p21 (but not p53) and a decrease in Mcl-1 protein were found in 2'-OH flavanone-treated COLO205 and HT-29 cells. Elevation of intracellular reactive oxygen species (ROS) was detected in 2'-OH flavanone-treated cells by the 2',7'-dichlorodihydrofluorescein diacetate (DCHF-DA) assay, and ROS scavengers including 4,5-dihydro-1,3-benzene disulfonic acid (tiron), catalase, superoxide dismutase (SOD), and pyrrolidine dithiocarbamate (PDTC) suppressed the 2'-OH flavanone-induced cytotoxic effect. Subcutaneous injection of COLO205 induced tumor formation in nude mice, and 2'-OH flavanone showed a significant inhibitory effect on tumor formation. The appearance of apoptotic cells with H and E staining, and an increase in p21, but not p53, protein by immunohistochemistry were observed in tumor tissues under 2'-OH flavanone treatment. Primary tumor cells (COLO205-X) derived from a tumor specimen elicited by COLO205 were established, and 2'-OH flavanone showed an significant apoptotic effect in COLO205-X cells in accordance with the

  4. Polarization and Strong Infra-Red Activity in Compressed Solid Hydrogen

    OpenAIRE

    Souza, Ivo; Martin, Richard M.

    1998-01-01

    Under a pressure of ~150 GPa solid molecular hydrogen undergoes a phase transition accompanied by a dramatic rise in infra-red absorption in the vibron frequency range. We use the Berry's phase approach to calculate the electric polarization in several candidate structures finding large, anisotropic dynamic charges and strongly IR-active vibron modes. The polarization is shown to be greatly affected by the overlap between the molecules in the crystal, so that the commonly used Clausius-Mossot...

  5. Routine daily physical activity and glucose variations are strongly coupled in adults with T1DM.

    Science.gov (United States)

    Farabi, Sarah S; Carley, David W; Cinar, Ali; Quinn, Lauretta

    2015-12-01

    Type 1 Diabetes (T1DM) is characterized by altered glucose homeostasis resulting in wide glucose variations throughout a 24-h period. The relationship between routine daily physical activity and glucose variations has not been systematically investigated in adults with T1DM. The objectives of this study were to characterize and quantify the relationship between routine daily activity and glucose variations in a small group of adults with T1DM. Adults with T1DM treated with an insulin pump were recruited for the study. Over a 3-day period, glucose variations were monitored with a continuous glucose monitoring system (CGMS) and routine daily physical activity was assessed using an accelerometer-based physical activity-monitoring band. Simultaneous glucose and physical activity data for one 24-h period were used for analysis. Cross-correlation function and wavelet coherence analyses were employed to quantify the coupling between physical activity and glucose. Twelve subjects were included in the analysis. Cross-correlation function analysis revealed strong coupling between activity and glucose. Wavelet Coherence demonstrated that slower oscillations (120-340 min) of glucose and physical activity exhibited significantly greater coherence (F = 12.6, P < 0.0001) than faster oscillations (10 and 120 min). Physical activity and glucose demonstrate strong time and frequency-dependent coupling throughout a 24-h time period in adults with T1DM. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  6. Biological activities, mechanisms of action and biomedical prospect of the antitumor ether phospholipid ET-18-OCH3 (edelfosine), a proapoptotic agent in tumor cells

    OpenAIRE

    Gajate, Consuelo; Mollinedo, Faustino

    2002-01-01

    The antitumor ether lipid ET-18-OCH3 (edelfosine) is the type of a new class of antineoplastic agents, synthetic analogues of lysophosphatidylcholine, that shows a high metabolic stability, does not interact with DNA and shows a selective apoptotic response in tumor cells, sparing normal cells. Unlike currently used antitumor drugs, ET-18-OCH3 does not act directly on the formation and function of the replication machinery, and thereby its effects are independent of the proliferative state of...

  7. The in Vitro and in Vivo Antitumor Activities of Tetracyclic Triterpenoids Compounds Actein and 26-Deoxyactein Isolated from Rhizome of Cimicifuga foetida L.

    Science.gov (United States)

    Wu, Desong; Yao, Qi; Chen, Yajuan; Hu, Xiaodong; Qing, Chen; Qiu, Minghua

    2016-07-30

    This work aims to study the in vitro and in vivo antitumor activities of tetracyclic triterpenoids compounds actein and 26-deoxyactein. Further, the mechanism is investigated. In vitro, a modified MTT method was used to assay the cytotoxicities of actein and 26-deoxyactein in 12 human tumor cell lines. In vivo, mouse sarcoma S180 and human lung cancer A549 cells were respectively implanted subcutaneously in ICR mice and nude mice to establish implanted tumor models. Flow cytometry (FCM) was used to assay the cycle distribution of the tumor cells. Immunohistochemistry was used to measure CD31-positive expression in the xenogrft tumor by analyzing microvessel density (MVD). In addition, acute toxicities of actein and 26-deoxyactein were also evaluated. Actein and 26-deoxyactein inhibited the proliferation of the 12 human cancer cell lines tested with the values of 50% inhibitory concentrations (IC50) between 12.29 and 88.39 μg/mL. In vivo, both actein (3-27 mg/kg) and 26-deoxyactein (3-27 mg/kg) significantly inhibited the growth of the implanted sarcoma S180 in a dose-dependent manner. Actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) markedly inhibited the xenograft growth with T/C (%) values of 38%, 55% for actein, and 35%, 49% for 26-deoxyactein. Compared with the vehicle control, actein (10, 30 mg/kg) and 26-deoxyactein (10, 30 mg/kg) significantly reduced the MVD in the xenograft tumor. The FCM result showed that human leukemia HL-60 cells were arrested at G₁ phase after treated with either actein (6.25-25 μg/mL) or 26-deoxyactein (6.25-25 μg/mL) for 48 h. A limited trial in mice showed that both of the minimal lethal doses (MLDs) of actein and 26-deoxyactein were over 5 g/kg. Both actein and 26-deoxyactein have low toxicities. Importantly, both these two tetracyclic triterpenoids compounds isolated from rhizome of Cimicifuga foetida L. have significant antitumor activities in vitro and in vivo, which is associated with cell cycle arrest and

  8. Evaluation of Magnetic Resonance Imaging Responsiveness in Active Psoriatic Arthritis at Multiple Timepoints during the First 12 Weeks of Antitumor Necrosis Factor Therapy.

    Science.gov (United States)

    Feletar, Marie; Hall, Stephen; Bird, Paul

    2016-01-01

    To assess the responsiveness of high- and low-field extremity magnetic resonance imaging (MRI) variables at multiple timepoints in the first 12 weeks post-antitumor necrosis factor (anti-TNF) therapy initiation in patients with psoriatic arthritis (PsA) and active dactylitis. Twelve patients with active PsA and clinical evidence of dactylitis involving at least 1 digit were recruited. Patients underwent sequential high-field conventional (1.5 Tesla) and extremity low-field MRI (0.2 Tesla) of the affected hand or foot, pre- and postgadolinium at baseline (pre-TNF), 2 weeks (post-TNF), 6 weeks, and 12 weeks. A blinded observer scored all images on 2 occasions using the PsA MRI scoring system. Eleven patients completed the study, but only 6 patients completed all high-field and low-field MRI assessments. MRI scores demonstrated rapid response to TNF inhibition with score reduction in tenosynovitis, synovitis, and osteitis at 2 weeks. Intraobserver reliability was good to excellent for all variables. High-field MRI demonstrated greater sensitivity to tenosynovitis, synovitis, and osteitis and greater responsiveness to change posttreatment. Treatment responses were maintained to 12 weeks. This study demonstrates the use of MRI in detecting early response to biologic therapy. MRI variables of tenosynovitis, synovitis, and osteitis demonstrated responsiveness posttherapy with high-field scores more responsive to change than low-field scores.

  9. Antiglycopeptide Mouse Monoclonal Antibody LpMab-21 Exerts Antitumor Activity Against Human Podoplanin Through Antibody-Dependent Cellular Cytotoxicity and Complement-Dependent Cytotoxicity.

    Science.gov (United States)

    Kato, Yukinari; Kunita, Akiko; Fukayama, Masashi; Abe, Shinji; Nishioka, Yasuhiko; Uchida, Hiroaki; Tahara, Hideaki; Yamada, Shinji; Yanaka, Miyuki; Nakamura, Takuro; Saidoh, Noriko; Yoshida, Kanae; Fujii, Yuki; Honma, Ryusuke; Takagi, Michiaki; Ogasawara, Satoshi; Murata, Takeshi; Kaneko, Mika K

    2017-02-01

    The interaction between podoplanin (PDPN) and C-type lectin-like receptor 2 (CLEC-2) is involved in tumor malignancy. We have established many monoclonal antibodies (mAbs) against human podoplanin using the cancer-specific mAb (CasMab) technology. LpMab-21, one of the mouse antipodoplanin mAbs, is of the IgG 2a subclass, and its minimum epitope was determined to be Thr76-Arg79 of the human podoplanin. Importantly, sialic acid is linked to Thr76; therefore, LpMab-21 is an antiglycopeptide mAb (GpMab). In this study, we investigated whether LpMab-21 shows antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against human podoplanin-expressing cancer cell lines in vitro and also studied its antitumor activities using a xenograft model. LpMab-21 showed high ADCC and CDC activities against not only podoplanin-expressing Chinese hamster ovary cells but also LN319 glioblastoma cells and PC-10 lung cancer cells, both of which endogenously express podoplanin. Furthermore, LpMab-21 decreased tumor growth in vivo, indicating that LpMab-21 could be useful for antibody therapy against human podoplanin-expressing cancers.

  10. Convolvulus galaticus, Crocus antalyensis, and Lilium candidum extracts show their antitumor activity through induction of p53-mediated apoptosis on human breast cancer cell line MCF-7 cells.

    Science.gov (United States)

    Tokgun, Onur; Akca, Hakan; Mammadov, Ramazan; Aykurt, Candan; Deniz, Gökhan

    2012-11-01

    Conventional and newly emerging treatment procedures such as chemotherapy, catalytic therapy, photodynamic therapy, and radiotherapy have not succeeded in reversing the outcome of cancer diseases to any drastic extent, which has led researchers to investigate alternative treatment options. The extensive repertoire of traditional medicinal knowledge systems from various parts of the world are being re-investigated for their healing properties. It has been reported that several members of the Convolvulaceae, Iridaceae, and Liliaceae families have antitumor activity against some tumor cell lines. Here we first report that Convolvulus galaticus, Crocus antalyensis, and Lilium candidum species have cytotoxic activity on human breast cancer cell line MCF-7 cells. Plant samples were collected and identified, and their cytotoxic effects on the MCF-7 cell line were examined at different concentrations of methanol extracts. We found that all three plants have cytotoxic effects on MCF-7 cells but that C. galaticus has the strongest cytotoxic effect even in the lowest extract concentration tested (0.32 μg/mL). Our results indicate that these plant extracts have cytotoxic effects on human breast carcinoma cell line MCF-7 cells and that this cytotoxic effect comes from p53-mediated stimulation of apoptosis.

  11. Vascular Targeting in Pancreatic Cancer: The Novel Tubulin-Binding Agent ZD6126 Reveals Antitumor Activity in Primary and Metastatic Tumor Models

    Directory of Open Access Journals (Sweden)

    Axel Kleespies

    2005-10-01

    Full Text Available ZD6126 is a novel vascular-targeting agent that acts by disrupting the tubulin cytoskeleton of an immature tumor endothelium, leading to an occlusion of tumor blood vessels and a subsequent tumor necrosis. We wanted to evaluate ZD6126 in primary and metastatic tumor models of human pancreatic cancer. Nude mice were injected orthotopically with L3.6pl pancreatic cancer cells. In single and multiple dosing experiments, mice received ZD6126, gemcitabine, a combination of both agents, or no treatment. For the induction of metastatic disease, additional groups of mice were injected with L3.6pl cells into the spleen. Twenty-four hours after a single-dose treatment, ZD6126 therapy led to an extensive central tumor necrosis, which was not seen after gemcitabine treatment. Multiple dosing of ZD6126 resulted in a significant growth inhibition of primary tumors and a marked reduction of spontaneous liver and lymph node metastases. Experimental metastatic disease could be significantly controlled by a combination of ZD6126 and gemcitabine, as shown by a reduction of the number and size of established liver metastases. As shown by additional in vitro and in vivo experiments, possible mechanisms involve antivascular activities and subsequent antiproliferative and proapoptotic effects of ZD6126 on tumor cells, whereas direct activities against tumor cells seem unlikely. These data highlight the antitumor and antimetastatic effects of ZD6126 in human pancreatic cancer and reveal benefits of adding ZD6126 to standard gemcitabine therapy.

  12. Antitumor Properties of Modified Detonation Nanodiamonds and Sorbed Doxorubicin on the Model of Ehrlich Ascites Carcinoma.

    Science.gov (United States)

    Medvedeva, N N; Zhukov, E L; Inzhevatkin, E V; Bezzabotnov, V E

    2016-01-01

    We studied antitumor properties of modified detonation nanodiamonds loaded with doxorubicin on in vivo model of Ehrlich ascites carcinoma. The type of tumor development and morphological characteristics of the liver, kidneys, and spleen were evaluated in experimental animals. Modified nanodiamonds injected intraperitoneally produced no antitumor effect on Ehrlich carcinoma. However, doxorubicin did not lose antitumor activity after sorption on modified nanodiamonds.

  13. Strong fascin expression promotes metastasis independent of its F-actin bundling activity.

    Science.gov (United States)

    Heinz, Lisa S; Muhs, Stefanie; Schiewek, Johanna; Grüb, Saskia; Nalaskowski, Marcus; Lin, Yuan-Na; Wikman, Harriet; Oliveira-Ferrer, Leticia; Lange, Tobias; Wellbrock, Jasmin; Konietzny, Anja; Mikhaylova, Marina; Windhorst, Sabine

    2017-12-15

    High expression of the actin bundling protein Fascin increases the malignancy of tumor cells. Here we show that fascin expression is up-regulated in more malignant sub-cell lines of MDA-MB-231 cells as compared to parental cells. Since also parental MDA-MB-231 cells exhibit high fascin levels, increased fascin expression was termed as "hyperexpression". To examine the effect of fascin hyperexpression, fascin was hyperexpressed in parental MDA-MB-231 cells and metastasis was analyzed in NOD scid gamma (NSG) mice. In addition, the effect of fascin mutants with inactive or constitutively active actin bundling activity was examined. Unexpectedly, we found that hyperexpression of both, wildtype (wt) and mutant fascin strongly increased metastasis in vivo , showing that the effect of fascin hyperexpression did not depend on its actin bundling activity. Cellular assays revealed that hyperexpression of wt and mutant fascin increased adhesion of MDA-MB-231 cells while transmigration and proliferation were not affected. Since it has been shown that fascin controls adhesion by directly interacting with microtubules ( MTs), we analyzed if fascin hyperexpression affects MT dynamics. We found that at high concentrations fascin significantly increased MT dynamics in cells and in cell-free approaches. In summary our data show that strong expression of fascin in breast cancer cells increases metastasis independent of its actin bundling activity. Thus, it seems that the mechanism of fascin-stimulated metastasis depends on its concentration.

  14. Mono-PEGylation of Alpha-MMC and MAP30 from Momordica charantia L.: Production, Identification and Anti-Tumor Activity.

    Science.gov (United States)

    Sun, Yun; Sun, Fenghui; Li, Jianlong; Wu, Minlu; Fan, Xiang; Meng, Yanfa; Meng, Yao

    2016-10-31

    PEGylation is a well-established and effective strategy to decrease immunogenicity, which can increase the stability and in vivo half-life time. However, the generation of multi-site modified products is inevitable due to the lysine chemistry, which will bring difficulties in subsequent research, such as purification and quantification. Site-specific modification by mPEG-succinimidyl carbonate (mPEG-SC) is a widely used method for N -terminal conjugation. In this study, we used it for site-directed modification on two ribosome-inactivating proteins (RIPs), alpha-momorcharin (α-MMC) and momordica anti-HIV protein (MAP30), from Momordica charantia L. According to the optimization of previous modification conditions, we compared Macro-Cap SP with SP-Sepharose FF chromatography for separating the final mPEGylated RIPs. Two kinds of methods both can obtain homogenous mPEGylated RIPs which were identified by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing electrophoresis (IEF), and matrix-assisted laser desorption ionization-time of flight/time of flight (MALDI-TOF/TOF) analysis. We also used iodine staining method to detect the amount of unmodified PEG. Furthermore, the inhibition activity of both mPEGylated and non-PEGylated RIPs against human lung adenocarcinoma epithelial A549 cells was detected. All of the results suggested that the mPEGylated α-MMC/MAP30 might be potentially developed as new anti-tumor drugs.

  15. Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6-substituted 3'-C-methyladenosine derivatives.

    Science.gov (United States)

    Cappellacci, Loredana; Franchetti, Palmarisa; Vita, Patrizia; Petrelli, Riccardo; Lavecchia, Antonio; Jayaram, Hiremagalur N; Saiko, Philipp; Graser, Geraldine; Szekeres, Thomas; Grifantini, Mario

    2008-07-24

    A series of cycloalkyl, bicycloalkyl, aryl, and heteroaryl N (6)-substituted derivatives of the antitumor agent 3'- C-methyladenosine (3'-Me-Ado), an inhibitor of the alpha Rnr1 subunit of mammalian ribonucleotide reductase (RR), were synthesized. The cytotoxicity of these compounds was evaluated against a panel of human leukemia and carcinoma cell lines and compared to that of some corresponding N (6)-substituted adenosine analogues. N (6)-cycloalkyl-3'- C-methylribonucleosides 2- 7 and N (6)-phenyl analogue 8 were found to inhibit the proliferation of K562 leukemia cells. N (6)-(+/-)- endo-2-norbornyl-3'- C-methyladenosine ( 7) was found to be the most cytotoxic compound, with GI 50 values slightly higher than that of 3'-Me-Ado against K562 and carcinoma cell lines and 2.7 fold higher cytotoxicity against human promyelocytic leukemia HL-60 cells. The SAR study confirms that an unsubstituted N (6)-amino group is essential for optimal cytotoxicity of 3'-Me-Ado against both K562 and carcinoma cell lines. Computational studies, carried out on the eukaryotic alpha subunit (Rnr1) of RR from Saccharomyces cerevisiae were performed to rationalize the observed structure-activity relationships.

  16. Antitumor activity of intratracheal inhalation of temozolomide (TMZ) loaded into gold nanoparticles and/or liposomes against urethane-induced lung cancer in BALB/c mice.

    Science.gov (United States)

    Hamzawy, Mohamed A; Abo-Youssef, Amira M; Salem, Heba F; Mohammed, Sameh A

    2017-11-01

    The current study aimed to develop gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) as drug carriers for temozolomide (TMZ) and investigate the possible therapeutic effects of intratracheal inhalation of nanoformulation of TMZ-loaded gold nanoparticles (TGNPs) and liposome-embedded TGNPs (LTGNPs) against urethane-induced lung cancer in BALB/c mice. Physicochemical characters and zeta potential studies for gold nanoparticles (GNPs) and liposome-embedded gold nanoparticles (LGNPs) were performed. The current study was conducted by inducing lung cancer chemically via repeated exposure to urethane in BALB/C mice. GNPs and LGNPs were exhibited in uniform spherical shape with adequate dispersion stability. GNPs and LGNPs showed no significant changes in comparison to control group with high safety profile, while TGNPs and LTGNPs succeed to improve all biochemical data and histological patterns. GNPs and LGNPs are promising drug carriers and succeeded in the delivery of small and efficient dose of temozolomide in treatment lung cancer. Antitumor activity was pronounced in animal-treated LTGNPs, these effects may be due to synergistic effects resulted from combination of temozolomide and gold nanoparticles and liposomes that may improve the drug distribution and penetration.

  17. Novel 2-(R-phenyl)amino-3-(2-methylpropenyl)-[1,4]-naphthoquinones: synthesis, characterization, electrochemical behavior and antitumor activity

    Energy Technology Data Exchange (ETDEWEB)

    Francisco, Acacio I.; Casellato, Annelise; Neves, Amanda P.; Carneiro, J. Walkimar de M.; Vargas, Maria D. [Universidade Federal Fluminense (UFF), Niteroi, RJ (Brazil). Inst. de Quimica], e-mail: mdvargas@vm.uff.br; Visentin, Lorenzo do C. [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Inst. de Quimica; Magalhaes, Alvicler [Universidade Estadual de Campinas, SP (Brazil). Inst. de Quimica; Camara, Celso A. [Universidade Federal Rural de Pernambuco (UFRPE), Recife, PE (Brazil). Inst. de Quimica; Pessoa, Claudia; Costa-Lotufo, Leticia V.; Marinho Filho, Jose D.B.; Moraes, Manoel O. de [Universidade Federal do Ceara (UFC), Fortaleza, CE (Brazil). Dept. de Fisiologia e Farmacologia

    2010-07-01

    Novel 2-(R-phenyl)amino-3-(2-methyl-propenyl)-[1,4]-naphthoquinones (R H, 4-OMe, 4-Ferrocenyl, 4-Me, 3-Me, 4-I, 3-I, 4-CN, 3-CN, 4-NO{sub 2} and 3-NO{sub 2}) derived from nor-lapachol [2-hydroxy-3-(2-methylpropenyl)-1,4-naphthoquinone] were obtained in good yields. Their structures were proposed on the basis of a single crystal X-ray diffraction study (R = OMe, 2b), {sup 1}H and {sup 13}C NMR studies and calculations using the B3LYP functional and the 6-311+G(2d,p) basis set. The half-wave potentials of the aminonaphthoquinones and 1H NMR chemical shifts of the 3-propenyl hydrogen in 2a-k show good correlation with the substituent Hammett constants on the phenylamino ring. The antitumor assays showed promising activity for substrate methoxy-nor-lapachol 1 and the 4-ferrocenyl derivative 2c. (author)

  18. Synthesis, Structural Characterization, and Antitumor Activity of a Ca(II Coordination Polymer Based on 1,6-Naphthalenedisulfonate and 4,4′-Bipyridyl

    Directory of Open Access Journals (Sweden)

    Xishi Tai

    2013-08-01

    Full Text Available A novel Ca(II coordination polymer, [CaL(4,4′-bipyridyl(H2O4]n (L = 1,6-naphthalenedisulfonate, was synthesized by reaction of calcium perchlorate with 1,6-naphthalenedisulfonic acid disodium salt and 4,4′-bipyridyl in CH3CH2OH/H2O. It was characterized by elemental analysis, IR, molar conductivity and thermogravimetric analysis. X-ray crystallography reveals that the Ca(II coordination polymer belongs to the orthorhombic system, with space group P212121. The geometry of the Ca(II ion is a distorted CaNO6 pengonal bipyramid, arising from its coordination by four water molecules, one nitrogen atom of 4,4′-bipyridyl molecule, and two oxygen atoms from two L ligands. The complex molecules form a helical chain by self-assembly. The antitumor activity of 1,6-naphthalenedisulfonic acid disodium salt and the Ca(II coordination polymer against human hepatoma smmc-7721 cell line and human lung adenocarcinoma A549 cell line reveals that the Ca(II coordination polymer inhibits cell growth of human lung adenocarcinoma A549 cell line with IC50 value of 27 μg/mL, and is more resistive to human lung adenocarcinoma A549 cell line as compared to 1,6-naphthalenedisulfonic acid disodium salt.

  19. Drag Effect of Kompsat-1 During Strong Solar and Geomagnetic Activity

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    J. Park

    2007-06-01

    Full Text Available In this paper, we analyze the orbital variation of the KOrea Multi-Purpose SATellite-1(KOMPSAT-1 in a strong space environment due to satellite drag by solar and geomagnetic activities. The satellite drag usually occurs slowly, but becomes serious satellite drag when the space environment suddenly changes via strong solar activity like a big flare eruption or coronal mass ejections(CMEs. Especially, KOMPSAT-1 as a low earth orbit satellite has a distinct increase of the drag acceleration by the variations of atmospheric friction. We consider factors of solar activity to have serious effects on the satellite drag from two points of view. One is an effect of high energy radiation when the flare occurs in the Sun. This radiation heats and expands the upper atmosphere of the Earth as the number of neutral particles is suddenly increased. The other is an effect of Joule and precipitating particle heating caused by current of plasma and precipitation of particles during geomagnetic storms by CMEs. It also affects the density of neutral particles by heating the upper atmosphere. We investigate the satellite drag acceleration associated with the two factors for five events selected based on solar and geomagnetic data from 2001 to 2002. The major results can be summarized as follows. First, the drag acceleration started to increase with solar EUV radiation with the best cross-correlation (r = 0.92 for 1 day delayed F10.7. Second, the drag acceleration and Dst index have similar patterns when the geomagnetic storm is dominant and the drag acceleration abruptly increases during the strong geomagnetic storm. Third, the background variation of the drag accelerations is governed by the solar radiation, while their short term (less than a day variations is governed by geomagnetic storms.

  20. Siderophoregenic Acinetobacter calcoaceticus Isolated From Wheat Rhizosphere With Strong PGPR Activity

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    Chaudhari Bhushan, L.

    2009-01-01

    Full Text Available Thirty-two bacterial isolates were obtained from wheat rhizosphere in black cotton soils of North Maharashtra region and subsequently tested for in-vitro siderophore production. Wheat isolate SCW1, being a strong siderophore producer, was selected, identified and confirmed as Acinetobacter calcoaceticus. The strain produced catechol type of siderophores during exponential phase which was influenced by iron content of medium. Seed bacterization with siderophoregenic A. calcoaceticus improved plant growth in pot and field studies. Such PGPR activity was attributed to the ability of strain to solubilise phosphates and produce IAA. Siderophore mediated antagonism was observed against common phytopathogens viz., Aspergillus flavus, A. niger, Colletotrichum capsicum and Fusarium oxysporum.

  1. Strong Optical Activity of HDE 245770/A0535+26 System

    Science.gov (United States)

    Giovannelli, Franco; Gualandi, Roberto; Sabau-Graziati, Lola

    2010-03-01

    The O9.7IIIe star HDE 245770, nicknamed Flavia' star, is the optical counterpart of the X-ray pulsar A0535+26. On March 19, 2010 from UT 18hh 45mm 37ss to 19hh 28mm 07ss at the Loiano 1.52 m telescope we performed optical spectroscopy of this star in the range 330 - 785 nm [Delta(lambda) from about 0.4 to 0.3 nm] by using the BFOSC (Bologna Faint Object Spectrograph & Camera). The first analysis of the spectra shows a strong optical activity of the star.

  2. A novel nontoxic alkyl-phospholipid with selective antitumor activity, plasmanyl-(N-acyl)-ethanolamine (PNAE), isolated from degenerating chick embryonal tissues and from an anticancer biopreparation cACPL.

    Science.gov (United States)

    Kára, J; Borovicka, M; Liebl, V; Smolíková, J; Ubik, K

    1986-01-01

    A novel alkyl-phospholipid with selective antitumor activity was isolated from an anticancer biopreparation cACPL (crude anticancer phospholipids) and from tissues of degenerating chick embryos. The alkyl-phospholipid was isolated and purified by chromatographic methods using silicic acid column chromatography and thin layer chromatography. The chemical structure of the alkyl-phospholipid was characterized by thin-layer chromatographic analysis of the degradation products after enzymatic digestion with phospholipase C from Bacillus cereus and with phospholipase D, by two-dimensional thin-layer chromatography, infrared spectrum, and mass spectrometric analysis. The alkyl-phospholipid was identified as 1-O-alkyl-2-acyl-sn-glycero-3-phospho-(N-acyl)-ethanolamine, i.e. plasmanyl-(N-acyl)-ethanolamine (PNAE), the main molecular species being 1-O-octadecyl-2-oleoyl-sn-glycero-3-phospho-(N-palmitoyl)-ethanol-amine. PNAE exhibits a selective cytolytic effect on human tumor cells HEp-2, HeLa and T24 in tissue cultures at the concentration of 25 micrograms PNAE per ml and 66-98% inhibition of DNA synthesis in the human tumor cells at concentration as low as 2.5 micrograms/ml, but it does not inhibit at a 50-fold higher concentration the DNA synthesis and normal growth of human fibroblasts (cell line LEP). PNAE represents the main biologically active antitumor component of the cACPL biopreparation and exhibits a significant antitumor effect in vivo in B10/An mice bearing Mc11 fibrosarcoma. Possible molecular mechanism of the selective antitumor activity of PNAE is discussed, involving the selective disturbance of phospholipid metabolism in tumor cells, leading to progressive destruction of tumor cell membranes. The fact that PNAE is nontoxic and selectively active against tumor cells at nanomolar concentrations in vitro as well as in vivo, indicates the possibility of its clinical use. PNAE and cACPL biopreparation might provide a very useful new tool for human anticancer

  3. Chloroquine upregulates TRAIL/TRAILR2 expression and potentiates doxorubicin anti-tumor activity in thioacetamide-induced hepatocellular carcinoma model.

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    Helmy, Sahar A; El-Mesery, Mohamed; El-Karef, Amro; Eissa, Laila A; El Gayar, Amal M

    2018-01-05

    Impaired apoptosis and systemic toxicity of chemotherapeutic drugs make cancer treatment suboptimal. Thus, there is urgency for drug repurposing which facilitates discovery of safe and effective combination therapy. This study aimed to evaluate chloroquine's (CQ) ability to trigger TRAIL/TRAILR2 apoptotic pathway in thioacetamide (TAA)-induced hepatocellular carcinoma (HCC) either alone or in combination with doxorubicin (DOX). Moreover, its ability to attenuate DOX-induced cardiotoxicity was investigated. TAA was injected in male Sprague Dawely rats (200 mg/kg; ip; 2 times/week) for 16 weeks. After the 16th week, rats were further divided into different groups (n = 10) and treated for 7 weeks. CQ group (received CQ 25 mg/kg/day; orally), DOX group (received DOX 1 mg/kg; ip; 2 times/week) and CQ/DOX group. Liver function biomarkers, AFP, hepatic levels of MDA and GSH, serum CK-MB and LDH enzymes activity were measured. Quantitative, Real-Time PCR was used to measure TRAIL, TRAILR2, caspase-8, caspase-9, caspase-3, BCL-2 and TGF-β1 genes expression levels. Necroinflammation and fibrosis were scored by histopathological examination. CQ improved liver functions, reduced AFP level and attenuated HCC progression. CQ induced apoptosis via upregulation of TRAIL/TRAILR2, caspase-8, caspase-3 and caspase-8 genes and downregulation of BCL-2 gene. Moreover, CQ/DOX showed marked decrease in hepatic MDA level, serum CK-MB, LDH enzymes activity, as well as marked increase in hepatic GSH level. In conclusion, this work assess the in vivo efficacy of CQ/DOX combination therapy in this HCC model that not only has enhanced anti-tumor activity but it also protects against DOX-induced cardiotoxicity. Nevertheless, more studies should be performed to illustrate the molecular mechanism of CQ's cardioprotective effect. Copyright © 2017. Published by Elsevier B.V.

  4. In vitro antitumor activity, metal uptake and reactivity with ascorbic acid and BSA of some gold(III) complexes with N,N'-ethylenediamine bidentate ester ligands.

    Science.gov (United States)

    Pantelić, Nebojša; Zmejkovski, Bojana B; Kolundžija, Branka; Crnogorac, Marija Đorđić; Vujić, Jelena M; Dojčinović, Biljana; Trifunović, Srećko R; Stanojković, Tatjana P; Sabo, Tibor J; Kaluđerović, Goran N

    2017-07-01

    Four novel gold(III) complexes of general formulae [AuCl 2 {(S,S)-R 2 eddl}]PF 6 (R 2 eddl=O,O'-dialkyl-(S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoate, R=n-Pr, n-Bu, n-Pe, i-Bu; 1-4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N'-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC 50 : 5.04-6.51μM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Cleavage mechanism and anti-tumor activity of 3,6-epidioxy-1,10-bisaboladiene isolated from edible wild plants.

    Science.gov (United States)

    Kimura, Ken-ichi; Sakamoto, Yoshimi; Fujisawa, Nozomi; Uesugi, Shota; Aburai, Nobuhiro; Kawada, Manabu; Ohba, Shun-ichi; Yamori, Takao; Tsuchiya, Eiko; Koshino, Hiroyuki

    2012-06-15

    A bisabolane sesquiterpene endoperoxide compound, 3,6-epidioxy-1,10-bisaboladiene (EDBD), was isolated from edible wild plants grown in the northern area of Japan, Cacalia delphiniifolia and Cacalia hastata, using a mutant yeast (cdc2-1 rad9Δ). It showed cytotoxicity at IC(50) = 3.4 μM and induced apoptosis against the human promyelocytic leukemia cell line HL60 through a new stable rearrangement product (1) when in the presence of FeSO(4). This conversion mechanism is different from another sesquiterpene endoperoxide lactone compound, dihydroartemisinin (DHA), which is an anti-malarial drug. The cytotoxicity of EDBD decreased in the presence of the ferrous ion chelating drug deferoxamine mesylate (DFOM), and this suggested that the structural change of the drug caused by Fe(2+) may be responsible for its biological activities. EDBD induced apoptosis via phosphorylation of p38 mitogen-activated protein kinase (MAPK) in HL60 cells, and was detected by Western blot. EDBD resulted in an immediate increase in DCF fluorescence intensity in HL60 cells using DCFH-DA (2',7'-dichlorofluorescin diacetate) assay. The in vitro reaction of EDBD with FeSO(4) also increased DCF fluorescence intensity in a dose dependent manner. These results showed that the biological activity of EDBD involves an unstable carbon-centered radical intermediate. Furthermore, there was no similarity between the JFCR39 fingerprints of EDBD and DHA (correlation coefficient on COMPARE Analysis γ = 0.158). EDBD showed anti-tumor effects against a xenograft of Lox-IMVI cells in vivo. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Intradermal immunization with combined baculovirus and tumor cell lysate induces effective antitumor immunity in mice.

    Science.gov (United States)

    Kawahara, Mamoru; Takaku, Hiroshi

    2013-12-01

    Although tumor lysate contains all the potential helper and killer epitopes capable of stimulating T cells, it is difficult to use as a cancer vaccine because it suppresses dendritic cell (DC) function. We report that wild-type baculovirus possesses an adjuvant effect to improve the immunogenicity of tumor lysate. When mice were administered CT26 tumor cell lysate combined with baculovirus intradermally, antitumor immunity was induced and rejection of CT26 tumor growth was observed in 40% of the immunized mice. In contrast, such antitumor immunity was not elicited in mice inoculated with tumor cell lysate or baculovirus alone. In tumor-bearing mice, which had previously received the combined baculovirus and tumor lysate vaccine, the established tumors were completely eradicated by administering a booster dose of the combined vaccine. This antitumor effect was attributed to tumor-specific T cell immunity mediated primarily by CD8⁺ T cells. Baculovirus also strongly activated DCs loaded with tumor lysate. Increased interleukin (IL)-6 and IL-12p70 production were also observed in DCs co-cultured with tumor cell lysate and baculovirus. Our study demonstrates that combined baculovirus and tumor lysate vaccine can effectively stimulate DCs to induce acquired antitumor immunity.

  7. Arginine-rich histones have strong antiviral activity for influenza A viruses.

    Science.gov (United States)

    Hoeksema, Marloes; Tripathi, Shweta; White, Mitchell; Qi, Li; Taubenberger, Jeffery; van Eijk, Martin; Haagsman, Henk; Hartshorn, Kevan L

    2015-10-01

    While histones are best known for DNA binding and transcription-regulating properties, they also have antimicrobial activity against a broad range of potentially pathogenic organisms. Histones are abundant in neutrophil extracellular traps, where they play an important role in NET-mediated antimicrobial killing. Here, we show anti-influenza activity of histones against both seasonal H3N2 and H1N1, but not pandemic H1N1. The arginine rich histones, H3 and H4, had greater neutralizing and viral aggregating activity than the lysine rich histones, H2A and H2B. Of all core histones, histone H4 is most potent in neutralizing IAV, and incubation with IAV with histone H4 results in a decrease in uptake and viral replication by epithelial cells when measured by qRT-PCR. The antiviral activity of histone H4 is mediated principally by direct effects on viral particles. Histone H4 binds to IAV as assessed by ELISA and co-sedimentation of H4 with IAV. H4 also induces aggregation, as assessed by confocal microscopy and light transmission assays. Despite strong antiviral activity against the seasonal IAV strains, H4 was inactive against pandemic H1N1. These findings indicate a possible role for histones in the innate immune response against IAV. © The Author(s) 2015.

  8. Platypus and opossum calcitonins exhibit strong activities, even though they belong to mammals.

    Science.gov (United States)

    Yamashita, Teruhito; Udagawa, Nobuyuki; Thirukonda, Gnanasagar Janardhanan; Uehara, Shunsuke; Yamauchi, Hirose; Suzuki, Nobuo; Li, Feng; Kobayashi, Yasuhiro; Takahashi, Naoyuki

    2017-05-15

    In mammalian assay systems, calcitonin peptides of non-mammalian species exhibit stronger activity than those of mammals. Recently, comparative analyses of a wide-range of species revealed that platypus and opossum, which diverged early from other mammals, possess calcitonins that are more similar in amino acid sequence to those of non-mammals than mammals. We herein determined whether platypus and opossum calcitonins exhibit similar biological activities to those of non-mammalian calcitonins using an assay of actin ring formation in mouse osteoclasts. We also compared the dose-dependent effects of each calcitonin on cAMP production in osteoclasts. Consistent with the strong similarities in their primary amino acid sequences, platypus and opossum calcitonins disrupted actin rings with similar efficacies to that of salmon calcitonin. Human calcitonin exhibited the weakest inhibitory potency and required a 100-fold higher concentration (EC 50 =3×10 -11 M) than that of salmon calcitonin (EC 50 =2×10 -13 M). Platypus and opossum calcitonins also induced cAMP production in osteoclast cultures with the same efficacies as that of salmon calcitonin. Thus, platypus and opossum calcitonins exhibited strong biological activities, similar to those of the salmon. In addition, phylogenetic analysis revealed that platypus and opossum calcitonins clustered with the salmon-type group but not human- or porcine-type group. These results suggest that platypus and opossum calcitonins are classified into the salmon-type group, in terms of the biological activities and amino acid sequences. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule.

    Directory of Open Access Journals (Sweden)

    Kazuyuki Sugahara

    Full Text Available The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl-3H-imidazole-4-carbaldehyde was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS, which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7 which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor.

  10. Andrographolide causes apoptosis via inactivation of STAT3 and Akt and potentiates antitumor activity of gemcitabine in pancreatic cancer.

    Science.gov (United States)

    Bao, Guo-Qing; Shen, Bai-Yong; Pan, Chun-Peng; Zhang, Ya-Jing; Shi, Min-Min; Peng, Cheng-Hong

    2013-09-12

    Gemcitabine is a first-line drug utilised in the chemotherapy of pancreatic cancer; however, this drug induces chemo-resistance and toxicity to normal tissue during treatment. Here, we firstly report that andrographolide (ANDRO) alone not only has anti-pancreatic cancer activity, but it also potentiates the anti-tumour activity of gemcitabine. Treatment with ANDRO alone inhibits proliferation of the pancreatic cancer cell lines in a dose- and time-dependent manner in vitro. Interestingly, ANDRO induces cell cycle arrest and apoptosis of pancreatic cancer cells by inhibiting STAT3 and Akt activation, upregulating the expression of p21(WAF1) and Bax, and downregulating the expression of cyclinD1, cyclinE, survivin, X-IAP and Bcl-2. Additionally, ANDRO combined with gemcitabine significantly induce stronger cell cycle arrest and more obvious apoptosis than each single treatment. The mechanistic study demonstrates that this synergistic effect is also dependent on the inhibition of STAT3 and Akt activations which subsequently regulates the pathways involved in the apoptosis and cell cycle arrest. Furthermore, both ANDRO alone and the combination treatments exhibit efficacious anti-tumour activity in vivo. Overall, our results provide solid evidence supporting that ANDRO alone or its combination with gemcitabine is a potential chemotherapeutic approach for treating human pancreatic cancer in clinical practice. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.